Malcolm Tingle

University of Auckland · Department of Pharmacology and Clinical Pharmacology

Clozapine is an effective atypical antipsychotic indicated for treatment-resistant schizophrenia but is under-prescribed due to the risk of severe adverse drug reactions such as myocarditis. A mechanistic understanding of clozapine cardiotoxicity remains elusive. This study aimed to investigate the contribution of selected CYP isoforms to cycling b...

Aims: To investigate ethnic disparities in the treatment and incidence of cardiotoxicity for patients prescribed clozapine in New Zealand. Methods: A post hoc analysis was undertaken using data from four studies investigating clozapine cardiotoxicities in New Zealand: two population studies (one prospective, one retrospective) conducted in the A...

Background Optimising intranasal distribution and retention of topical therapy is essential for effectively managing patients with chronic rhinosinusitis, including those that have had functional endoscopic sinus surgery (FESS). This study presents a new technique for quantifying in vitro experiments of fluticasone propionate deposition within the...

Background: Despite the widespread prescription of antibiotics for the treatment of chronic rhinosinusitis (CRS), their efficacy remains uncertain. Limited penetration of systemic antibiotics into the sinonasal mucosa has been reported previously by this group. This study aimed to investigate the short-term effects of antibiotics on the sinus and...

Clozapine is a uniquely effective antipsychotic indicated for treatment-resistant schizophrenia. However, its use is underutilised and often delayed for years due to potential adverse reactions including myocarditis and cardiomyopathy. The purpose of this study was to conduct a retrospective review of the clinical records of patients initiating clo...

• Despite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa occurs remains largely undefined. • Twenty subjects undergoing functional endoscopic sinus surgery (FESS) for CRS were randomized to one of two groups: 1) doxycycline (100 mg daily for se...

Background: Despite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa influences their efficacy remains largely undefined. Methods: Thirty subjects undergoing functional endoscopic sinus surgery (FESS) for bilateral CRS were randomized to one of t...

Purpose: This work investigated the utility of circulating microRNA (miRNA) as biomarkers of clozapine (CLZ)-induced cardiotoxicities: serious adverse events with an unusually high incidence in Australia and New Zealand. Methods: Global plasma miRNA expression was analysed by microarray in patients taking CLZ, to investigate differential expression...

Background The evidence supporting the efficacy of antibiotic therapy in the treatment of chronic rhinosinusitis is not compelling. A limited number of studies show that the changes in the nasal microbiome in patients following drug therapy are unpredictable and variable. The evidence for the impact of oral antibiotics on the gut microbiota is stro...

Subcutaneous delivery of nicotine was performed using a novel electrically-operated needle-free jet injector, and compared to hypodermic needle delivery in a porcine model. Nicotine was delivered as a single, one-milligram dose into the abdominal skin, formulated as a 50 microliter aqueous solution. Plasma levels of nicotine and cotinine, its main...

Cytisine, a partial agonist for the α4β2-nAChR, is used as a smoking cessation medication. Cytisine’s current dosing is complex and involves taking 1.5 mg several times a day. The aim of this study was to explore the effect of dose on the pharmacokinetics and safety of cytisine after a single dose in healthy adult smokers. Participants were assigne...

Cytisine is a partial agonist at the alpha-4-beta-2 nictoinic acetylcholine receptor that has been used as a smoking medication since the 1960s in Eastern Europe. The current recommended dosing schedule is complex but there is no published information that shows this dosing regimen is supported by a pharmacokinetic rationale or that it is the most...

Introduction: Deleterious variants in the DPYD gene result in a deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme. This increases the risk of life threatening normal tissue toxicity after administration of the anticancer drug 5 fluorouracil (5-FU). The relationship between DPYD pharmacogenes and metabolism of 5-FU by human liver has no...

