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Adverse Reactions to Fluoroquinolones. An Overview on Mechanistic Aspects
Abstract
This review focuses on the most recent research findings on adverse reactions caused by quinolone antibiotics. Reactions of the gastrointestinal tract, the central nervous system (CNS) and the skin are the most often observed adverse effects. Occasionally major events such as phototoxicity, cardiotoxicity, arthropathy and tendinitis occur, leading to significant tolerability problems. Over the years, several structure-activity and side-effect relationships have been developed, in an effort to improve overall antimicrobial efficacy while reducing undesirable side-effects. In this article we review the toxicity of fluoroquinolones, including the newer derivatives such levofloxacin, sparfloxacin, graepafloxacin and the 7-azabicyclo derivatives, trovafloxacin and moxifloxacin. A special attention is given to new data on mechanistic aspects, particularly those regarding CNS effects. In recent years extensive in vivo and in vitro experiments have been performed in an attempt to explain the neurotoxic effects of quinolones sometimes observed under therapeutic conditions. However, the molecular target or receptor for such effects is still not exactly known. Several mechanisms are thought to be responsible. The involvement of gamma-aminobutyric acid (GABA) and excitatory amino acid (EAA) neurotransmission and the kinetics of quinolones distribution in brain tissue are discussed. In addition, quinolones may interact with other drugs--theophylline and nonsteroidal antiflammatory drugs (NSAID(s))--in producing CNS effects This article provides information about the different mechanisms responsible of quinolones interaction with NSAID(s), methylxanthines, warfarin and antiacids.
... Fluoroquinolones are known to have a number of side effects which are unique to this class [4][5][6][7]. These side effects range from mild to severe, life threatening side effects class [4][5][6][7]. ...
... Fluoroquinolones are known to have a number of side effects which are unique to this class [4][5][6][7]. These side effects range from mild to severe, life threatening side effects class [4][5][6][7]. These side effects can be classified according to organ system into cardiovascular, CNS, gastrointestinal, dermatologic, hepatic, renal, musculoskeletal and others [4,6,7]. ...
... These side effects range from mild to severe, life threatening side effects class [4][5][6][7]. These side effects can be classified according to organ system into cardiovascular, CNS, gastrointestinal, dermatologic, hepatic, renal, musculoskeletal and others [4,6,7]. Examples of some of the common side effects include QTc prolongation, nausea/vomiting/ diarrhoea, phototoxicity, renal failure, elevation in hepatic enzymes, hepatitis, seizures and tremors [4,6,7]. ...
... FQ-associated musculoskeletal disability has been previously described [11]. Historically, after gastrointestinal symptoms, nervous system disturbances are among the most reported adverse drug reactions (ADRs) from FQs [2,4,5,[12][13][14]. A systematic review found that the occurrence of central nervous system (CNS)-related ADRs (along gastrointestinal [GI]) was significantly higher with FQs compared to other antimicrobials [15]. ...
... A systematic review found that the occurrence of central nervous system (CNS)-related ADRs (along gastrointestinal [GI]) was significantly higher with FQs compared to other antimicrobials [15]. Such reactions vary in severity and include headache, dizziness, agitation, sleep disorders, psychoses, and, rarely, convulsions [13]. ...
... found that the occurrence of central nervous system (CNS)-related ADRs (along gastrointestinal [GI]) was significantly higher with FQs compared to other antimicrobials [15]. Such reactions vary in severity and include headache, dizziness, agitation, sleep disorders, psychoses, and, rarely, convulsions [13]. ...
Background:
Recent drug safety concerns described fluoroquinolone (FQ)-induced peripheral nervous system reactions. The objective of this study was to characterize such reports from VigiBase.
Methods:
The analysis included FQ-induced peripheral nervous system disorder adverse drug reaction (ADR) reports (up to July 2019). We looked into the disproportionality data in terms of proportional reporting ratio (PRR) and information component (IC) values, and descriptive analysis was performed for FQ-ADRs positive associations (ADRs, suspected FQs, potential risk factors, such as associated therapy and underlying disease).
Results:
Disproportionality analysis revealed 4374 reports (3531 serious) with peripheral nervous system ADRs associated with at least three FQs (neuropathy peripheral, 5492; neuralgia, 481; polyneuropathy, 220; sensory loss, 99; peripheral sensorimotor neuropathy, 39). Among these, both time-to-onset and duration of reaction were mostly between 1-7 days and ≥30 days. Most of the ADRs were not recovered/resolved at the time of reporting.
Conclusion:
The results augment the existing data on FQ safety concerns, specifically their potential effect on the nervous system.
... The VN plays the leading role in the parasympathetic nervous system (PNS) as it connects and transmits signals from the brain to many organs and the digestive system. It is known as the miracle neurotoxicity mechanism of FQs is not fully clarified, but it was found that it is closely associated with their structures (104)(105)(106)(107)(108)(109)(110)(111). ...
... BPAA > indomethacin = ketoprofen > naproxen > ibuprofen > pranoprofen was the inhibitory potency for quinolones and NSAIDs in combination with enoxacin. Enoxacin, acetaminophen, piroxicam, and diclofenac did not affect GABA responses (110). In another study on mice, quinolones were convulsed with/without antiinflammatory and analgesic/antipyretic drugs. ...
Fluoroquinolones (FQs) are highly potent bactericidal antibiotics with broad-spectrum activity against Gram-negative/positive bacteria. The Food and Drug Administration (FDA) anticipated the presence of a long-lasting incapacity of Fluoroquinolone Associated Toxicity (FQAT), which is not officially documented yet. This review aimed to précis the existing information on FQA long-term toxicity, such as cardiotoxicity, aortic aneurysm, tendon rupture, nephrotoxicity, hepatotoxicity, peripheral neuropathy, vagus nervous dysfunction, reactive oxygen species (ROS), phototoxicity, glucose hemostasis, and central nervous system (CNS) toxicity. We are focused on the CNS toxicity of FQs, either due to the direct action of the FQs on CNS receptors or by other drug co-administration, including nonsteroidal anti-inflammatory disease (NSAIDs) and theophylline. Due to the nature of the R7 side chain, FQs containing unsubstituted 7-piperazine and 7-pyrrolidine have the most significant effect. The gamma-aminobutyric acid-A (GABAA) receptor and CNS effects are inhibited through at least three possible mechanisms. Firstly, by the pharmacological action of the quinolone directly. Secondly, FQ-NSAIDs interact pharmacodynamically in which the interaction between the FQ and a receptor is significantly altered by the presence of another drug that interacts with the same receptor. An example may be the interaction between NSAIDs and some FQs. Thirdly, a pharmacokinetic drug-drug interaction leads to a higher concentration of quinolone or the other drug. An example may be the interaction between theophylline and benzodiazepines with some FQs.
... Magnesium competitively blocks the entry of calcium into the presynaptic nerve terminal -a process that is crucial for the release of ACh into the synaptic cleft. The Pittinger and Adamson, 1972;Singh et al., 1978a,b;Caputy et al., 1981;Kaeser, 1984 Fluoroquinolone antibiotics Moore et al., 1988;Mumford and Ginsberg, 1990;Azevedo et al., 1993;Roquer et al., 1996;De Sarro and De Sarro, 2001;Gunduz et al., 2006 Macrolide/ ketolide antibiotics (telithromycin) ...
... There is a long list of anecdotal reports indicating (sometimes severe) symptom deterioration following the administration of fluoroquinolones, i.e., gyrase inhibitors, which led to a "black box" warning by the FDA, for their use in patients with MG (De Sarro and De Sarro, 2001). Notably, the fluoroquinolones, particularly levofloxacin, ofloxacin and ciprofloxacin, may cause acute and severe exacerbations of myasthenic symptoms (Moore et al., 1988;Mumford and Ginsberg, 1990;Azevedo et al., 1993;Roquer et al., 1996;Gunduz et al., 2006). ...
Myasthenic syndromes are typically characterized by muscle weakness and increased fatigability due to an impaired transmission at the neuromuscular junction (NMJ). Most cases are caused by acquired autoimmune conditions such as myasthenia gravis (MG), typically with antibodies against the acetylcholine receptor (AChR). Different drugs are among the major factors that may complicate pre-existing autoimmune myasthenic conditions by further impairing transmission at the NMJ. Some clinical observations are substantiated by experimental data, indicating that presynaptic, postsynaptic or more complex pathomechanisms at the NMJ may be involved, depending on the individual compound. Most robust data exist for the risks associated with some antibiotics (e.g., aminoglycosides, ketolides, fluoroquinolones) and cardiovascular medications (e.g., class Ia antiarrhythmics, beta blockers). Apart from primarily autoimmune-mediated disorders of the NMJ, de novo myasthenic manifestations may also be triggered by medical treatments that induce an autoimmune reaction. Most notably, there is growing evidence that the immune checkpoint inhibitors (ICI), a modern class of drugs to treat various malignancies, represent a relevant risk factor to develop severe and progressive medication-induced myasthenia via an immune-mediated mechanism. From a clinical perspective, it is of utmost importance for the treating physicians to be aware of such adverse treatment effects and their consequences. In this article, we aim to summarize existing evidence regarding the key molecular and immunological mechanisms as well as the clinical implications of medication-aggravated and medication-induced myasthenic syndromes.
... The second-generation compounds are characterized by good to excellent Gram-negative activity, with ciprofloxacin exhibiting the strongest Gram-negative spectrum. The third-and fourthgeneration quinolones are characterized by increased structural novelty and complexity, which has resulted in new and useful characteristics [2,3] . In-silico literally Latin for "in silicon", alluding to the mass use of silicon for semiconductor computer chips is an expression used to mean performed on computer or via computer simulation. ...
The In-silico studies considered as complementary to in vivo and in vitro biological studies are performed by using a computer and are playing increase larger and more important role in drug discovery and development. We describe here in In-silico study of various hypothetical Quinolines and their interactions with CYP450 enzymes by computational methods including chem draw ultra, Avogadro and ochem database software methods. We worked on a chemical reaction scheme of Quinolines and we prepared different 20 Quinolines derivatives. The CYP450 super family of heme enzymes plays an important role in the metabolism of a large number of endogenous and exogenous compounds including most of the drugs currently on the market. Comprehensive studies of the quantum approaches on the quinolines derivatives like QD1, QD8 and QD13 was found to be CYP450 enzymes inhibitors interactions. The quantum approaches by lead optimization will require further studies; the data reported in this work may be helpful guide for medicinal chemist who is working in this area.
... The third-and fourthgeneration quinolones are characterized by increased structural novelty and complexity, which has resulted in new and useful characteristics. [2,3] Insilico literally Latin for "in silicon", alluding to the mass use of silicon for semiconductor computer chips is an expression used to mean performed on computer or via computer simulation. The phrase was coined in 1989 as an allusion to the Latin phrases in vivo, in vitro, and in situ, which are commonly used in biology and refer to experiments done in living organisms, outside of living organisms, and where they are found in nature, respectively. ...
The In-silico studies considered as complementary to in vivo and in vitro biological studies are performed by using
a computer and are playing increase larger and more important role in drug discovery and development. We
describe here in In-silico study of various hypothetical Quinolines and their interactions with CYP450 enzymes by
computational methods including chem draw ultra, Avogadro and ochem database software methods. We worked
on a chemical reaction scheme of Quinolines and we prepared different 20 Quinolines derivatives. The CYP450
super family of heme enzymes plays an important role in the metabolism of a large number of endogenous and
exogenous compounds including most of the drugs currently on the market. Comprehensive studies of the quantum
approaches on the quinolines derivative QD17, was found to be CYP450 enzymes inhibitors interactions. The
quantum approaches by lead optimization will require further studies; the data reported in this work may be helpful
guide for medicinal chemist who is working in this area.
... In the high dose group, additionally red discolouration of face and ear, defecation and licking of urination was observed. There were no WCK 771 related change in body weight gain (Figure 3), food consumption, ECG, ophthalmic examination, haematology (Table 7), clinical chemistry (Table 8), relative organ weights ( (0) 0.20 ± 0.00 (0) 0.20 ± 0.00 (0) 0.21 ± 0.00 (0) 0.20 ± 0.00 (0) 0.21 ± 0.00 (0) WCK 771 (sc) 200 0.20 ± 0.00 (0) 0.20 ± 0.00 (0) 0.21 ± 0.01 (0) 0.20 ± 0.00 (0) 0.20 ± 0.00 (0) 0.20 ± 0.00 (0) 300 0.20 ± 0.00 (0) 0.20 ± 0.00 (0) 0.20 ± 0.00 (0) 0.20 ± 0.00 (0) 0.20 ± 0.00 (0) 0.20 ± 0.00 (0) (de Sarro & de Sarro, 2001). Hence, proconvulsive potential of WCK 771 (IV) was evaluated in mice by administrating it with a subconvulsive dose of PTZ, a GABA A receptor antagonist. ...
Fluoroquinolone (FQ) antibacterials have drawn heightened attention from various international regulatory agencies due to their class specific side effects. Levonadifloxacin is a novel broad spectrum benzoquinolizine FQ active against methicillin-resistant Staphyloccocus aureus (MRSA). Owing to FQ associated safety concerns, extensive preclinical safety pharmacology (central nervous system and cardiac safety) and toxicology studies (subacute repeat dose toxicity, genotoxicity, phototoxicity and chondrotoxicity) of levonadifloxacin were performed at relatively high doses. Intravenous (IV) and oral studies were conducted using WCK 771 (L-arginine salt of levonadifloxacin) and WCK 2349 (L-alanine ester prodrug of levonadifloxacin), respectively. Safety pharmacology studies following single dose revealed no adverse effects on central nervous system (including seizure) in mice and cardiovascular system (hERG and monkey telemetry). In repeat-dose toxicity studies, except for IV bolus dosing related effects in rat (hyperactivity, mild convulsion, polypnoea, injection site irritation) and dog (emesis and salivation); no other adverse findings limiting the dosing duration were observed. No major biochemical, haematological, gross or histopathological changes suggestive of damage to vital organs were observed in either WCK 771 or WCK 2349 treated groups. WCK 771/WCK 2349 were found to be non-genotoxic, however they showed weak phototoxicity that was comparable to levofloxacin. WCK 771 showed chondrotoxicity in the Beagle dog pups on repeat dose administration; however the severity level was lower than ofloxacin. Overall, preclinical safety studies helped establish wider safety margin for WCK 771 and WCK 2349 that supports administration of higher therapeutic doses in humans by both IV and oral routes, thereby enabling safe anti-MRSA treatment.
... 3 Most of the quinolone antibacterial research has been focused on substitution at the C-7 as it is the most adaptable site for chemical change.C-7 position is an area that determines potency and target preference and also controls the pharmacokinetic properties of the drugs, with basic nitrogen. [4][5][6] The most commonly found substitution at the C-7 position is a five-or six-membered ring. For example, aminopyrrolidine substituent at C-7 in trova-floxacinandgemifloxacinandPiperazine substitution at the C-7 position in norfloxacin, ciprofloxacin, pefloxacin, pefloxacin, ofloxacin, amifloxacin, fleroxacin, lomefloxacin, sparfloxacin, difloxacin, enoxacin, enrofloxacin, levofloxacin, marbofloxacin, and orbifloxacin which has triggered a wide range of clinically useful fluoroquinolone antibacterial agents. ...
... Log P values and biological activity score have been finally tested online by Molinspiration. 6,7 C-5 Substituted morpholine derivative of Norfloxacin 3 METHODOLOGY Norfloxacin 2 (IUPAC: 1-ethyl-6-flouro-1,4-dihydro-4-oxo-7-(1-N-piperazinyl-3-quinolone carboxylic acid) is a fluoroquinolone antibiotic used to treat and prevent diseases caused by bacteria that can cause illness. However, FDA issued a Drug Safety Communication about the risk of aortic aneurysm and dissection with fluoroquinolones. ...
... CNS effects that are caused by FQs range from mild reactions such as irritability, insomnia and dizziness [10,73], to more concerning and long-lasting side effects including anxiety, depression, hallucinations [73], convulsions [42], seizures [9] and peripheral neuropathy [10,42,[74][75][76]. Evidence showed that the peripheral neuropathies that are associated with FQs can even lead to patients developing Guillain-Barré syndrome [17]. ...
Fluoroquinolones (FQs) are a broad class of antibiotics typically prescribed for bacterial
infections, including infections for which their use is discouraged. The FDA has proposed the
existence of a permanent disability (Fluoroquinolone Associated Disability; FQAD), which is yet to
be formally recognized. Previous studies suggest that FQs act as selective GABAA receptor inhibitors,
preventing the binding of GABA in the central nervous system. GABA is a key regulator of the vagus
nerve, involved in the control of gastrointestinal (GI) function. Indeed, GABA is released from the
Nucleus of the Tractus Solitarius (NTS) to the Dorsal Motor Nucleus of the vagus (DMV) to tonically
regulate vagal activity. The purpose of this review is to summarize the current knowledge on FQs in
the context of the vagus nerve and examine how these drugs could lead to dysregulated signaling to
the GI tract. Since there is sufficient evidence to suggest that GABA transmission is hindered by FQs,
it is reasonable to postulate that the vagal circuit could be compromised at the NTS-DMV synapse
after FQ use, possibly leading to the development of permanent GI disorders in FQAD.
... Pemilihan antibiotik ciprofloxacin sebagai kontrol positif karena ciprofloxacin merupakan antibiotik berspektrum luas. Antibiotik dengan spektrum luas, yaitu antibiotik yang memiliki aktivitas terhadap banyak jenis bakteri, virus, jamur dan protozoa (Sarro, 2001). Penelitian ini memperoleh zona hambat di sekitar sumuran yang diberi ciprofloxacin. ...
White galangal rhizome (Alpinia galanga (L.) Willd's) scientifically proven has properties as antibacterial, antifungal, anticancer, antitumor, antioxidant and cytotoxic. In nano size, the contact surface area of the particle becomes larger which can increase the amount of active substance which is isolated more so that the antibacterial activity is stronger. This study aims to determine whether the white galangal extract nanoparticles have antibacterial activity against the bacteria Klebsiella pneumoniae and measure the inhibitory ability of white galangal extract nanoparticles against bacterial growth and compared with white galangal ethanol extract. White galangal was extracted using maceration method with ethanol solvent and nanoparticle formulation made of white galangal extract by ionic gelation method. The antibacterial activity test was carried out using agar diffusion method and observations were made 1x24 hours incubation period, with inhibition zones measured using a millimeter ruler. The results showed that the white galangal extract nanoparticles had antibacterial activity to inhibit the bacteria Klebsiella pneumoniae, with the results of inhibition zone measurements of 22.5 mm. Keywords : Antibacterial, Extraction, Klebsiella pneumoniae, Nanoparticles, White galangal. ABSTRAKRimpang lengkuas putih (Alpinia galanga (L.) Willd) memiliki khasiat yang sudah dibuktikan secara ilmiah sebagai antibakteri, antijamur, antikanker, antitumor, antioksidan dan sitotoksik. Dalam ukuran nano, luas kontak permukaan partikel menjadi lebih besar yang dapat meningkatkan jumlah zat aktif yang terisolasi lebih banyak sehingga aktivitas antibakteri semakin kuat. Penelitian ini bertujuan untuk mengetahui apakah nanopartikel ekstrak lengkuas putih memiliki aktivitas antibakteri terhadap bakteri Klebsiella pneumoniae serta mengukur kemampuan daya hambat nanopartikel ekstrak lengkuas putih terhadap pertumbuhan bakteri dan dibandingkan dengan ekstrak etanol lengkuas putih. Lengkuas putih diekstraksi menggunakan metode maserasi dengan pelarut etanol dan dibuat formulasi nanopartikel ekstrak lengkuas putih dengan metode gelasi ionik. Untuk pengujian aktivitas antibakteri dilakukan dengan metode difusi agar dan pengamatan dilakukan 1x24 jam masa inkubasi, dengan zona hambat diukur menggunakan penggaris millimeter. Hasil penelitian menunjukkan bahwa nanopartikel ekstrak lengkuas putih memiliki aktivitas antibakteri untuk menghambat bakteri Klebsiella pneumoniae, dengan hasil pengukuran zona hambat sebesar 22,5 mm. Kata Kunci : Lengkuas putih, Nanopartikel, Antibakteri, Ekstraksi, Klebsiella pneumoniae.
... Ciprofloxacin dipilih sebagai kontrol positif untuk melihat apakah bakteri Klebsiella pneumoniae yang diujikan benar resisten terhadap antibiotik ciprofloxacin. Menurut Sarro (2001) antibiotik Ciprofloxacin merupakan antibiotik dengan spektrum luas, yaitu antibiotik yang memiliki aktivitas banyak jenis bakteri, virus, jamur dan protozoa. Pada penelitian ini, didapatkan hasil adanya zona hambat yang terbentuk di sekitar sumur yang diberi antibiotik ciprofloxacin. ...
Nanoparticles can increase the solubility of compounds, reduce the treatment dose and increase absorption. Flavonoid and phenol compounds in red galangal can inhibit the growth of bacteria that have been resistant to antibiotics. The bioactivity of red galangal compounds is expected to increase when the size of nanoparticles increases antibacterial activity. This study aims to determine the inhibition of the content of Red Galangal nanoparticles (Alpinia purpurata K.Schum) using chitosan on the growth of Klebsiella pneumoniae bacterial urine isolates of UTI antibiotic-resistant Ciprofloxacin. Nanoparticles extracts of red galangal rhizome was made using ionic gelation method, using extract concentration of 0.4%, tested for antibacterial activity using the wells method with a comparison of chitosan 0.4%, acetic acid 5%, red galangal extract 25%. Red galangal rhizome nanoparticles gave antibacterial activity value to the bacteria Klebsiella pneumoniae of 13.5 mm. Therefore, red galangal extracts nanoparticles can inhibit the growth of Klebsiella pneumoniae urine isolate in patients with urinary tract infections with strong inhibitory categories based on Davis and Stout categories.Keywords: Alpinia purpurata K. Schum, Klebsiella pneumonia, Nanoparticles. ABSTRAK Nanopartikel dapat meningkatkan kelarutan senyawa, mengurangi dosis pengobatan dan meningkatkan absorbsi. Senyawa flavonoid dan fenol dalam lengkuas merah mampu menghambat pertumbuhan bakteri yang telah resisten terhadap antibiotik. Sifat bioaktivitas senyawa lengkuas merah diharapkan akan meningkat ketika berukuran nanopartikel untuk meningkatkan aktivitas antibakteri. Penelitian ini bertujuan untuk mengetahui daya hambat kandungan nanopartikel rimpang Lengkuas Merah (Alpinia purpurata K.Schum) menggunakan kitosan terhadap pertumbuhan bakteri Klebsiella pneumoniae isolat urin penderita ISK yang resisten antibiotik Ciprofloxacin. Nanopartikel ekstrak rimpang lengkuas merah dibuat dengan menggunakan metode gelasi ionik, dengan menggunakan konsentrasi esktrak sebesar 0,4 %, dilakukan pengujian aktivitas antibakteri mengunakan metode sumuran dengan pembanding kitosan 0,4%, asam asetat 5%, ekstrak lengkuas merah 25%. Nanopartikel rimpang lengkuas merah memberikan nilai aktifitas antibakteri terhadap bakteri Klebsiella pneumoniae sebesar 13,5 mm. Oleh karena itu nanopartikel ekstrak rimpang lengkuas merah dapat menghambat pertumbuhan bakteri Klebsiella pneumoniae isolate urin penderita infeksi saluran kemih dengan kategori daya hambat kuat berdasrkan kategori Davis dan Stout.Kata Kunci: Alpinia purpurata K. Schum, Nanopartikel, Klebsiella pneumoniae
... Ofloxacin (±-9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylicacid) (Supplementary Materials, Figure S1) is a fluoroquinolone antibiotic with superior antimicrobial properties and acts through the inhibition of bacterial gyrase, an enzyme involved in DNA replication, recombination, and repair. However, they have been associated with disabling and irreversible serious adverse reactions (tendinitis and tendon rupture, peripheral neuropathy, central nervous system effects, etc.) that have occurred [31,32]. Figure S2) is a broad-spectrum beta-lactam penicillin antibiotic with bactericidal activity. ...
Graphitic carbon nitride (CN) was prepared by the heating of melamine (CN-M) and melamine-cyanurate complex (CN-MCA), respectively, in air at 550 ◦C for 4 h. The specific surface area of CN-M and CN-MCA was 12 m2 g−1 and 225 m2g−1 and the content of oxygen was 0.62 wt.% and 1.88 wt.%, respectively. The band gap energy (Eg) of CN-M was 2.64 eV and Eg of CN-MCA was 2.73 eV. The photocatalytic activity of the CN materials was tested by means of the decomposition of antibiotics ofloxacin and ampicillin under LED irradiation of 420 nm. The activity of CN-MCA was higher due to its high SSA, which was determined based on the physisorption of nitrogen. Ofloxacin was decomposed more efficiently than ampicillin in the presence of both photocatalysts.
... Nearly all quinolone antibiotics in use are FQs, which contain a fluorine atom in their chemical structure and are effective against both gram-negative and gram-positive bacteria [36,37]. Qs and FQs can cause allergic reactions, affect cartilage development, cause liver damage, and have other adverse effects, especially in juvenile animals, and in children, these drugs can cause arthropathy [38]. ...
Veterinary drugs are used to treat livestock and aquatic diseases and thus are introduced into animal-derived foods, endangering consumer health and safety. Antibiotic resistance is rapidly becoming a major worldwide problem, and there has been a steady increase in the number of pathogens that show multi-drug resistance. Illegal and excessive use of veterinary drugs in animals and aquaculture has serious adverse effects on humans and on all other environmental organisms. It is necessary to develop simple extraction methods and fast analytical methods to effectively detect veterinary drug residues in animal-derived foods. This review summarizes the application of various sample extraction techniques and detection and quantification methods for veterinary drug residues reported in the last decade (2010-2020). This review compares the advantages and disadvantages of various extraction techniques and detection methods and describes advanced methods, such as those that use electrochemical biosensors, piezoelectric biosensors, optical biosensors, and molecularly imprinted polymer biosensors. Finally, the future prospects and trends related to extraction methods, detection methods and advanced methods for the analysis of veterinary drug residues in animal-derived foods are summarized.
... The experimental plan ( Figure S1) consisted of exposing PHHs co-cultured with PHKCs in the liver MPS 9 to trovafloxacin, which induces idiosyncratic hepatotoxicity in humans, 24 or to levofloxacin, 25 which does not cause hepatotoxicity. 26 Lactate dehydrogenase (LDH) production (Figures 1A-1C) and cytochrome P450 3A4 (CYP3A4) activity (Figures 1D-1F) were quantified following exposure of the MPSs to compounds at concentrations of 25 µM and 100 µM, and in the presence or absence of LPS. Increased levels of LDH to above 4-fold of baseline were observed for all treatments with 100 µM trovafloxacin with LPS, and no significant differences relative to control were detected in LDH production when LPS was not co-dosed with trovafloxacin. ...
Liver microphysiological systems (MPSs) are promising models for predicting hepatic drug effects. Yet, after a decade since their introduction, MPSs are not routinely used in drug development due to lack of criteria for ensuring reproducibility of results. We characterized the feasibility of a liver MPS to yield reproducible outcomes of experiments assaying drug toxicity, metabolism, and intracellular accumulation. The ability of the liver MPS to reproduce hepatotoxic effects was assessed using trovafloxacin, which increased lactate dehydrogenase (LDH) release and reduced cytochrome P450 3A4 (CYP3A4) activity. These observations were made in two test sites and with different batches of Kupffer cells. Upon culturing equivalent hepatocytes in the MPS, spheroids, and sandwich cultures, differences between culture formats were detected in CYP3A4 activity and albumin production. Cells in all culture formats exhibited different sensitivities to hepatotoxicant exposure. Hepatocytes in the MPS were more functionally stable than those of other culture platforms, as CYP3A4 activity and albumin secretion remained prominent for greater than 18 days in culture, whereas functional decline occurred earlier in spheroids (12 days) and sandwich cultures (7 days). The MPS was also demonstrated to be suitable for metabolism studies, where CYP3A4 activity, troglitazone metabolites, diclofenac clearance, and intracellular accumulation of chloroquine were quantified. To ensure reproducibility between studies with the MPS, the combined use of LDH and CYP3A4 assays were implemented as quality control metrics. Overall results indicated that the liver MPS can be used reproducibly in general drug evaluation applications. Study outcomes led to general considerations and recommendations for using liver MPSs.
Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Microphysiological systems (MPSs) have been designed to recreate organ‐ or tissue‐specific characteristics of extracellular microenvironments that enhance the physiological relevance of cells in culture. Liver MPSs enable long‐lasting and stable culture of hepatic cells by culturing them in three‐dimensions and exposing them to fluid flow. WHAT QUESTION DID THIS STUDY ADDRESS?
What is the functional performance relative to other cell culture platforms and the reproducibility of a liver MPS for assessing drug development and evaluation questions, such as toxicity, metabolism, and pharmacokinetics? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The liver MPS systematically detected the toxicity of trovafloxacin. When compared with spheroids and sandwich cultures, this system had a more stable function and different sensitivity to troglitazone, tamoxifen, and digoxin. Quantifying phase II metabolism of troglitazone and intracellular accumulation of chloroquine demonstrated the potential use of the liver MPS for studying drug metabolism and pharmacokinetics. Quality control criteria for assessing chip function were key for reliably using the liver MPS. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
Due to its functional robustness and physiological relevance (3D culture, cells expose to fluid flow and co‐culture of different cell types), the liver MPS can, in a reproducible manner: (i) detect inflammatory‐induced drug toxicity, as demonstrated with trovafloxacin, (ii) detect the toxicity of other drugs, such as troglitazone, tamoxifen, and digoxin, with different effects than those detected in spheroids and sandwich cultures, (iii) enable studies of hepatic function that rely on prolonged cellular activity, and (iv) detect phase II metabolites and drug accumulation to potentially support the interpretation of clinical data. The integration of MPSs in drug development will be facilitated by careful evaluation of performance and reproducibility as performed in this study.
... 4 Molecular weight (≤500 Da). 5 Number of H-bond acceptors (<10). 6 Number of H-bond donors (<5). 7 Number of violations (≤1). ...
Norfloxacin (I) and its 1, 3, 4-oxadiazole, thiazolidin-4-one, 1,3,4-oxadiazoline, 1, 2, 4-triazole, Schiff's base, hydrazide and 1, 3, 4-thiadiazole analogues (II-VIII), were screened for drug-likeness using molinspiration chemoinformatics software, and found that only the analogues (I-IV) and (VI), were possessed the bioactivity score in the zone of an active drug molecule. Then the analogues (II-VIII) lead to the synthesis and characterization by spectroscopic methods such as FT-IR, NMR (1 H and 13 C), and Mass spectroscopy, etc. Moreover, the antimicrobial assessment was performed using the methods of disc diffusion and serial dilutions and the findings revealed that the analogue (VI-VIII) have been found to express better antibacterial effects than the reference drug norfloxacin (I). The MTT assay was also carried out to assess the toxic effects of norfloxacin and its analogues (I-VIII), against HepG2 cells and found to be less toxic, with percent viability of the cells in the range of 71-75 % @ 100 µM. Molecular docking studies were performed using AutoDock Tools-1.5.6, against the receptor GlcN-6P (2VF5), to estimate the extent of hydrogen bonding and binding affinities. Hydrogen bonding was not observed in accordance with the experimental findings, while good binding affinities were observed in the range of-5.6 to 7.7, kcal/mole.