1. Cytisine is a plant alkaloid that is a partial agonist for the α4β2 -nAChRs and is used as an aid to smoking cessation. To date, there are no published data on cytisine concentrations in humans following multiple dosing. The aim of this study was to determine cytisine plasma concentrations after taking recommended doses for smoking cessation and...

Forensic pathology is remarkably under-represented in research: considering the obstacles a researcher must overcome to obtain post-mortem tissue for research, it is perhaps not surprising. We are investigating whether there is any role for altered drug metabolism in potentially fatal clozapine-associated myocarditis and/or cardiomyopathy. As part...

Despite speculation that the CYP2C19 gene may contain CpG islands, there has been little direct assessment of the role for epigenetics in the regulation of this pharmacogene. The effect of 5-aza-2’-deoxycytidine (5azaDC), a DNA methyltransferase inhibitor, and trichostatin A (TSA), an inhibitor of histone deacetylases, on the expression of CYP2C19...

Noise-induced hearing loss (NIHL) is a global health problem affecting over 5% of the population worldwide. We have shown previously that acute noise-induced cochlear injury can be ameliorated by administration of drugs acting on adenosine receptors in the inner ear, and a selective A 1 adenosine receptor agonist adenosine amine congener (ADAC) has...

Objective: Studies in the post mortem human brain and in genetic mouse model suggest that dysfunctional cholinergic neurotransmission, through a loss of agonist rather than receptors may be a significant contributing factor to HD pathology. If correct, pharmacological replacement may therefore be a potential treatment strategy. We have investigate...

The aim of this study was to describe the effects of varenicline, a smoking cessation aid that acts as a nicotinic agonist, on cognitive function in patients with early clinical Huntington's disease (HD) who were current smokers. Three gene-positive patients transition-ing to symptomatic HD were evaluated using the Unified Huntington's Disease Rati...

The aim of this study was to describe the effects of varenicline, a smoking cessation aid that acts as a nicotinic agonist, on cognitive function in patients with early clinical Huntington’s disease (HD) who were current smokers. Three gene-positive patients transitioning to symptomatic HD were evaluated using the Unified Huntington’s Disease Ratin...

We have shown previously that Adenosine Amine Congener (ADAC), a selective A1 adenosine receptor agonist, can ameliorate noise- and cisplatin-induced cochlear injury. More recently, we have demonstrated the dose-dependent rescue effect of ADAC on noise-induced cochlear injury in a rat model and established the time window for treatment (unpublished...

We have previously shown that Adenosine Amine Congener (ADAC), a selective A1 adenosine receptor agonist, can ameliorate noise- and cisplatin-induced cochlear injury. More recently, we have demonstrated the dose-dependent rescue effects of ADAC on noise-induced cochlear injury in a rat model and established the time window for treatment (unpublishe...

Cytisine, an α4β2 nicotinic receptor partial agonist, is a plant alkaloid that is commercially extracted for use as a smoking cessation medication. Despite its long history of use, there is very little understanding of the pharmacokinetics of cytisine. To date, no previous studies have reported cytisine concentrations in humans following its use as...

Unlabelled: We have previously shown that adenosine amine congener (ADAC), a selective A1 adenosine receptor agonist, can ameliorate noise- and cisplatin-induced cochlear injury. Here we demonstrate the dose-dependent rescue effects of ADAC on noise-induced cochlear injury in a rat model and establish the time window for treatment. Methods: ADAC...

Owing to the increasing availability of new, and legal, psychoactive drugs (NPDs),1 the New Zealand government enacted ground breaking legislation in May 2013; the Psychoactive Substance Act requires evidence of low risk before NPDs can be legally sold.2 3 A transitional period was created until safety testing regimes were finalised. Public outrage...

A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia - with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within e...

Letter to the editor.

Triethylenetetramine (TETA), a copper II chelator and a polyamine analog traditionally used for the treatment of Wilson's disease, is currently in Phase I clinical trials for cancer in combination with carboplatin. However, the metabolism of TETA has never been thoroughly investigated, which is crucial for its further development in cancer treatmen...