... In addition to the hypothesis of chloroquine effect on muscarinic and dopaminergic pathways, it was found to be antagonist to both 5-HT3A and 5-HT3B receptors [18]. Since chloroquine belongs to quinolone group, it may also, as well as fluoroqouinolones, act as an angonist to N-methyl-d-aspartate (NMDA) and as an antagonist to gamma-aminobutyric acid (GABA ) receptors [19]. Dopamine, serotonin, acetylcholine glutamate and gamma-aminobutyric acid are all known as neurotransmitters that play a key role in cognition, perception and mood pathways. ...
Chloroquine and hydroxy chloroquine are widely use in Africa and all over the world as anti-malarial drugs but also in the treatment of chronic inflammatory diseases. Since the outbreak of COVID-19 pandemic, Morocco have included this medication in the COVID-19 treatment guidelines in association with azithromycine. Besides dermatologic problems, ocular impairments and gastro-intestinal effects, quinolines may also cause rarely described psychiatric adverse effects. To our knowledge, there has been no reports of psychiatric side effects of chloroquine or hydroxy chloroquine in the actual context of COVID-19 pandemic. Here, we present the description of two COVID-19 patients who showed psychiatric side effects after chloroquine treatment. One patient expressed psychotic symptoms and the other one experienced acute and intense anxiety. In both cases, and according to Naranjo score, the association between chloroquine and psychiatric side effects was probable.
... 46 However, CPX neurologic adverse effects at therapeutic doses have been previously reported being associated with different mechanisms including neurotransmitters and inflammatory mediators. 47,48 Also, oxidative stress inducing capacity is another factor causing its neurotic side effects. 49 Although the different biological effects of GO were reported in many literature studies, none has underlined the mechanism of its neuroprotective effect. ...
The chemical constituents of Allium sativum (Garlic) oil were investigated using GC/Ms technique after silylation, and revealed the presence of several fatty acids and their esters. The most dominant was 9, 12-octadecadienoic acid (linoleic acid), a precursor of arachidonic acid, which is essential for brain development. Garlic oil-loaded chitosan nanoparticles (GCN) were prepared to enhance its cerebral effects, and to mask its odor and taste. Two-level orthogonal factorial design, followed by regression analysis, was used to study the influence of different formulation variables. GCN3, the formula with the smallest particle size and the highest mucoadhesion, was selected as the optimized one. TEM showed that GCN3 has a short nanorod-shape outline. We aimed to investigate the influence of orally administered GCN3 compared to the plain Garlic oil (GO), on ciprofloxacin-induced (CPX) neurotoxicity in rats and the probable underlying mechanisms. The results show the significantly higher neurological curative effect of GCN3 compared to GO, and its greater antidepression-like and antianxiety-like potential via the alteration of brain neurotransmitter levels and inhibition of oxidative stress and inflammatory pathways. The histopathological examination showed the higher capability of GCN3 to repair the damages induced by CPX in the cerebral cortex, hippocampus area and substantia nigra brain sections. Similar results were proved immunohistochemically using Cox-2 antibody. The nanoencapsulation of GO represents a promising strategy for brain-targeting.
... Children and the elderly individuals are at greater risk to adverse effects (Angela and Giovambattista, 2001;Iannini, 2007). Adverse reactions may manifest during as well as sometimes long after fluoroquinolone therapy has been discontinued (Saint et al., 2000). ...
Acute toxicity and subacute repeated dose 28 day oral toxicity studies with
norfloxacin were conducted in Wistar albino rats. Acute oral toxicity was conducted in
female rats. An LD50 value obtained was 4541.1067 mg/ kg. The repeated dose 28 day
subacute oral toxicity study was carried out in five groups of male and female Wistar
albino rats separately. The doses administered orally were Sodium Acetate Buffer (50
mmol/L), pH 4.5 (vehicle control), 380, 1140 and 3800 mg/kg norfloxacin daily orally
for a period of 28 days. The hematological parameters viz., TEC, Hb, Hct and TLC
showed significant decreased level in treated (Group II, III and IV) male and female rats
compared to their respective control groups. Similarly biochemical parameters viz.,
aspartate aminotransferase, alanine aminotransferase, BUN, creatinine showed significant
increased level in treated (Group II, III and IV) male and female rats compared to their
respective control groups. Satellite high dose group animals showed partial recovery in
terms of haematological as well as biochemical parameters after cessation administration
of norfloxacin for 14 days. There was a significant decrease in body weight gain in both
male and female rats which were administered norfloxacin during the study period.
However satellite high dose group animals both males and females showed partial
recovery in body weight gain after the administration of norfloxacin was stopped. Histopathology of both male and female rats revealed toxic effect of norfloxacin on liver, kidney, heart, spleen and intestines. Satellite high dose group showed recovery to normalcy in histopathological study.
... These ADRs seem to be rare, affecting <1 in 5,000 patients receiving quinolones with an overall incidence of three cases per 1,000 patient years, even though some quinolones, such as pefloxacin, show an increased risk (Ball, 2003). On the other hand, the occurrence of both neurological and psychiatric ADRs may have several underlying factors, including the higher penetration of quinolones across the blood-brain barrier (such as pefloxacin that shows convulsant activity) (Kushner et al., 2001;Sarro and Sarro, 2012) and the interaction with the activity of neurotransmitters, including the displacement of GABA from its receptors GABA-A or the direct effect on excitatory brain pathways on N-methyl-D-aspartate and a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors (Mehlhorn and Brown, 2007;Rubio-Nazabal et al., 2013). Differences in binding potency of quinolones to the GABA-A receptors may explain the variability in neurotoxic effects (Akahane et al., 1989). ...
Background:
The use of quinolones has been associated with the development of serious and persistent adverse drug reaction (ADR) mainly affecting muscles, joints and the nervous system. This risk has led the European Medicines Agency (EMA) to endorse some restrictions on the use of this class of antibiotic. Therefore, we performed a study to primary estimate the reporting probability of musculoskeletal, neurological, and psychiatric ADRs among quinolone generations using national data.
Methods:
We retrieved Individual Case Safety Reports (ICSRs) with a quinolone as suspected drug among those reported through the Campania spontaneous reporting system from January 1st, 2001 to April 30th 2019. Moreover, we retrieved national aggregated safety data from the online public report system (RAM system) for the period from January 1st, 2002 to March 31st, 2019. Risk factors were classified as "age greater than 60 years," "therapeutic indication," "renal failure," "organ transplantation," "use of corticosteroid," and "history of side effects". Reporting odds ratio (ROR) was computed to evaluate the reporting probability of musculoskeletal, neurological, or psychiatric events among quinolones generations.
Results:
A total of 87 ICSRs with a quinolone as suspected drug that reported at least one musculoskeletal, neurological, and psychiatric adverse event were identified in the Campania spontaneous reporting system. Forty-nine (56.3%) ICSRs reported risk factors (total risk factors 59). The most reported risk factor was "age greater than 60 years" (69.5%), followed by "therapeutic indication" (16.9%), "renal failure" (5.1%), "organ transplantation" (3.4%), "use of corticosteroid" (3.4%), and "history of side effects" (1.7%). Second-generation quinolones were associated with a lower reporting probability of musculoskeletal (ROR 0.70; 95% CI 0.63-0.79), neurological (ROR 0.81; 95% CI 0.73-0.90), and psychiatric (ROR 0.55; 95% CI 0.44-0.63) ADRs compared to the third generation of quinolones.
Conclusions:
Our findings showed that third-generation quinolones were always associated with a higher reporting probability of musculoskeletal, neurological, and psychiatric ADRs compared to the second generation ones. Moreover, we described risk factors in more than half of our cases suggesting that the inappropriate use of quinolones is a phenomenon that may frequently predispose patients to the occurrence of these ADRs.
... The widespread use of LFX in animal production inevitably causes residues in animal foodstuffs. The residual drugs will lead to the accumulation if human consumes these foodstuffs for long-term, and may cause some adverse health effects such as nausea, diarrhea, headache, serious phototoxicity in melanin containing tissues and enhanced resistance of pathogenic bacteria toward antibiotics [2,3]. To ensure human food safety, China has issued a ban on the use of LFX in animals intended for human consumption [4]. ...
A novel molecularly imprinted polymer (MIP) electrochemical sensor for the sensitive detection of lomefloxacin (LFX) was developed for the first time. For this, Fe-doped porous carbon (Fe-PC) was firstly synthesized and then used to modify the Au electrode. MIP film with binary functional monomers was fabricated on the Fe-PC modified Au electrode surface by electropolymerization, with LFX as template molecule, o-phenylenediamine (o-PD) and β-cyclodextrin (β-CD) as binary functional monomers. The results showed that the developed sensor exhibited high selectivity and sensitivity in detection of LFX, which was attributed to the large specific surface area, rich porosity and good catalytic property of Fe-PC, as well as high selectivity and affinity of MIP prepared with binary functional monomers. Under the optimal conditions, the current response was linear to the concentration of LFX ranging from 1 to 120 nM, with a detection limit of 0.2 nM (S/N = 3). Moreover, the developed sensor showed good reproducibility and stability toward LFX detection, and it was applied to detect LFX in water and milk samples with good recoveries ranging from 86.6% to 105.0%.
... 10 Pemilihan ciprofloxacin sebagai kontrol positif dengan pertimbangan Ciprofloxacin merupakan antibiotik spektrum luas (broad spectrum), dan termasuk dalam golongan florokuinolon yang paling umum digunakann dengan mekanisme kerja menghambat DNA girase (topoisomerase II) dan topoisomerase IV yang terdapat dalam bakteri. 11 Penghambatan terhadap enzim yang terlibat dalam replikasi, rekombinasi dan reparasi DNA tersebut mengakibatkan penghambatan terhadap pertumbuhan sel bakteri. ...
This study was aimed to evaluate the antibacterial effect of Chromodoris annae taken from Bunaken waters. This was an experimental study. The antibacterial effect was tested by using the Kirby-Bauer method. Chromodoris annae extract was made by maceration using 95% ethanol and was tested to Staphylococcus aureus and Escherichia coli bacteria. Ciprofloxacin was used as the positive control and aquadest as the negative control. The results showed that the mean inhibition zone diameter of Chromodoris annae extract to Staphylococcus aureus was 22.3 mm meanwhile of ciprofloxacin was 34.7 mm. The mean inhibition zone diameter of Chromodoris annae extract to Escherichia coli was 23.0 mm meanwhile of ciprofloxacin was 40.3 mm. Moreover, aquadest showed no inhibition zone. In conclusion, Chromodoris annae had very strong antibacterial effect to the growths of Staphylococcus aureus and Escherichia coli.Keywords: Chromodoris annae, Staphlococcus aureus, Escherichia coli Abstrak: Penelitian ini bertujuan untuk mengevaluasi efek antibakteri dari Chromodoris annae yang diambil dari perairan Bunaken. Jenis penelitian ialah eksperimental. Pengujian aktivitas antibakteri menggunakan metode Kirby-Bauer. Ekstrak Chromodoris annae dibuat dengan cara maserasi menggunakan pelarut etanol 95% dan diujikan aktivitas antibakteri terhadap bakteri Staphylococcus aureus dan Escherichia coli. Sebagai kontrol positif digunakan antibiotik ciprofloxacin dan sebagai kontrol negatif digunakan akuades. Hasil penelitian memperlihatkan rerata zona hambat ekstrak Chromodoris annae terhadap Staphylococcus aureus sebesar 22,3 mm sedangkan zona hambat ciprofloxacin sebesar 34,7 mm. Rerata zona hambat ekstrak Chromodoris annae terhadap Escherichia coli sebesar 23,0 mm sedangkan zona hambat ciprofloxacin sebesar 40,3 mm. Akuades tidak memperlihatkan adanya zona hambat. Simpulan penelitian ini ialah Chromodoris annae memiliki efek antibakteri kategori sangat kuat terhadap pertumbuhan bakteri Staphylococcus aureus dan Escherichia coli.Kata kunci: Chromodoris annae, Staphylococcus aureus, Escherichia coli
... The pharmacological importance of fluoroquinolones is continually attracting medicinal chemists' to use as a scaffold for the development of potent antibacterial agents. Fluoroquinolones can show adverse effects in the central nervous system, skin, and gastrointestinal tract (Sarro & Sarro, 2001). Over the past few years, different positions of the fluoroquinolones were modified to improve the potency and overcome the associated drug resistance (Allaka et al., 2016;Bartzatt, Cirillo, & Cirillo, 2013;Rajulu et al., 2014;Towle et al., 2018;Zhang et al., 2014). ...
A series of new fluoroquinolone conjugates 8a–g and 9a–f were synthesized via benzotriazole‐mediated synthetic approach with good yield and purity. Some of the synthesized analogs exhibited significant antibacterial properties against E. coli and S. aureus with potency higher than that of the parent drugs through in vitro standard bio‐assay procedure (conjugates 8c and 8d reveal antimicrobial properties with potency 1.9, 61.9, 20.7 and 2.4, 37.1, 8.3 folds relative to the parent antibiotic 6 against E. coli, S. aureus and E. faecalis, respectively). The observed experimental data supported by enzymatic DNA gyrase inhibitory property. Developed BMLR‐QSAR model validates the observed experimental data and recognizes the parameters responsible for the enhanced antibacterial properties. A new set of fluoroquinolone‐dichloroacetic acid hybrid conjugates were synthesized in good yields with selective antibacterial properties. DNA gyrase inhibitory and QSAR studies support the experimental data.
... 9,14,21,29,30,31,32 Topical nadifloxacin very rarely causes mild cutaneous adverse effects. 20,33,34,35 Studies also suggest that the effectiveness of the highly efficacious and safe topical antibiotic nadifloxacin in inflammatory acne lesions may be attributed to its inhibitory effect on pro-inflammatory cytokines like interleukin (IL)-1α, IL-6 and IL-8, which play an important role in acne pathogenesis. Nadifloxacin also inhibits the enzyme DNA topoisomerase IV, which enhances its anti-bacterial spectrum to Gram-positive, Gram-negative as well as anaerobic bacteria such as Propionibacterium acnes as well as against methicillin-susceptible Staphylococcus aureus (MSSA) and Staphylococcus epidermidis, among others. ...
BACKGROUND
Topical adapalene and tretinoin, are comedolytic, anti-comedogenic and anti-inflammatory, on RAR (α, β, ℽ) receptors binding.
Due to higher chemical stability, lipophilicity and lesser photo-lability, adapalene enables quicker follicular penetration, by lesser
anti-AP-1 (c-Jun, c-Fos) and no CRBPII mRNA action, thus producing lesser photosensitivity and no skin irritation, unlike
tretinoin; in which, these are reducible by overnight application, combination therapy, slow-release polymers or emollients.
Topical nadifloxacin is bactericidal, anti-inflammatory and comedolytic, with inhibitory effect on DNA gyrase, DNA topoisomerase
IV and IL-1α, IL-6, IL-8. The Global Alliance to Improve Outcomes in Acne guidelines recommend synergistic and additive
combination therapies, which enhance therapeutic efficacy and reduce adverse effects. Due to inadequacy of data, this study
was conducted, to compare the safety between topical 1% nadifloxacin and 0.1% adapalene combination therapy and topical
1% nadifloxacin and 0.025% tretinoin combination therapy, in mild to moderate acne, in tertiary care hospitals, in India.