PR-104, the phosphate ester of a dinitrobenzamide mustard [PR-104A; 2-((2-bromoethyl)-2-{[(2-hydroxyethyl) amino] carbonyl}-4,6-dinitroanilino)ethyl methanesulfonate], is currently in clinical trial as a hypoxia- and aldo-keto reductase 1C3 (AKR1C3)-activated prodrug for cancer therapy. Here, we investigate species (human, dog, rat, mouse) differen...

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Triethylenetetramine (TETA), a copper II chelator traditionally used for the treatment of Wilson's disease, and a number of structural analogs are currently in clinical trials for cancer. However, the metabolism of TETA has never been thoroughly investigated, which is cr...

There is a need in New Zealand for a new, more advanced generation of toxins to minimize the impact of these invasive animals. A new pest control agent, para-aminopropiophenone (PAPP) represents a lead candidate undergoing registration for the humane control of stoats and feral cats, it exhibits low toxicity to most bird species, no secondary poiso...

The role of CYP pharmacogenetics in the bioactivation of cyclophosphamide is still controversial. Recent clinical studies have suggested a role for either CYP2C19 or CYP2B6. The aim of this study was to clarify the role of these pharmacogenes. We used a combined in vitro-in vivo approach to determine the role of these pharmacogenes in the bioactiva...

PA-824 is a 2-nitroimidazooxazine prodrug currently in Phase II clinical trial for tuberculosis therapy. It is bioactivated by a deazaflavin (F(420) )-dependent nitroreductase (Ddn) isolated from Mycobacterium tuberculosis to form a des-nitro metabolite. This releases toxic reactive nitrogen species which may be responsible for its anti-mycobacteri...

An LC-MS method was developed for benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP), constituents of "party pills" or "legal herbal highs," and their metabolites in human blood plasma. Compounds were resolved using a mixture of ammonium formate (pH 4.5, 0.01 M) and acetonitrile (flow rate of 1.0 mL/min) with a C18 column. Calibrati...

BZP and TFMPP are amphetamine-like recreational drugs and the major active components of 'party pills'. The pharmacodynamic effects of these neurally active drugs are thought to be dependent on their activity at DA and 5-HT receptors and several studies report drug-drug interactions at a pharmacodynamic level. Their metabolism involves the hepatic...

This study explores potential drug-drug interactions between BZP and TFMPP. This was achieved by comparing the metabolism and pharmacokinetics of BZP and TFMPP when taken together with previously published data on their individual metabolism and pharmacokinetics. Blood and urine samples were collected from seven participants given a combined dose o...

'Party pills' have found use worldwide as a substitute for amphetamine-derived designer drugs. Whilst some information exists about the metabolism of these drugs, there is little information about their ability to inhibit the metabolism of co-administered drugs. This study aimed to determine whether predictions can be made about global interactions...

Norbormide's species-selective lethality displays 150-fold and 40-fold more sensitivity to rats than mice and guinea pigs, respectively. Our previous study revealed marked inter-species differences in rate and route of metabolism in liver preparations from different species, with hydroxylation the major route. To examine whether rapid metabolic cle...

There have been many reports of benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) being used as recreational drugs which have been widely marketed in the form of 'party pills' since the late 1990's. However, there is no information currently available describing the pharmacokinetics of these drugs in humans. Human plasma concentrat...

This study aimed to explore the potential for drug-drug interactions involving benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP). This was achieved by determining the effects of BZP and TFMPP on the metabolism of drugs commonly found in the clinical setting by using pooled human liver microsomes. Incubations consisted of a probe su...

Differences between species in response to norbormide (NRB) may arise through differential pharmacodynamic and/or pharmacokinetic properties. We hypothesise that species-selectivity is at least partly determined by differences in metabolism based on in vitro data generated in liver preparations from rats, mice and guinea pigs. HPLC separation and L...