METHODS
Groups A and B (50 patients each), applied topical 1% nadifloxacin and 0.1% adapalene combination therapy and 1%
nadifloxacin and 0.025% tretinoin combination therapy, respectively, over their mild to moderate facial acne lesions, once daily
overnight; and adverse effects, like erythema, scaling, dryness, pruritus, burning or stinging, were assessed on 0, 15, 30, 60,
90 days and follow-ups, by Local Irritation Scale. This is a multi-centre, prospective, randomised, open-labelled, comparative,
rational pharmacotherapeutic study. Data was statistically analysed, with the calculation of Z values and p values, along with
the Z test for proportions.
RESULTS
In both groups, no adverse effects were observed, with no statistically significant difference among the observations.
CONCLUSIONS
The therapies were well tolerated and safe among both groups.
... 9,14,21,23 Topical nadifloxacin very rarely causes mild cutaneous adverse effects. 20,[24][25][26] Studies also suggest that the effectiveness of nadifloxacin in inflammatory acne lesions may be attributed to its inhibitory effect on pro-inflammatory cytokines like interleukin (IL)-1α, IL-6 and IL-8, which play an important role in acne pathogenesis. Nadifloxacin also inhibits the enzyme DNA topoisomerase IV, which enhances its anti-bacterial spectrum to Gram-positive, Gram-negative as well as anaerobic bacteria such as Propionibacterium acnes as well as against methicillinsusceptible Staphylococcus aureus (MSSA) and Staphylococcus epidermidis, among others. ...
Background: Topical adapalene and tretinoin, are comedolytic, anti-comedogenic and anti-inflammatory, on RAR (α, β, γ) receptors binding. Adapalene enables quicker follicular penetration, by lesser anti-AP-1 (c-Jun, c-Fos) and no CRBPII mRNA actions, causing chemical stability, lipophilicity and less photo-lability, producing lesser photosensitivity and no skin irritation, unlike tretinoin; wherein reducible by overnight application and combination therapy, slow-release polymers or emollients, respectively. Topical nadifloxacin is bactericidal, anti-inflammatory and comedolytic, with inhibitory effect on DNA gyrase, DNA topoisomerase IV and IL-1α, IL-6, IL-8. The Global Alliance to Improve Outcomes in Acne Guidelines recommend synergistic and additive combination therapies, which enhance therapeutic efficacy and reduce adverse effects. Due to inadequacy of data, this study was conducted, to compare the safety among topical anti-acne monotherapies and combination therapies, and to easily detect any adverse effect producing component in the topical combination therapy.Methods: In this multi-centre, prospective, randomised, open-labelled, comparative study, groups A, B, C, D and E (20 patients each), applied topical 1% nadifloxacin monotherapy, 0.1% adapalene monotherapy, 0.025% tretinoin monotherapy, 1% nadifloxacin and 0.1% adapalene combination therapy and 1% nadifloxacin and 0.025% tretinoin combination therapy, respectively, over their facial mild to moderate acne lesions, once daily overnight; and adverse effects, like erythema, scaling, dryness, prutitus, burning, or stinging, were assessed on 0, 15, 30, 60, 90 days and follow-ups, by Local Irritation Scale.Results: In all 5 groups, no adverse effects were observed, with no statistically significant difference among the observations.Conclusions: The therapies were well tolerated and safe among all 5 groups.
... Indeed, FQ, a popular group of antibiotics, are widely used in the treatment of humans and animals [37][38][39]. Piperazine substitution at the C-7 position has resulted in broad coverage of clinically useful FQ antibacterial agents like LVFX, ciprofloxacin, and norfloxacin [40,41]. LVFX, a third-generation FQ, has been reported to be active against Gram-negative and Gram-positive bacteria [42]. ...
Despite the numerous studies on dendrimers for biomedical applications, the antibacterial activity of anionic phosphorus dendrimers has not been explored. In our research, we evaluated the antibacterial activity of modified polycationic and polyanionic dendrimers in combination with levofloxacin (LVFX) against Gram-negative (Escherichia coli ATCC 25922, Proteus hauseri ATCC 15442) and Gram-positive (Staphylococcus aureus ATCC 6538) bacteria. In the case of Gram-negative bacteria, we concluded that a combination of dendrimers and antibiotic gave satisfactory results due to a synergistic effect. The use of fluoroquinolone antibiotics, such as LVFX, not only caused resistance in disease-causing microorganisms but also increased environmental pollution. Therefore, reduction of drug dosage is of general interest.
... 7 Penghambatan terhadap enzim yang terlibat dalam replikasi, rekombinasi dan reparasi DNA tersebut mengakibatkan penghambatan terhadap pertumbuhan sel bakteri. 8 Pada kelompok perlakuan yang diberi ekstak akar kuning terbentuk zona hambat pada bakteri S. aureus dengan rerata 12 Batang akar kuning mengandung senyawa alkaloid protoberberin yang terdiri dari berberin, jatorrhizin, dan palmatin. Alkaloid protoberberin dilaporkan aktif sebagai antibiotika melawan bakteri Gram positif maupun Gram negatif. ...
Indonesia has a high diversity of flora and fauna in the world. Many types of plants can be used as a medicinal plant; one of them is yellow root (Arcengelisia flava Merr.) which has been known empirically by the Dayak community in Central Kalimantan as natural herbs to treat jaundice. This study aimed to determine the antibacterial effect of the yellow root bark extract against Staphylococcus aureus and Escherichia coli. This study was conducted in the Laboratory of Pharmacology and the Laboratory of Microbiology Faculty of Medicine University of Sam Ratulangi. This was an experimental laboratory study using the Kirby-Bauer modified technique. Yellow root bark extract was obtained from maceration process using ethanol 96%. The antibacterial effect was tested by using the well diffusion method. The results showed that distilled water, the negative control, did not generate inhibition zone around the wells. Ciprofloxacin, the positive control, had the greatest diameter of inhibitory zone. The average diameter of inhibition zone generated by ciprofloxacin was 39.23 mm against Staphylococcus aureus and 40.95 mm against Escherichia coli. Meanwhile, yellow root extract generated an average diameter inhibition zone of 12.27 mm against Staphylococcus aureus and 14.44 mm against Escherichia coli. Conclusion: Yellow root bark extract potentially had antibacterial effect against Staphylococcus aureus and Escherichia coli. Keywords: antibacterial, yellow root bark, Staphylococcus aureus, Escherichia coli. Abstrak: Indonesia memiliki keberagaman flora dan fauna yang tinggi di dunia. Banyak jenis tanaman yang dapat dijadikan sebagai tanaman obat, salah satunya akar kuning (Arcangelisia flava Merr.) yang telah lama dikenal secara empiris oleh masyarakat dayak di Kalimantan Tengah sebagai tanaman herbal alami untuk mengobati penyakit kuning. Penelitian ini bertujuan untuk mengetahui efek antibakteri dari ekstrak batang akar kuning terhadap bakteri Staphylococcus aureus dan Escherichia coli dan dilakukan di Laboratorium Farmakologi, dan Laboratorium Mikrobiologi Fakultas Kedokteran Universitas Sam Ratulangi. Jenis penelitian ini eksperimental laboratorium dengan metode modifikasi Kirby-Bauer. Uji efek antibakteri menggunakan metode sumuran. Esktrak batang akar kuning diperoleh dari proses maserasi dengan etanol 96%. Hasil penelitian memperlihatkan akuades sebagai kontrol negatif tidak menimbulkan zona hambat di sekitar sumur. Siprofloksasin sebagai kontrol positif memiliki diameter zona hambat yang paling besar. Rerata diameter zona hambat yang dihasilkan oleh siprofloksasin 39,23 mm terhadap Staphylococcus aureus dan 40,95 mm terhadap Escherichia coli. Ekstrak akar kuning menghasilkan rerata diameter zona hambat sebesar 12,27 mm terhadap Staphylococcus aureus dan 14,44 mm terhadap Escherichia coli. Simpulan: Ekstrak batang akar kuning berpotensi memiliki efek antibakteri terhadap bakteri Staphylococcus aureus dan Escherichia coli. Kata kunci: antibakteri, ekstrak akar kuning, staphylococcus aureus, escherichia coli
... 10 Penghambatan terhadap enzim yang terlibat dalam replikasi, rekombinasi dan reparasi DNA tersebut mengakibatkan penghambatan terhadap pertumbuhan sel bakteri. 11 Berdasarkan hasil pengamatan yang dilakukan pada tiga kali pengulangan masing-masing terhadap bakteri S. aureus dan E. coli tidak memperlihatkan adanya zona hambat yang terbentuk di sekitar sumur yang diberi akuades. Pada penelitian ini, akuades digunakan sebagai kontrol negatif karena merupakan larutan pengencer pada kontrol positif. ...
This study was aimed to evaluate the antibacterial effect of Chromodoris dianae on E.coli and S. aureus. This was an experimental study. Samples of Chromodoris dianae was taken from Bunaken waters by diving. Extract of Chromodoris dianae was obtained by using maceration technique with 96% etanol. Antibacterial activity of this extract was tested by using the Kirby-Bauer method. The results showed that the mean diameter of the inhibition zone of E. coli was 22.3±1.5 mm and of S. aureus was 23.0±1.0 mm; both were were less than of ciprofloxacin as the positive control repeated for three times. Conclusionn: Chromodoris dianae has antibacterial effects on the growth of Escherichia coli and Staphylococcus aureus.Keywords: Chromodoris dianae, Staphylococcus aureus, Escherichia coli Abstrak: Penelitian ini bertujuan untuk melihat adanya efek antibakteri dari Chromodoris dianae terhadap bakteri E.coli dan S. aureus. Jenis penelitian ialah eksperimental. Sampel Chromodoris dianae diambil dari perairan Bunaken dengan cara menyelam. Ekstrak Chromodoris dianae dibuat dengan cara maserasi menggunakan etanol 96%. Pengujian aktivitas antibakteri dilakukan dengan menggunakan metode Kirby-Bauer. Hasil penelitian menunjukkan adanya zona hambat terhadap E. coli dan S. aureus dengan rerata diameter 22,3±1,5 mm dan 23,0±1,0 mm, yang lebih kecil daripada rerata diameter kontrol positif siprofloksasin pada tiga kali pengulangan. Simpulan: Chromodoris dianae memiliki efek antibakteri terhadap pertumbuhan bakteri Staphylococcus aureus dan Escherichia coli.Kata kunci: Chromodoris dianae, Staphylococcus aureus, Escherichia coli
Phosphorus-modified copper ferrite (P-CuFe2O4) nanoparticles were prepared by a simple sol-gel auto-combustion process and used for the photocatalytic ozonation of lomefloxacin (LOM). The morphology, crystallinity, and structure of the synthesized CuFe2O4 and P-CuFe2O4 nanoparticles were investigated using various techniques. The high-performance liquid chromatography (HPLC) analysis revealed that the degradation of LOM achieved a 99% reduction after a duration of 90 min in the photocatalytic ozonation system. In accordance with the charge-to-mass ratio, four intermediates were proposed with the help of their fragments obtained in LC-MS/MS. The degradation kinetics of lomefloxacin followed a pseudo-first order reaction, and the degradation mechanism was proposed based on the results. P0.035Cu0.965Fe2O4 showed the highest total organic carbon (TOC) removal with 20.15% in 90 min, highest specific surface area and the highest fluoride and ammonium production using the ion chromatography (IC). The experimental results obtained from the electron paramagnetic resonance (EPR) analysis indicated that the modified P-CuFe2O4 samples exhibited significantly elevated levels of superoxide (.O2-) production compared to the CuFe2O4 samples. The findings of this study demonstrate that the introduction of phosphorus modification into the copper ferrite photocatalyst led to an augmentation of both the specific surface area and the total pore volume. Furthermore, the incorporation of phosphorus served to promote the efficient separation of electron-hole pairs by effectively trapping electrons in the conduction band, hence enhancing the degradation efficiency.
Drug-induced liver injury induced by already approved substances is a major threat to human patients, potentially resulting in drug withdrawal and substantial loss of financial resources in the pharmaceutical industry. Trovafloxacin, a broad-spectrum fluoroquinolone, was found to have unexpected side effects of severe hepatotoxicity, which was not detected by preclinical testing. To address the limitations of current drug testing strategies mainly involving 2D cell cultures and animal testing, a three-dimensional microphysiological model of the human liver containing expandable human liver sinusoidal endothelial cells, monocyte-derived macrophages and differentiated HepaRG cells was utilized to investigate the toxicity of trovafloxacin and compared it to the structurally-related non-toxic drug levofloxacin. In the model, trovafloxacin elicited vascular and hepatocellular toxicity associated with pro-inflammatory cytokine release already at clinically relevant concentrations, whereas levofloxacin did not provoke tissue injury. Similar to in vivo, cytokine secretion was dependent on a multicellular immune response, highlighting the potential of the complex microphysiological liver model for reliably detecting drug-related cytotoxicity in preclinical testing. Moreover, hepatic glutathione depletion and mitochondrial ROS formation were elucidated as intrinsic toxicity mechanisms contributing to trovafloxacin toxicity.
Context: Several studies have shown that chloroquine can effectively diminish the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As such, other studies have also supported this statement, but the psychiatric side effects of chloroquine have not been taken into account. So, the current study aimed to briefly review and discuss the safety of chloroquine. Methods: A narrative literature search on databases was carried out on studies without time limitations. A combination of the two main keywords of “Chloroquine” and “Psychiatric Side Effects” was used to search databases. A manual search was performed to find the relevant articles, and finally, 15 studies were reviewed. Data were shown in the table and then summarized by narrative synthesis. Results: The literature review revealed the pharmaceutical characteristics of chloroquine, the safety of chloroquine, and the management of chloroquine's side effects. Also, the studies showed that chloroquine had psychiatric symptoms varying from insomnia to catatonia, toxic psychosis, and suicidal attempts, as well as behavioral manifestations, including most frequently extreme irritability, restlessness, abusiveness, distractibility, pressured speech, flight of ideas, grandiosity delusion, and auditory and visual hallucinations. Conclusions: Given the probability of a wide range of possible psychiatric symptoms following chloroquine, physicians should cautiously prescribe antiviral agents, and healthcare workers should also notice any psychiatric symptoms after administrating the chloroquine.
Moxifloxacin is a broad-spectrum antimicrobial agent that is commonly used in clinical practice. Here we report an unusual case of a patient with persistent hiccups caused by moxifloxacin. A man aged in his 40s was treated with moxifloxacin for tuberculous pleurisy. Hiccups occurred 2 hours after intravenous injection of moxifloxacin and lasted into evening. On the second day after injection, hiccups occurred again and made it difficult for him to fall asleep. The clinician ruled out gastrointestinal disease, nervous system disease, electrolyte disturbance and other factors. On assessing causality of the adverse drug reaction, the Naranjo scale for moxifloxacin was six, indicating a probable relationship of hiccups with moxifloxacin. Hiccups stopped 2 min after intramuscular injection of metoclopramide. To our knowledge, this is the first case report about moxifloxacin-induced persistent hiccups. Clinicians should be aware of the rare adverse reaction.
In human medical neurology, the clinical neurological examination is variably augmented by specific tests that may be either unsuitable for veterinary patients or not included in the clinical evaluation of veterinary neurological patients due to clinicians presumably being unfamiliar with these tests. An example of the latter can be found in testing for the Stewart and Holmes’ rebound phenomenon (“rebound test”). In this article, a veterinary case example is presented in which a modified version of this test was performed (“head rebound test”). The interpretation of the results of this test is discussed, and the literature on the Stewart and Holmes’ rebound phenomenon and testing thereof is reviewed.
Many pathogenic bacteria are getting more and more resistant against antibiotic treatment and even become up to 1.000× times more resilient in the form of a mature biofilm. Thus, one is currently prospecting for alternative methods for treating microbial infections, and photodynamic therapy is a highly promising approach by creating so-called reactive oxygen species (ROS) produced by a photosensitizer (PS) upon irradiation with light. Unfortunately, the unspecific activity of ROS is also problematic as they are harmful to healthy tissue as well. Notably, one knows that uncontrolled existence of ROS in the body plays a major role in the development of cancer. These arguments create need for advanced theranostic materials which are capable of autonomous targeting and detecting the existence of a biofilm, followed by specific activation to combat the infection. The focus of this contribution is on mesoporous organosilica colloids functionalized by orthogonal and localized click-chemistry methods. The external zone of the particles is modified by a dye of the Hoechst family. The particles readily enter a mature biofilm where adduct formation with extracellular DNA and a resulting change in the fluorescence signal occurs, but they cannot cross cellular membranes such as in healthy tissue. A different dye suitable for photochemical ROS generation, Acridine Orange, is covalently linked to the surfaces of the internal mesopores. The spectral overlap between the emission of Hoechst with the absorption band of Acridine Orange facilitates energy transfer by Förster resonance with up to 88% efficiency. The theranostic properties of the materials including viability studies were investigated in vitro on mature biofilms formed by Pseudomonas fluorescens and prove the high efficacy.
Neurotoxicity can be resulted from many diverse clinical drugs, which has been a cause of concern to human populations across the world. The detection of drug-induced neurotoxicity (DINeurot) potential with biological experimental methods always required a lot of budget and time. In addition, few studies have addressed the structural characteristics of neurotoxic chemicals. In this study, we focused on the computational modeling for drug-induced neurotoxicity with machine learning methods and the insights into the structural characteristics of neurotoxic chemicals. Based on the clinical drug data with neurotoxicity effects, we developed 35 different classifiers by combining five different machine learning methods and seven fingerprint packages. The best-performing model achieved good results on both 5-fold cross-validation (balanced accuracy of 76.51%, AUC value of 0.83, and MCC value of 0.52) and external validation (balanced accuracy of 83.63%, AUC value of 0.87, and MCC value of 0.67). The model can be freely accessed on the web server DINeuroTpredictor (http://dineurot.sapredictor.cn/). We also analyzed the distribution of several key molecular properties between neurotoxic and non-neurotoxic structures. The results indicated that several physicochemical properties were significantly different between the neurotoxic and non-neurotoxic compounds, including molecular polar surface area (MPSA), AlogP, the number of hydrogen bond acceptors (nHAcc) and donors (nHDon), the number of rotatable bonds (nRotB), and the number of aromatic rings (nAR). In addition, 18 structural alerts responsible for chemical neurotoxicity were identified. The structural alerts have been integrated with our web server SApredictor (http://www.sapredictor.cn). The results of this study could provide useful information for the understanding of the structural characteristics and computational prediction for chemical neurotoxicity.
Fluoroquinolones are a class of antibiotics with potent bactericidal, broad spectrum activity against many clinically important pathogens which are responsible for variety of infections including urinary tract infections (UTI), gastrointestinal infections, respiratory tract infections (RTI), sexually transmitted diseases (STD) and skin infections. They are primarily used against urinary tract infections and are also clinically useful against prostatitis, infections of skin and bones and penicillin resistant sexually transmitted diseases. The growth in understanding of structure activity relationships with fluoroquinolones has enabled the development of even better compounds. The targets in fluoroquinolone research during the last few years include: improvements in pharmacokinetic properties, greater activity against gram-positive cocci and anaerobes, activity against fluoroquinolone-resistant strains, and improvements in activity against non-fermentative gram-negative species. The compounds developed in the recent years have fulfilled some but not all of these goals; improved bioavailability is one target achieved with most of the more recent compounds allowing for once-daily dosing.© 2011 IGJPS. All rights reserved.
The extensive use of antibiotics in livestock farming poses increased concerns for human health as residues of these substances are present in edible tissues. The aim of this study was the determination of the levels of four groups of antibiotics (sulfonamides—SAs, tetracyclines—TCs, streptomycines—STr and quinolones—QNLs) in meat samples (muscles, livers and kidneys from beef, chicken and pork) and the estimation of the dietary exposure to antibiotics from meat consumption and the potential hazard for human health. Fifty-four samples of raw meat were randomly collected in 2018 from the Cretan market, Greece and analyzed both with an enzyme-linked immunosorbent assay (ELISA) and liquid chromatography–mass spectrometry (LC–MS). According to the results derived from the ELISA method, only 2% of the meat samples were free from antibiotics, 2% were detected with 4 antibiotics and the great majority of the samples (87%) were detected with 2 to 3 antibiotics. SAs presented the highest detection frequencies for all samples whereas TCs were not detected in any bovine sample. The highest median concentration was detected for STr in bovine muscles (182.10 μg/kg) followed by QNLs (93.36 μg/kg) in pork kidneys whereas the chicken samples had higher burdens of QNLs compared to the other meat samples. LC–MS analysis showed that oxytetracycline (OTC) was the most common antibiotic in all samples. The highest median concentration of all antibiotics was detected for doxycycline (DOX) (181.73 μg/kg in pork kidney) followed by OTC in bovine liver (74.46 μg/kg). Risk characterization was applied for each of the two methods; The hazard quotients (HQ) did not exceed 0.059 for the ELISA method and 0.113 for the LC–MS method for any group of antibiotics, whereas the total hazard indexes (HI) were 0.078 and 0.021, respectively. The results showed the presence of different groups of antibiotics in meat from the Cretan market and that the health risk to antibiotics is low. A risk assessment analysis conducted for meat consumption and corrected for the aggregated exposure revealed no risk for the consumers.
In Covid-19 cases, elderly patients in long-term care facilities, children younger than five years with moderate symptoms, and patients admitted to ICU or with comorbidities are at a high risk of coinfection due to evidence. Thus, in these patients, antibiotic therapy based on empirical evidence is necessary. Finding appropriate antimicrobial agents, especially with antiviral and anti-inflammatory properties, is a promising approach to target the virus and its complications, hyper-inflammation, and microorganisms resulting co-infection. Moreover, indiscriminate use of antibiotics can be accompanied by Clostridioides difficile colitis, the emergence of resistant microorganisms, and adverse drug reactions, particularly kidney damage and QT prolongation. Therefore, rational administration of efficient antibiotics is an important issue. The main objective of the present review is to provide a summary of antibiotics with possible antiviral activity against SARS-CoV-2 and anti-immunomodulatory effects to guide scientists for further research. Besides, the findings can help health professionals in the rational prescription of antibiotics in Covid-19 patients with a high risk of coinfection.
he antimicrobial activity of five brands (A, B, C, D and E) of ciprofloxacin hydrochloride tablets commonly sold in Lagos Nigeria, were compared and assessed against susceptible clinical isolates (Staphylococcus aureus, Escherichia coli and Salmonella enterica serotypetyphi). Susceptibility test, minimum inhibitory concentration test and the bactericidal activity were determined. All sampled brands were within their shelf life. Most (60%) of the sampled brands were made in India while the remaining 40% were made in Nigeria. All the brands complied with the official specification in British Pharmacopeia (BP) for uniformity of weight as they show less than 5% deviation in weight. The mean antibacterial activities of the brands at 25µg/ml were found to be within the range of 38.0mm to 42.2mm zone of inhibition while the MICs range between 0.012µg/ml to 1.5µg/ml.All the sampled brands were effective against all the test organisms to varying degree with brands A and E been more potent while brand D was the least effective. The order of MICs (decreasing order of potency) was D>B>C>A>E for Staphylococcus aureus and D>C>B>E>A for Escherichia coli while that of Salmonella enterica serotypeTyphiwas D>B>C>A>E. The bactericidal activity of each ciprofloxacin brand D and E are concentration-dependent; with brand E more active at all tested concentrations.
Lower respiratory tract infections are the leading cause of death due to infectious diseases in both the developing world and developed world. The clinical problem is more complicated than the high profile killers, HIV, tuberculosis and malaria, since the infections are caused by a wide variety of infectious agents, including bacteria and viruses, and covers a variety of clinical conditions. For some of the infectious agents, effective vaccines are available, but in all cases there is a need for new medicines, especially in antibacterial therapy. Over the last fifty years many new classes of antibiotics have been discovered, and antimicrobial therapy created the era of modern medicine. However, this trend has slowed down in recent years. The existing progress is being eroded by emergence of resistance against most of the classes of antibiotics. The challenge is that there is now very little research and development of new antibiotics within the pharmaceutical industry: it has become a neglected disease. The majority of drugs under development are improvements on existing classes of medicines. There are two major reasons for this lack of investment. First, the difficulty of achieving a return on investment, given the costs of drug development and the short period of therapy. Second, in recent years, there have been many uncertainties around the regulatory pathway. On top of all this, the promised fruit of the pathogen sequencing and target-based high-throughput screens has not added much to our armamentarium. However, given the mortality and morbidity, the identification of new antibiotics is still a fertile area for research, and a major commitment is needed to keep us from falling behind in the fight against these infections. Without new classes of drugs to fight infection, the long term consequence will be dramatic: a return to the pre-antibiotic era.
Background
Mycoplasma genitalium (MG) causes a sexually transmitted infection (STI) with a rising rate of antimicrobial resistance. Currently, guidelines do not recommend screening asymptomatic men who have sex with men (MSM). We developed a mathematical model of MG transmission to examine the impact of various screening strategies on the incidence and prevalence of MG among MSM attending a sexual health clinic.
Methods
A compartmental mathematical model of MG transmission among MSM was constructed and calibrated using data from the Melbourne Sexual Health center, where resistance-guided therapy provides high treatment effectiveness (92–95%). The model stratified men by symptom status, sexual risk behaviours and whether or not they had MG with macrolide resistance. We simulated the impact on endemic steady-state MG prevalence and incidence of the following screening scenarios, namely screening: 1) no MSM; 2) only symptomatic MSM (the current recommendation); 3) all symptomatic and high-risk asymptomatic MSM; and 4) all MSM. Our base case analysis assumed a treatment effectiveness of 92–95% using resistance-guided therapy. We also examined the impact of treatment effectiveness (i.e. the proportion of detected MG that were cured) and screening coverage (i.e. testing rate) on MG prevalence.
Findings
The model predicts that the overall endemic MG prevalence is 9.1% (95% CI: 7.9–10.0) in the current situation where screening is only offered to symptomatic MSM (base-case). This would increase to 11·4% (95% confidence intervals (CI): 10.2–13.7) if no MSM are offered screening, but would decrease to 7.3% (95% CI: 5.7–8.4) if all symptomatic and high-risk asymptomatic MSM were offered screening and 6.4% (95% CI: 4.7–7·7) if all MSM were offered screening. Increasing coverage of MSM screening strategies shows a similar effect on decreasing endemic MG incidence. When evaluating the simultaneous impact of treatment effectiveness and screening coverage, we found that offering screening to more MSM may reduce the overall prevalence but leads to a higher proportion of macrolide-resistant MG, particularly when using treatment regimens with lower effectiveness.
Interpretation
Based on the available treatment options, offering screening for MG to other MSM (beyond the currently recommended group of symptomatic MSM) could slightly reduce the prevalence and incidence of MG. However, further increasing screening coverage must be weighed against the impact of lower treatment effectiveness (i.e. when not using resistance-guided therapy), increasing the selection of macrolide resistance, and other negative consequences related to AMR and management (e.g. unnecessary psychological morbidity from infections that do not need treatment).
Review of the use of nonexperimental xenobiotics in terrestrial animal models and the potential unintended consequences of these compounds, including drug-related side effects and adverse reactions.
Fluoroquinolones are one of the world’s most valuable and popularly used categories of antimicrobial agents. This paper attempts to review the substantial progress of fluoroquinolones from its discovery to black box warning. Antibiotic drug choice will remain difficult in the presence of increasing resistance, but introduction of the fluoroquinolones has created a new and exciting era in antimicrobial treatment. These are a synthetic heterogeneous group of compounds used in both hospital and community practices to treat numerous severe infections. The era of quinolone antibiotics began with the serendipitous discovery of the quinolone prototype in 1962. The chronological development of fluoroquinolone reported that nalidixic acid was the first quinolone that gained popular choice for the treatment of urinary tract infection. The subsequent agents like levofloxacin, ofloxacin, norfloxacin, gatifloxacin, moxifloxacin, clinafloxacin, sparfloxacin, ciprofloxacin were derived through side chain and nuclear manipulation from basic pharmacphore. The fluoroquinolone motifs have been found as a milestone, is effective in certain infections are respiratory tract infection, urinary tract infection, bone disorders, meningococcal & mycobacterial infections, sexually transmitted diseases and skin infections etc. Fluoroquinolones are first entirely man made antibiotics exhibit antibacterial activity through the inhibition of topoisomerase II, topoisomerase IV and deoxy ribonucleic acid gyrase, which is vital for chromosome replication and function. The post marketing surveillance pointed out the favorable side effects associated with fluoroquinolones such as phototoxicity, QT interval prolongation and anaphylaxis. The discovery, development and clinical use of fluoroquinolone antibiotics in the last century contributed to a decline in morbidity and mortality rates.
This chapter covers the primary chemical literature on the synthetic methodologies, structural features, reactions and applications of the title bicyclic ring systems and their benzo derivatives published between 2008 and 2019. Earlier literature was discussed in Comprehensive Heterocyclic Chemistry III. The aim of this chapter is to give an overview of the diverse methodologies that have been reported on the chemistry of pyrido[2,1-b][1,3]oxazine, pyrido[1,2-c]-[1,3]oxazine, pyrido[2,1-c][1,4]oxazine, pyrido[1,2-b][1,2]oxazine, pyrido[2,1-b][1,3]thiazine, pyrido[2,1-c][1,4]thiazine, pyrido[1,2-b][1,2]thiazine, pyrido[1,2-c][1,3]thiazine, pyrido[1,2-a]-pyrimidine, pyrido[1,2-c]pyrimidine, pyrido[1,2-a]pyrazine, pyrido[1,2-b]pyridazine, pyrido[2,1-f][2,1]azaborine, pyrido[2,1-b][1,3]selenazine and their benzo analogs. This chapter is divided into sections in accordance with the type of extra heteroatom; synthesis, reactivity, structural features, application, and important compounds are discussed within each section.
The fluoroquinolones absorb light in the 320 to 330 nm ultraviolet A (UV‐A) wavelength and produce reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical, and hydrogen peroxide; thus, the photodynamic generation of ROS may be the basis of phototoxicity of quinolones in human beings and animals. This study aimed to evaluate the damaging effects of UV‐A radiation at different periods of exposure on rats' brains administered with ciprofloxacin. Ciprofloxacin administration in UV‐A exposed animals exaggerated the brain‐oxidative stress biomarkers and decreased the locomotor activity. Exposure of rats to UV‐A for 60 minutes induced a significant increase of malondialdehyde (MDA), myeloperoxidase (MPO), and a decrease in the values of superoxide dismutase (SOD), glutathione (GSH) compared to a normal one; these changes were UV‐A exposure time–dependent. However, the administration of vitamin C to the UV‐60‐treated group decreased the values of MDA, MPO, and shifted the values of SOD, GSH toward the normal values. Vitamin C, probably due to its strong antioxidant properties, could improve and partially counteract the toxic effect of UV‐A on oxidative stress parameters and prevent the damage in rat's brain tissues.
While the description of resistance to quinolones is almost as old as these antimicrobial agents themselves, transferable mechanisms of quinolone resistance (TMQR) remained absent from the scenario for more than 36 years, appearing first as sporadic events and afterward as epidemics. In 1998, the first TMQR was soundly described, that is, QnrA. The presence of QnrA was almost anecdotal for years, but in the middle of the first decade of the 21st century, there was an explosion of TMQR descriptions, which definitively changed the epidemiology of quinolone resistance. Currently, 3 different clinically relevant mechanisms of quinolone resistance are encoded within mobile elements: (i) target protection, which is mediated by 7 different families of Qnr (QnrA, QnrB, QnrC, QnrD, QnrE, QnrS, and QnrVC), which overall account for more than 100 recognized alleles; (ii) antibiotic efflux, which is mediated by 2 main transferable efflux pumps (QepA and OqxAB), which together account for more than 30 alleles, and a series of other efflux pumps (e.g., QacBIII), which at present have been sporadically described; and (iii) antibiotic modification, which is mediated by the enzymes AAC(6′)Ib-cr, from which different alleles have been claimed, as well as CrpP, a newly described phosphorylase.
Fluoroquinolones are the commonly used antimicrobials in the treatment of urinary tract infection, bacterial diarrhea, and infections of soft tissue, bone, and joints. They may cause adverse effects ranging from gastrointestinal disturbances, headache, insomnia, and cutaneous reactions. Their rare adverse effects include phototoxicity, cardiotoxicity, arthropathy, and tendinitis. Among the fluoroquinolones, levofloxacin has more propensity to cause the central nervous system adverse effects such as headache, tremor, insomnia, dizziness, convulsions, psychosis, auditory, and visual hallucinations. A case of acute sinusitis in a young male treated with levofloxacin presented with tactile hallucination and acute anxiety reaction is reported for its rarity of occurrence. According to the Naranjo causality scale, the association of tactile hallucination and acute anxiety is a probable adverse drug reaction due to levofloxacin.
The binding of plasmid DNA to norfloxacin, a quinolone antibacterial agent, was investigated by fluorescence, electrophoretic DNA unwinding, and affinity chromatography techniques. The amount of quinolone bound to DNA was modulated by the concentration of Mg2+. No interaction was evident in the absence of Mg2+ or in the presence of an excess of Mg2+, whereas maximum binding was observed at a Mg2+ concentration of 1-2 mM. The experimental data can be fitted to the formation of three types of Mg adducts: a binary adduct with norfloxacin and Mg2+, a binary adduct with DNA and Mg2+, and a ternary adduct with quinolone, plasmid, and Mg2+. We propose a model for the ternary complex, in which Mg acts as a bridge between the phosphate groups of the nucleic acid and the carbonyl and carboxyl moieties of norfloxacin. Additional stabilization may arise from stacking interactions between the condensed rings of the drug and DNA bases (especially guanine and adenine), which may account for the preference exhibited by quinolones for single-stranded and purine-rich regions of nucleic acids. Other possible biochemical pathways of drug action are suggested by the observation that norfloxacin binds Mg2+ under conditions that are close to physiological.
Some quinolone antibiotics cause increases in levels of theophylline in plasma that lead to serious adverse effects. We investigated the mechanism of this interaction by developing an in vitro system of human liver microsomes. Theophylline (1,3-dimethylxanthine) was incubated with human liver microsomes in the presence of enoxacin, ciprofloxacin, norfloxacin, or ofloxacin. Theophylline, its demethylated metabolites (3-methylxanthine and 1-methylxanthine), and its hydroxylated metabolite (1,3-dimethyluric acid) were measured by high-pressure liquid chromatography, and Km and Vmax values were estimated. Enoxacin and ciprofloxacin selectively blocked the two N demethylations; they significantly inhibited the hydroxylation only at high concentrations. Norfloxacin and ofloxacin caused little or no inhibition of the three metabolites at comparable concentrations. The extent of inhibition was reproducible in five different human livers. Inhibition enzyme kinetics revealed that enoxacin caused competitive and mixed competitive types of inhibition. The oxo metabolite of enoxacin caused little inhibition of theophylline metabolism and was much less potent than the parent compound. Nonspecific inhibition of cytochrome P-450 was ruled out since erythromycin N demethylation (cytochrome P-450 mediated) was unaffected in the presence of enoxacin. These in vitro data correlate with the clinical interaction described for these quinolones and theophylline. We conclude that some quinolones are potent and selective inhibitors of specific isozymes of human cytochrome P-450 that are responsible for theophylline metabolism. This in vitro system may be useful as a model to screen similar compounds for early identification of potential drug interactions.
Quinolones are a class of antibiotics structurally related to nalidixic acid. They exhibit bactericidal activity primarily by inhibiting bacterial DNA gyrase. The early quinolones had a limited spectrum of activity, low potency, high frequency of spontaneous bacterial resistance, low serum drug concentrations and short half-lives, which virtually restricted their use to urinary tract infection. The new fluorinated quinolones differ from their predecessors in their broad antibacterial spectrum, including both Gram-negative and Gram-positive aerobic, and facultative anaerobic bacteria as well as many Mycobacterium spp., Chlamydia spp., Legionella spp. and Mycoplasma spp., in addition to many strains of bacteria that are multiresistant to β-lactam antibiotics and aminoglycosides. They also exhibit high potency, a low incidence of resistance, high oral bioavailability, extensive tissue penetration, low protein binding and long elimination half-lives. They are generally well tolerated apart from some gastrointestinal disturbance and rashes, including photosensitive eruptions and a propensity to cause central nervous system excitation. Clinically important interactions include those with antacids, theophylline, fenbufen and warfarin. Potential toxic effects include cartilage damage, ocular toxicity, teratogenicity and impairment of spermatogenesis. The role of fluoroquinolones continues to widen, encompassing infections of the urinary tract, respiratory tract, skin and soft tissues, bone and joints, infections in immunocompromised patients, sexually transmitted diseases, infectious diarrhoea, gynaecological infections and surgical prophylaxis. The convenience of oral therapy is an added advantage of the new fluoroquinolones.
Levofloxacin, the optically pure levorotatory isomer of ofloxacin, is a fluoro-quinolone antibacterial agent. Like other fluoroquinolones, it acts on bacterial topoisomerase and has activity against a broad range of Gram-positive and Gram-negative organisms. Levofloxacin also appears to have improved activity against Streptococcus pneumoniae compared with ciprofloxacin or ofloxacin. Levofloxacin distributes well and achieves high levels in excess of plasma concentrations in many tissues (e.g. lung, skin, prostate). High oral bioavailability allows switching from intravenous to oral therapy without dosage adjustment.
In patients with mild to severe community-acquired pneumonia receiving treatment for 7 to 14 days, oral levofloxacin was similar in efficacy to amoxicillin/clavulanic acid, and intravenous and/or oral levofloxacin was superior to intravenous ceftriaxone and/or oral cefuroxime axetil. With levofloxacin use, clinical success (clinical cure or improvement) rates were 87 to 96% and bacteriological eradication rates were 87 to 100%. In the 5-to 10-day treatment of acute exacerbations of chronic bronchitis, oral levofloxacin was similar in efficacy to oral cefuroxime axetil or cefaclor. Levofloxacin resulted in clinical success in 78 to 94.6% of patients and bacteriological eradication in 77 to 97%. Oral levofloxacin was also similar in efficacy to amoxicillin/clavulanic acid or oral clarithromycin in patients with acute maxillary sinusitis treated for 7 to 14 days.
Equivalence between 7-to 10-day therapy with oral levofloxacin and ciprofloxacin was seen in patients with uncomplicated skin and soft tissue infections. Clinical success was seen in 97.8 and 96.1% of levofloxacin recipients and bacteriological eradication in 97.5 and 93.2%. Complicated urinary tract infections, including pyelonephritis, responded similarly well to oral levofloxacin or ciprofloxacin for 10 days or lomefloxacin for 14 days. Clinical success and bacteriological eradication rates with levofloxacin occurred in 92 to 93.3% and 93.6 to 94.7% of patients.
Conclusions: Levofloxacin can be administered in a once-daily regimen as an alternative to other fluoroquinolones in the treatment of infections of the urinary tract, skin and soft tissues. Its more interesting use is as an alternative to established treatments of respiratory tract infections. S. pneumoniae appears to be more susceptible to levofloxacin than to ciprofloxacin or ofloxacin. Other newer fluoroquinolone agents that also have enhanced in vitro antipneumococcal activity may not share the well established tolerability profile of levofloxacin, which also appears to improve on that of some older fluoroquinolones.
Pharmacology
Levofloxacin has a broad range of activity against Gram-positive and Gram-negative, atypical and intracellular bacteria and is moderately active against anaerobes.
Methicillin-or oxacillin-susceptible staphylococci (including Staphylococcus aureus, S. saprophyticus and S. epidermidis) are also susceptible to levofloxacin. Levofloxacin is similar in activity against methicillin-or oxacillin-susceptible S. epidermidis to ofloxacin or ciprofloxacin, but less active against these strains than sparfloxacin or trovafloxacin. However, staphylococci that were resistant to methicillin or oxacillin were also resistant to levofloxacin, ciprofloxacin, ofloxacin and sparfloxacin.
Streptococcus pneumoniae that were susceptible, intermediately susceptible or resistant to penicillin and S. pyogenes were all susceptible to levofloxacin. When evaluated on the basis of a 2-dilution difference between agents, the inhibitory activity of levofloxacin against S. pneumoniae appeared to be similar to that of ofloxacin, ciprofloxacin and sparfloxacin, but less than that of trovafloxacin. However, at optimum bactericidal concentrations, levofloxacin is more active against S. pneumoniae than ofloxacin, ciprofloxacin or sparfloxacin. Further, S. pneumoniae strains had minimum inhibitory concentrations below National Committee for Clinical Laboratory Standards recommended susceptibility breakpoints for levofloxacin but not for ofloxacin.
Most enterococci and Enterobacteriaceae were susceptible to levofloxacin, including Enterococcus faecalis, Citrobacter freundii, C. diversus, Enterobacter aerogenes, E. cloacae, Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Morganella morganii, Proteus mirabilis and P. vulgaris. However, Providencia stuartii and P. rettgeri were resistant or had intermediate susceptibility; most Serratia spp. were only intermediately susceptible. E.coli and K. pneumoniae with cephalosporin resistance were also resistant to levofloxacin. Resistance of these organisms to other fluoroquinolones tested was also evident.
P. aeruginosa is only moderately susceptible to levofloxacin or other fluoroquinolones, and nonpseudomonas nonfermenters also do not appear to be susceptible to levofloxacin. Anaerobes vary in susceptibility to levofloxacin, with Bacteroides fragilis strains ranging from susceptible to resistant, although Clos-tridium perfringens is susceptible. In contrast, Gram-negative bacteria, such as Haemophilus influenzae, Moraxella catarrhalis and Legionella pneumophila, and ‘atypical’ pathogens, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, are susceptible to levofloxacin and other fluoroquinolones.
Oral levofloxacin is 100% systemically available and its bioavailability is not affected by meals. Intravenous or oral routes of administration may be used interchangeably. The drug has linear pharmacokinetics over 50 to 1000mg doses. Steady state is reached after ≈3 days; the elimination half-life is 6.8 to 8.9 hours. ≈80% of a dose is found in the urine as unchanged drug and ≤5% as inactive N-oxide and demethyl metabolites within 24 hours. The active drug distributes well to target body tissues and fluids in the respiratory tract, skin, urine and prostate and its uptake by cells makes it suitable for use against intracellular pathogens. Dosages should be reduced in patients with renal failure, in whom levofloxacin elimination is decreased. Old age and gender do not affect levofloxacin pharmacokinetics.
Clinical Use
Published and unpublished studies support the use of levofloxacin in patients with community-acquired pneumonia (CAP), acute maxillary sinusitis, acute exacerbations of chronic bronchitis (AECB), uncomplicated skin and soft tissue infections (SSTIs) or complicated urinary tract infections (UTIs, including acute pyelonephritis). Its efficacy has been demonstrated in a small number of comparative studies in each of these indications, supplemented by noncomparative trials in some indications. A total of >5600 patients in these trials were evaluated on at least 1 of the major outcome indicators: clinical cure rate, clinical success rate (clinical cure or improvement) and bacteriological eradication rate.
In patients with mild to severe CAP, oral levofloxacin 500 mg/day produced a similar clinical success rate (95.2%) to that seen with amoxicillin/clavulanic acid 1500/375 mg/day (95.3%) when these regimens were administered for 7 to 10 days in a double-blind study. In contrast, intravenous or oral levofloxacin 500 mg/day resulted in a statistically superior clinical success rate (96%) to that seen with the combined results of intravenous ceftriaxone 1 or 2 g/day or oral cefur-oxime axetil 1000 mg/day (90%) after 7 to 14 days' treatment of patients with mild to severe CAP in a single-blind study. Patients with moderate to severe CAP achieved clinical cure and success rates of 65 and 87% after levofloxacin 500mg twice daily orally or intravenously and 55 and 86% after intravenous ceftriaxone 4000mg once daily. Bacteriological eradication was seen in 87 to 100% of patients receiving levofloxacin and in similar proportions of those receiving comparator agents (amoxicillin/clavulanic acid 97.5%; ceftriaxone and/or cefuroxime axetil 87%).
In AECB, oral levofloxacin 250 or 500mg once daily for 7 to 10 days was similar in efficacy to oral cefuroxime axetil 250mg twice daily for the same duration. Levofloxacin 500mg once daily was also equivalent in efficacy to cefuroxime axetil 250mg twice daily or cefaclor 250mg 3 times daily when given in shorter courses than its comparators (5 to 7 days vs 10 or 7 to 10 days). Clinical success and bacteriological eradication rates were similar between patients receiving levofloxacin (78 to 94.6% and 77 to 97%, respectively) and those receiving cefuroxime axetil (66 and 92.6%, and 68 and 95%, respectively) or cefaclor (92 and 87%, respectively).
When used for 10 to 14 days to treat radiologically confirmed acute maxillary sinusitis, oral levofloxacin 500mg once daily was similar in efficacy to oral amoxicillin/clavulanic acid 500mg/125mg 3 times daily or oral clarithromycin 500mg twice daily. Clinical cure rates with levofloxacin ranged from 58.3 to 63.2% (and were similar to that for amoxicillin/clavulanic acid, 58.6%). Bacteriological eradication rates in 2 noncomparative trials were 88.6 and 92%. Levofloxacin clinical success rates of 88.3 to 96% were also similar to those of amoxicillin/clavulanic acid (87.3%) and clarithromycin (93.3%).
When per-pathogen eradication rates were examined for respiratory pathogens detected in clinical trials, eradication rates with levofloxacin against S. aureus, M. catarrhalis, E. coli, H. influenzae, H. parainfluenzae, K. pneumoniae, C. pneumoniae, M. pneumoniae and L. pneumophila were very good to excellent and ranged from 89.1 to 100%. A lower eradication rate was seen for levofloxacin against P. aeruginosa (63%).
In patients with uncomplicated skin and soft tissue infections, oral levofloxaein 500mg once daily for 7 to 10 days was similar in efficacy to oral ciprofloxacin 500mg twice daily. Clinical success occurred in 96.1 and 97.8% of levofloxacin recipients and 93.5 and 94.3% of ciprofloxacin recipients, whereas bacteriological eradication rates were 93.2 and 97.5% for levofloxacin and 88.8 and 91.7% for ciprofloxacin. Comparisons between levofloxacin and either ciprofloxacin or lomefloxacin in patients with complicated urinary tract infections also resulted in similar efficacy between these groups. Levofloxacin 250 mg/day for 10 days produced clinical success in 92 and 92.9% of patients and bacteriological eradications in 93.6 and 95.3%. The clinical success rates were 88% after ciprofloxacin 250mg twice daily for 10 days and 88.5% after lomefloxacin 400mg once daily for 14 days; bacteriological eradication rates were 97.5 and 92.1%, respectively.
Tolerability
Adverse events associated with levofloxacin are usually transient, mild to moderate in severity and generally similar to that of other fluoroquinolone agents. Nausea (1.1 to 3%) and diarrhoea (1.1. to 2.89%), are among the more common events seen after oral or intravenous use of the drug in clinical trials. Phlebitis and reddening at the infusion site may also occur with intravenous levofloxacin. According to an overview, the overall incidence of drug-related adverse events appears to be lower with levofloxacin (3.3%) than with the other fluoroquinolones ofloxacin (4.3%), ciprofloxacin (5.5 to 10.2%) or pefloxacin (8%).
Serious adverse events include rare cases of pseudomembranous colitis and haemolytic anaemia. The safety and efficacy of levofloxacin in children and adolescents below the age of 18 years have not been established. Fluoroquinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. Photosensitisation with levofloxacin is similar in incidence to that seen with ofloxacin and ciprofloxacin. CNS events such as seizures may be related to concurrent use of theophylline or nonsteroidal anti-inflammatory drugs and may occur less frequently with levofloxacin than ofloxacin.
Sucralfate and antacids that contain di-or trivalent cations may chelate with levofloxacin and thus limit its absorption. Cimetidine and probenecid may compete with levofloxacin for renal tubular secretion and thus prolong the half-life of levofloxacin. Both hyper-and hypoglycaemia have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent.
Dosage and Administration
Levofloxacin may be used to treat acute maxillary sinusitis, AECB, CAP, SSTIs or complicated UTIs (including pyelonephritis). The drug is available in both oral and intravenous dosage forms. European and US dosage guidelines for levofloxacin differ.
In the US, levofloxacin may be administered orally or intravenously for all indications. The usual dose of 500mg once daily may be used for acute sinusitis (administered for 10 to 14 days), AECB (7 days), CAP (7 to 14 days) and uncomplicated SSTIs (7 to 10 days). Levofloxacin 250mg once daily should be administered for 10 days to treat complicated UTIs or pyelonephritis.
In Europe, oral levofloxacin 500mg once daily is used to treat sinusitis (duration 10 to 14 days) and 250 to 500mg once daily is used for AECB (7 to 10 days). In patients with CAP, intravenous or oral levofloxacin 500mg once or twice daily is administered for 7 to 14 days. Levofloxacin 250mg once daily orally or intravenously may be used for 7 to 10 days in patients with complicated UTIs or pyelonephritis, but higher intravenous dosages may be considered for patients with severe disease. A 250mg once-daily or 500mg once-or twice-daily dosage of oral levofloxacin may be administered for 7 to 14 days for SSTIs; if intravenous levofloxacin is used, 500mg twice daily is recommended.
Use of levofloxacin is contraindicated in children, adolescents, pregnant or breastfeeding women, and patients with epilepsy or a history of tendon disorders related to fluoroquinolones. Caution is warranted when patients with renal impairment receive levofloxacin concomitantly with probenecid or cimetidine; levofloxacin dosages should be adjusted according to creatinine clearance. Administration of sucralfate, iron salts or antacids containing magnesium or aluminium should be separated from levofloxacin administration by 2 hours.
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Penicillins are thought to be GABA receptor antagonists. In order to determine the affinities of various penicillin derivatives for the GABA receptor, their potencies as inhibitors of specific [3H]GABA binding to rat brain membranes were investigated. All investigated penicillins inhibit specific [3H]GABA binding, with IC50 values ranging from 2 to 60 mM. The results are consistent with the assumption that penicillins are weak GABA receptor antagonists.
The recently described potent and selective GABAA antagonist SR 95531 (gabazine) is compared to six other GABAA antagonists: (+)-bicuculline, (-)-securinine, (+)-tubocurarine, iso-THAZ, R-5135, and pitrazepine. Starting from ab initio molecular orbital calculations performed on crystal atomic coordinates, attempts were made to identify in each structure the functional groups that are involved in receptor recognition and binding. A molecular modeling study revealed that (a) all compounds possess accessible cationic and anionic sites separated by an 4.6-5.2 A intercharge distance, (b) the antagonistic nature of the compounds can be explained by the presence of additional binding sites, (c) the correct spatial orientation of the additional binding sites is crucial for GABAA selectivity, and (d) the criteria determining the potency of the antagonist effect are an accurate intercharge distance (greater than 5 A) and the existence of hydrogen-bonding functionalities on one of the additional ring system. The presented pharmacophore accounts also for the inactivity of closely related compounds such as (-)-bicuculline, adlumidine, virosecurinine, allosecurinine, and the 4,6-diphenyl analogue of gabazine.
The mechanisms of phototoxicity induced in mice by five quinolone antibacterial agents were investigated using mouse 3T3 fibroblast cells and Balb/c mice. In the in vitro study, the cultured cells were exposed to ultraviolet-A (UVA) in the presence of the five quinolones lomefloxacin, enoxacin, ciprofloxacin, ofloxacin and DR-3355 (the s-isomer of ofloxacin). Cytotoxicity after irradiation was assayed by the neutral red and MTT assay methods, both of which revealed dose-dependent phototoxicity for all five quinolones. Phototoxicity was inhibited by the addition of catalase, and was augmented by the addition of superoxide dismutase. Dimethylthiourea (a hydroxyl radical scavenger) protected against phototoxicity induced by four quinolones, but not against that by enoxacin. These results indicated that superoxide anions, hydrogen peroxide and hydroxyl radicals were generated in solutions of these quinolones under UVA irradiation. In the in vivo study, mice were injected in the auricle with hydrogen peroxide. Ear swelling reactions appeared dose dependently. When irradiated, these reactions were significantly augmented. These data suggested that cutaneous phototoxicity in Balb/c mice is initiated by the generation of reactive oxygens in the target tissue, especially of hydroxyl radicals.
The effects of fenbufen on the serum concentrations and penetration into the brain and CSF of sparfloxacin (AT-4140), a new quinolone antibacterial agent, were investigated in rats. At designated times after a bolus iv dose of sparfloxacin 10 mg/kg with or without fenbufen 20 mg/kg, arterial blood, CSF and whole brain were simultaneously collected from each rat. Sparfloxacin concentrations were assayed by HPLC. Serum concentration of sparfloxacin declined bi-exponentially with time and was not changed by coadministered fenbufen. Binding sparfloxacin to serum protein slightly decreased after the coadministration. No elevation of sparfloxacin concentrations was observed in either brain or CSF after coadministration with fenbufen except for only a few time-points. The pharmacokinetic analysis based on the physiological model indicated that fenbufen did not affect the permeability across the blood-brain or blood-CSF barrier. These results suggest that fenbufen may be unlikely to affect the pharmacokinetics, involving the entry into the central nervous system, of sparfloxacin.
The entry of two new quinolone antibacterial agents, norfloxacin and ofloxacin, into the central nervous system (CNS) of rats, and the effect of fenbufen on this was investigated. At various times after the administration of a bolus intravenous dose of norfloxacin or ofloxacin (10 mg kg-1) with or without fenbufen (20 mg kg-1), serum and cerebrospinal fluid (CSF) samples and whole brain were collected from the rats and the concentration of norfloxacin or ofloxacin in each sample was determined. Serum concentrations of both quinolones declined biexponentially with time and were significantly elevated by coadministration with fenbufen at the terminal phase. The fractions of these quinolones bound to serum protein were not altered by coadministration with fenbufen. Coadministered fenbufen raised the brain concentrations of both quinolones but did not affect their brain to serum unbound concentration ratios. In contrast, CSF to serum unbound concentration ratios as well as CSF concentrations of norfloxacin and ofloxacin were elevated by coadministration with fenbufen. Apparent diffusional clearances between blood and CSF of norfloxacin and ofloxacin estimated by the physiological model analysis increased by 1.9 and 2.6 times, respectively, after coadministration with fenbufen. These findings suggest that coadministered fenbufen may facilitate the entry of norfloxacin and ofloxacin into the CNS.
1. The effects of a chronic treatment with several quinolone derivatives on on the aminophylline-induced convulsions in the genetically epilepsy-prone rat have been investigated. 2. Two series of experiments have been performed: in the first one animals received the quinolone twice a day for 5 days, then were given aminophylline (80-140 mg.kg-1, i.p.); in the second series of experiments the rats were treated once a day with the quinolone plus 120 mg.kg-1 of aminophylline for 5 days. The changes induced by both treatment protocols on electrocortical activity and on the occurrance of seizures have been evaluated. 3. Enoxacin reduced the dose of aminophylline necessary for the induction of seizures in a higher degree with respect to the other quinolone derivatives. The derivatives which showed minor proconvulsant properties were ofloxacin, ciprofloxacin and cinoxacin. The potentiation of seizures induced by quinolones appeared a dose-dependent phenomenon which was more evident when high doses of quinolones were used. 4. The chronic treatment carried out daily with quinolones and aminophylline suggests that additive neurotoxic effects of both classes of drugs may contribute to the increase of severity of seizure scores. 5. The possible role of GABA-benzodiazepine, excitatory amino acid, purinergic mechanisms as well as the role of pharmacokynetic factors are discussed.
Recent animal studies have demonstrated a proconvulsant effect of certain quino-lone and non-steroidal anti-inflammatory drug combinations. Radioligand binding experiments have indicated that these actions may be mediated by antagonism of the GABAA receptor. The present study has further investigated this hypothesis ina functional assay by examining the effects of the quinolones ciprofloxacin and ofloxacin alone and in combination with either fenbufen or biphenyl acetic acid (BPAA) upon GABA-evoked currents recorded from voltage-clampedrat dorsal root ganglion neurones (DRG) maintained in cell culture.
GABA-evoked whole cell currents were weakly but dose-dependently (30 μM—1 mM) reduced in the presence of ciprofloxacin and ofloxacin. The IC50 for ciprofloxacin was 100 μm but greater than 1 mM for ofloxacin. Application of either fenbufen (100 μm) or BPAA (100 μm) alone produced little effect on the GABA-evoked currents. However, the inhibitory action of ciprofloxacin was enhanced in the presence of 100 μm fenbufen by approximately five-fold whereas the antagonism of GABA responses by ofloxacin was unaffected. In contrast, BPAA (100 μm) had a dramatic effect on the inhibitory actions of both antibiotics such that the IC50 for ciprofloxacin and ofloxacin was reduced to 0.03 and 0.3 μM respectively.
The present results support earlier binding studies and extend them by demonstrating electrophysiologically a potent quinolone/NSAID drug interaction at the GABAA receptor. The mechanism(s) of this novel interaction remains to be determined. These results are commensurate with clinical observations of an increased risk of fits in patients prescribed certain quinolones together with certain NSAIDs.
The combined administration of enoxacin, a new quinolone, and fenbufen, a non-steroidal anti-inflammatory drug induced convulsions in mice, but convulsion did not occur when a single administration of each drug was given. Inhibition by enoxacin of [3H]muscimol binding to mouse and human brain membranes was remarkably facilitated by fenbufen. These inhibitions were much more prominent in the hippocampus and frontal cortex than in the cerebellum of human and mouse brain. Enoxacin and fenbufen each at a high concentration produced a moderate and slight inhibition of the [3H]muscimol binding, respectively, in the hippocampus and frontal cortex but not in the cerebellum. It would thus appear that the drug interaction between enoxacin and fenbufen on the gamma-aminobutyric acidA receptor in hippocampus and frontal cortex plays a role in inducing convulsions.
1. Interaction of quinolone antibiotics and the anti-inflammatory agent fenbufen with the gamma-aminobutyric acid-A (GABAA) receptor-chloride channel complex in pyramidal neurons freshly dissociated from the hippocampal CA1 region of the rats was investigated in whole-cell mode, using the patch-clamp technique under voltage-clamp conditions. 2. Quinolones in clinical doses had no effects on the GABA-gated Cl- current (ICl) but slightly suppressed the response at concentrations greater than 10(-5) M. A metabolite of fenbufen, 4-biphenylacetic acid (BPA), also had little effect on the GABA response at therapeutic concentrations. 3. Coadministration of one of quinolones and BPA suppressed the GABA-gated ICl with increase in each of them in a concentration-dependent manner, and there was a parallel shift of the concentration-response curve for GABA to the right but with no effect on the maximum response, thereby indicating a competitive antagonism. The inhibitory potency of antibiotics in combination with BPA was in the order of norfloxacin much greater than enoxacin greater than cyprofloxacin greater than pipemidic acid much greater than ofloxacin greater than cinoxacin = piromidic acid = nalidixic acid = 0. 4. Norfloxacin and BPA, administered simultaneously, also strongly suppressed pentobarbital sodium (PB)-gated ICl, but they did not act on benzodiazepine (BZP) receptors. 5. Both GABA- and PB-induced ICls reversed at the Cl- equilibrium potential (ECl). In the presence of BPA, the quinolone-induced inhibition of GABA-gated ICls showed no voltage dependence. 6. It was concluded that, in the presence of an anti-inflammatory agent, the quinolone antibiotics decrease the affinity of GABAA receptors, the result being induction of epileptogenic neurotoxicities.
There have been several reports that convulsions, although rare, occur in patients who received fluoroquinolones. In this study, conducted for the evaluation of the convulsant action of fluoroquinolones, the effect of ofloxacin and ciprofloxacin on pentylenetetrazol-induced convulsions were investigated in mice. Mice were pretreated intraperitoneally (IP) with saline, ofloxacin (20 or 80 mg/kg) or ciprofloxacin (20 or 80 mg/kg) 30 minutes before subcutaneous (SC) administration of pentylenetetrazol (40 or 60 mg/kg). In another experiment, diazepam (5 mg/kg) was injected (IP) in mice alone or in combination with ofloxacin (80 mg/kg) 30 minutes before pentylenetetrazol (40 mg/kg) administration (SC). In each experiment mice were observed over the following hour for the incidence and onset of clonic convulsions. Results showed that both doses of ofloxacin increased the incidence of clonic convulsions induced by 40 mg/kg pentylenetetrazol. This effect, however was only significant in the higher dose and inhibited by diazepam. On the other hand, a similar proconvulsant effect by ciprofloxacin could not be demonstrated.
Following the discovery of nalidixic acid in 1962, numerous structural modifications have been made to the quinolone nucleus to increase antimicrobial activity and improve pharmacokinetic performance. A major advance occurred during the 1980s with the discovery that a fluorine at position 6 conferred broad and potent antimicrobial activity, (e.g. norfloxacin) but still with relatively less activity for Gram-positive and anaerobic organisms than Gram-negative bacteria. Subsequent developments produced quinolones with further improvements, predominantly in either solubility (e.g. ofloxacin), antimicrobial activity (e.g. ciprofloxacin) or prolonged serum half-life (e.g. pefloxacin). Recent modifications have attempted to achieve an optimal blend of favourable properties together with minimal potential for undesirable side-effects. An example is temafloxacin with comparatively enhanced activity against Gram-positive pathogens, a balanced pharmacokinetic profile, minimal CNS penetration, and without interaction with theophylline elimination. Improvements in antimicrobial activity combined with adequate blood and tissue concentrations do offer expectancy of enhanced therapeutic efficacy for new derivatives in those infections by organisms which are 'marginally' sensitive to currently used quinolones. The possibility of resistance emerging in these organisms during treatment, should also be reduced.
The excitatory amino acid antagonists, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline) and GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine) that act on non-NMDA receptors, provide potent anticonvulsant protection against AMPA [RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in Swiss mice and against sound-induced seizures in seizure-susceptible DBA/2 mice. Maximal anticonvulsant protection is observed 5-30 min after the i.p. administration of NBQX and 5-15 min after the i.p. administration of GYKI 52466 in DBA/2 mice. The ED50 values for the protection against AMPA-induced seizures by NBQX (30 min, i.p.) and GYKI 52466 (15 min, i.p.) are 23.6 (11.6-48.0) and 18.5 (11.5-29.5) mumol/kg, respectively. The ED50 values at 15 min for the protection against sound-induced seizures in DBA/2 mice are 31.3 (24.9-39.4) mumol/kg (NBQX, i.p.), 37.8 (21.2-67.4) mumol/kg (NBQX, i.v.) and 13.7 (11.5-16.5) mumol/kg (GYKI 52466, i.p.). In DBA/2 mice the therapeutic index (ratio of ED50 values for impaired rotarod performance and anticonvulsant action) is 6.6 for NBQX (15 and 30 min, i.p.) and 2.0 for GYKI 52466 (15 min, i.p.).
Interaction of quinolone antimicrobials and fenbufen, anti-inflammatory agents, with the N-methyl-D-aspartate (NMDA) receptor was investigated in rat hippocampal neurons with the conventional patch-clamp technique. Simultaneous applications of quinolones and a metabolite of fenbufen had no effects on the glutamate- and NMDA-induced currents. The blocking effects of Mg2+ and MK-801 on NMDA responses were also unaffected. Therefore, the convulsive action induced by quinolones and fenbufen does not seem to involve the function change of NMDA receptor.
The authors sought to determine whether different responsiveness to seizures induced by aminophylline existed between the genetically epilepsy-prone and normal rats. It was found that the seizure latency was consistently shorter in the genetically epilepsy-prone rats than in normal ones. A different pattern of response was observed in the progression to tonic seizures. In addition, seizures appeared to be more marked in genetically epilepsy-prone than in normal rats. A pretreatment with some quinolones (nalidixic acid, pipemidic acid, ciprofloxacin, norfloxacin, ofloxacin and enoxacin) significantly increased the convulsant properties of aminophylline. These studies demonstrated that the order of proconvulsant activity was ciprofloxacin greater than enoxacin greater than ofloxacin greater than norfloxacin greater than nalidixic acid greater than pipemidic acid. In addition, the present results showed that quinolones, having a fluorine atom showed the most marked proconvulsant activity.
The effects of fenbufen on the transport of ciprofloxacin (CPFX) into the brain and cerebrospinal fluid (CSF) were investigated in rats. Periodically after a bolus i.v. dose of CPFX (10 mg/kg), alone or with fenbufen (20 mg/kg), to rats, aliquots of CSF and blood were collected and then the whole brain was readily excised from the animal after sacrifice by microwave irradiation. Serum levels of CPFX in the terminal phase were significantly elevated by the coadministration with fenbufen. However, the extent of CPFX binding to serum protein was not affected by fenbufen. Immediately after the coadministration with fenbufen, brain and CSF levels of CPFX were raised by about 15 to 70% and 70 to 100%, respectively. Both brain/serum unbound and CSF/serum unbound level ratios were increased by fenbufen at relatively early periods after drug injection. Analysis based on physiological models indicated that fenbufen significantly increased the apparent diffusion clearances of CPFX across blood-brain and blood-CSF barriers. These findings suggest that coadministered fenbufen may facilitate the entry of CPFX into the central nervous system not only by elevation of serum level but also by enhancement of permeability across the blood-brain or blood-CSF barrier.
The side-effect profile of quinolone antibiotics in man includes CNS disturbances such as dizziness, insomnia and convulsions. Although it has been suggested that the proconvulsive liability of quinolones involves an interaction with GABA receptors in the central nervous system, no animal model has been described to evaluate or confirm the mechanism of this effect. The proconvulsive activity of the quinolone antibiotics, nalidixic (NAL) and oxolinic (OXO) acid were tested in male mice following oral doses of 10-100 mg/kg utilizing the convulsive stimuli pentylenetetrazole (PTZ), picrotoxin, strychnine or electroshock. While NAL and OXO did not alter the threshold for convulsions induced by PTZ, strychnine or picrotoxin, both agents lowered the threshold for electroshock-induced seizures. Furthermore, the proconvulsive actions of NAL and OXO were completely blocked by the excitatory amino acid receptor antagonists, MK-801 and 2-amino-4-phosphonobutyric acid (AP-4). These data indicate that the mechanism of convulsive liability of quinolone antibiotics does not involve GABA receptor interactions as previously thought, but appears to involve activation of excitatory amino acid (EAA) receptors, possibly located in the optic region of the central nervous system.
Five patients had apparently drug-induced seizures while simultaneously receiving theophylline and either imipenem (three patients), ciprofloxacin (one patient), or ciprofloxacin and metronidazole (one patient). Seizures ceased upon reduction in dosage or discontinuation of the suspected offending agents. Imaging studies failed to reveal new structural lesions in the central nervous system in any patient, and only one had a history of neurologic disease. Although the exact mechanism for seizure induction cannot be determined from these cases, potential drug interactions exist, because theophylline, imipenem, and ciprofloxacin are all believed to increase excitation of the central nervous system by inhibition of gamma-aminobutyric acid binding to receptors. In addition, ciprofloxacin decreases the clearance of theophylline from the body, predisposing the patient to elevated theophylline levels. Physicians prescribing theophylline with imipenem, ciprofloxacin, or metronidazole should carefully monitor patients for indications for drug therapy, drug dosage, organ impairment affecting drug metabolism, and signs of toxicity. Seizures may accompany oral theophylline therapy, even at "therapeutic" serum theophylline concentrations.
To investigate the relationship between the chemical structures of quinolones, enoxacin (ENX) and its analogues, and their metabolic inhibitory effects on theophylline, a xanthine derivative closely related to theophylline, 1-methyl-3-propylxanthine (MPX), was used as a model of theophylline in rats. The disappearance of MPX from plasma was significantly delayed by treatment with ENX and analogue A (derivatives without substituent group at both 3'- and 5'- carbon atom in the piperazinyl ring): total body clearance of MPX was significantly decreased by approximately 50%. However, analogue A was converted into ENX in the rat body (about 14% of dose). Analogues B and C (derivatives with substituent group at 3'- or 5'-carbon atom in the piperazinyl ring) had little or no effect on MPX disposition. No significant change in the volume of distribution of MPX was observed after coadministration with these quinolones. The results of this study indicate that the substitutions on 3' and 5'-carbon atoms of piperazinyl ring at 7-position of the quinolone molecule may play important role in the inhibition of theophylline metabolism.
To clarify the mechanism of interaction between theophylline and enoxacin, the effects of enoxacin and its metabolite, 4-oxo-enoxacin, on the disposition of new xanthine derivatives, 1-methyl-3-propylxanthine (MPX) and 3-propylxanthine (enprofylline), as models of theophylline have been investigated in rats. Pretreatment with enoxacin significantly delayed the elimination of MPX from plasma. No significant change in the volume of distribution of MPX was observed in the presence of enoxacin, but the total body clearance of MPX was significantly decreased by approximately 60 and 80% after pretreatment with 25 and 100 mg kg-1 of enoxacin, respectively. The amount of the decrease in total body clearance depended on the dose of enoxacin. 4-Oxo-enoxacin had little or no effect on MPX disposition. A newly developed quinolone, NY-198, which does not affect the disposition of theophylline, also did not affect the disposition of MPX. Enoxacin also had no effect on the disposition of enprofylline. These results indicate that the mechanism for decrease in theophylline clearance induced by enoxacin may not be due to its metabolite, 4-oxo-enoxacin, but to enoxacin itself, and that enoxacin does not inhibit solely the elimination process depending on cytochrome P450 isoenzyme for N-demethylation. It is likely that enoxacin has no influence on the renal excretion of xanthines.
The change in plasma concentration-time profile, serum protein binding and renal and biliary clearances of ciprofloxacin caused by coadministration of fenbufen has been studied in rats administered an intravenous dose of ciprofloxacin (5 mg kg-1) alone or with fenbufen (10 mg kg-1). Coadministered fenbufen significantly prolonged the plasma elimination half-life of ciprofloxacin from 40.5 to 57.6 min and tended to reduce the total body clearance of this quinolone by about 20%. The extent of ciprofloxacin binding to rat serum protein was not affected by fenbufen, nor did it affect the biliary clearance of the quinolone. However, fenbufen tended to reduce renal clearance and significantly decreased the cumulative renal excretion of the quinolone during at least the first 3 h after drug administration. These results suggest a possible reduction of ciprofloxacin clearance owing to inhibition of renal excretion by fenbufen.
The quinolone antibacterials are proving very useful in the management of infection, notably for the treatment of Gram-negative bacteria. With the increasing use of these drugs, adverse effects are being recognised more often and careful documentation is still required.
In general, the quinolones are of low toxicity. Gastrointestinal adverse effects are the most common, and are usually mild; indeed, all adverse events are generally mild and resolve on withdrawal of the offending drug. Certain precautions and contraindications are apparent. Because drug-induced arthropathies occur in juvenile animals, quinolones should not be administered to pregnant or lactating women or to growing children, unless the clinical benefit outweighs the risk. Caution should also be observed in patients with previous epilepsy or severe cerebral arteriosclerosis. Neurological effects may require the use of appropriate neuro-and psychoactive drugs, as well as the withdrawal of the precipitating agent. Hypersensitivity reactions to a fluoroquinolone may require the use of antihistamines, and in some cases topical or systemic steroids, and may well preclude future use of a fluoroquinolone.
Dose adjustments may be necessary in patients with reduced renal function, when the measurement of serum concentrations may be desirable. Interstitial nephritis, haematuria and acute renal failure are rare effects of quinolone therapy which will require appropriate management including withdrawal of the precipitating drug. Interactions with theophylline and warfarin are of clinical significance, and may require plasma concentration monitoring and adjustment of dosage.
2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) is an analog of the quinoxalinedione antagonists to the non-N-methyl-D-aspartate (non-NMDA) glutamate receptor. NBQX is a potent and selective inhibitor of binding to the quisqualate subtype of the glutamate receptor, with no activity at the NMDA and glycine sites. NBQX protects against global ischemia, even when administered 2 hours after an ischemic challenge.
In order to clarify the possibility of pharmacokinetic interaction between quinolone and fenbufen, the plasma concentration-time profiles and serum protein binding of enoxacin, fenbufen and its active metabolite, felbinac, were investigated in rats. The rats were administered an intravenous dose of enoxacin (5 mg/kg) and fenbufen (10 mg/kg) alone or concomitantly. Coadministration with fenbufen tended to prolong the plasma elimination half-life of enoxacin by about 20%, whereas it showed no effect on the area under plasma concentration-time curve, total body clearance or distribution volume of enoxacin. The extent of enoxacin binding to rat serum tended to be slightly reduced by fenbufen in vivo and in vitro. Plasma concentration-time curves, pharmacokinetic parameters and serum protein binding of fenbufen and felbinac were not affected at all by the coadministration with enoxacin. These aspects suggest that there may be only a minor possibility of the pharmacokinetic interaction between enoxacin and fenbufen.
The transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system (CNS) was studied using in vivo, in situ and in vitro experimental techniques. After i.v. bolus administration, the imipenem concentration in the cerebrospinal fluid (CSF) rose to a peak within 30 min and declined with time. The CSF/serum unbound concentration ratio of imipenem was 0.22 at 2 hr after i.v. administration, substantially higher than that reported for benzylpenicillin. By using an in situ brain perfusion technique, we found that imipenem was transported through the blood-brain barrier principally via passive diffusion with a permeability-surface area product comparable to that of mannitol. In vitro, imipenem was accumulated by the isolated choroid plexus via an active organic anion transport system, although much less rapidly than benzylpenicillin. In vivo, after i.c.v. administration, imipenem was cleared from the CNS in a manner comparable to that of mannitol with only a small probenecid-sensitive process. Imipenem thus has minimal affinity for the organic anion transport system in the choroid plexus, resulting in the slow elimination of this drug from the CNS. These results suggest that the difference between imipenem and benzylpenicillin in the ratio of CSF to unbound serum drug concentration is determined principally by the efflux process in the choroid plexus rather than the influx process through the blood-brain barrier.
The anticonvulsant activity of two competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, 2-amino-7-phosphonoheptanoic acid (APH) and 3-[2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP), and two non-competitive NMDA antagonists, phencyclidine (PCP) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), were compared in 4 models of induced seizures in mice. All 4 drugs protected against tonic extensor seizures induced by pentylenetetrazol (PTZ), by submaximal (15 mA) electroconvulsive shock (ECS) and by maximal (50 mA) ECS. Similar orders of potency (i.e., MK-801 greater than PCP greater than or equal to CPP greater than APH) were seen in each of the 3 seizure models. All 4 drugs failed to block clonic seizures induced by picrotoxin in the dose ranges that protected from tonic seizures. These data are consistent with other data demonstrating that competitive and non-competitive NMDA antagonists have similar pharmacologic effects. These results also support the suggestion that the anticonvulsant effects of competitive and non-competitive NMDA antagonists are mediated by the NMDA receptor-ionophore complex.
Seizure predisposition in the genetically epilepsy-prone rat (GEPR) is innately determined and these animals exhibit consistent and reproducible convulsive patterns. This epilepsy model is made up of 2 independently derived colonies of animals with each exhibiting a characteristic convulsive pattern. In response to a standardized acoustic stimulus, GEPR-3s exhibit moderate or clonic convulsions and GEPR-9s exhibit more severe tonic extensor convulsions. Besides exhibiting convulsions in response to sound stimulation, some GEPRs experience spontaneous and hyperthermic seizures. They are also abnormally sensitive to a number of seizure provoking stimuli that produce seizures in normal animals. The neurochemical basis for the seizure predisposition in GEPRs is increasingly well understood. Abnormalities in central nervous system norepinephrine and serotonin are widespread and may play a prominent role in regulation of seizures in the GEPR. Amino acid neurotransmitter systems are less well defined in the GEPR but abnormalities exist and may be, along with other documented deficiencies, responsible in part for the seizure predisposition that is characteristic of GEPRs.
In the present study, we confirm that spermidine increases [ 3 H]TCP binding (in the presence of glutamate) to well washed rat brain membranes, and show that this effect is potently antagonised by ifenprodil and SL 82.0715 at concentrations that themselves have no effect on [ 3 H]TCP binding in the absence of spermidine
Non-competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor have been evaluated as anticonvulsants against sound-induced seizures in DBA/2 mice. The ED50 values for protection against sound-induced clonic seizures 15 min following the intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration are: MK-801, ED50 = 0.5 nmol (i.c.v.); 0.14 mumol/kg (i.p.); phencyclidine, ED50 = 14 nmol (i.c.v.); 1.9 mumol/kg (i.p.); dextrorphan, ED50 = 35 nmol (i.c.v.); 18.5 mumol/kg (i.p.); tiletamine, ED50 = 40 nmol (i.c.v.); 5.6 mumol/kg (i.p.); SKF-10047, ED50 = 50 nmol (i.c.v.); 23.5 mumol/kg (i.p.); dextromethorphan, ED50 = 70 nmol (i.c.v.); 28.0 mumol/kg (i.p.); ketamine, ED50 = 110 nmol (i.c.v.); 15.5 mumol/kg (i.p.). The anticonvulsant effects of ketamine and tiletamine are of short duration (10-30 min), whereas the anticonvulsant effects of MK-801 and dextromethorphan last for 45 min or longer. The effects of phencyclidine, SKF-10047 and dextrorphan are of intermediate duration. Mild to moderate behavioural excitation is associated with the anticonvulsant activity of all the non-competitive NMDA antagonists. For MK-801, phencyclidine, dextrorphan, SKF-10047 and ketamine there is a close correlation between their relative anticonvulsant potencies and their potencies for displacing [3H]MK-801. The anticonvulsant effect is likely to be primarily mediated via NMDA antagonism at the PCP/MK-801 site.