Norbormide is a vasoactive compound that displays remarkable species and tissue selectivity. In rat peripheral arteries it has vasoconstrictor activity, which results in coronary constriction leading to irreversible cardiac damage. In marked contrast, in rat aorta and arteries of other species it exhibits vasorelaxant properties. The species variat...

Satraplatin is an investigational orally administered platinum‐based antitumour drug. The present study compared the plasma protein binding, stability and degradation of satraplatin with that of its active metabolite JM118 and cisplatin. The platinum complexes were incubated in human plasma for up to 2 h at 37°C and quantified in plasma fractions b...

The dinitrobenzamide mustards are a class of bioreductive nitro-aromatic anticancer prodrugs, of which a phosphorylated analog (PR-104) is currently in clinical development. They are bioactivated by tumor reductases to form DNA cross-linking cytotoxins. However, their biotransformation in normal tissues has not been examined. Here we report the aer...

Investigations into the metabolism of drugs used in aquatic animal therapy are useful for understanding the mechanisms of xenobiotic transformation systems and can aid the development of dosing regimens. This study investigated the metabolism of the synthetic anthelmintic praziquantel, which has application in helminthiasis treatment for several fi...

Norbormide (NRB) is a rat-selective toxicant. The species-selectivity of drug action is thought to be due to its differing effects on the small versus large arteries, since it causes constriction of small arteries and dilation of large arteries in rats whereas it dilates both small and large arteries in non-rat species. The endothelin (ET) receptor...

5-(Aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954), a promising anti-tumour compound, is associated with clinical hepatotoxicity. We have previously demonstrated that human liver preparations are capable of endogenous 2- and 4-nitroreduction of CB 1954 to generate highly potent cytotoxins. The present study initially examined the in vitro metabolism...

Oral praziquantel (PZQ) preparations, administered using multiple dosing regimens, have recently been investigated for the treatment of monogenean parasites of Seriola species cultured in sea-cages. To evaluate existing dosing regimens, the pharmacokinetics of two oral PZQ doses, 50 mg kg− 1 body weight (BW) and 150 mg kg− 1 BW, administered every...

We have developed a specific assay for cisplatin in human plasma ultrafiltrate (PUF) and cell culture medium ultrafiltrate (MUF) using HPLC on-line with inductively coupled plasma mass spectrometry (ICP-MS). Separation of cisplatin (6 min) and monohydrated cisplatin (12 min) was achieved using a muBondapak C(18) column (Waters) and a mobile phase (...

Oral praziquantel (PZQ) preparations have recently been investigated for the treatment of monogeneans that infect the skin and gills of kingfish Seriola lalandi cultured in sea-cages. To evaluate an oral PZQ dosing strategy, the pharmacokinetics of a dissolved and in feed oral PZQ preparation (40 mg kg(-1) body weight) were compared with an intrave...

Satraplatin is thought to require reduction to a reactive Pt(II) complex (JM118) before exerting chemotherapeutic activity. In this study, we investigated the role of heme proteins in this reductive activation of satraplatin. Satraplatin was incubated in solution with heme proteins and liver microsomes. The oxidation state of heme iron was monitore...

Animals provide a physiologically relevant system for evaluation of drug metabolism, but marked inter-species differences limit extrapolation to humans. Liver microsomes are used extensively as an in vitro human drug metabolising system, and with appropriate selection of parameters, such as substrate and enzyme concentrations, may predict both rout...

5-(Aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) is an anti-tumour prodrug which recently entered clinical trials in combination with Escherichia coli nitroreductase in a gene-directed enzyme prodrug therapy (GDEPT) context. A Phase I trial of the prodrug, however, revealed dose-limiting hepatotoxicity (transaminitis). The aim of this study was to...

Thalidomide has a variety of biological effects that vary considerably according to the species tested. We sought to establish whether differences in pharmacokinetics could form a basis for the species-specific effects of thalidomide. Mice and rabbits were administered thalidomide (2 mg/kg) p.o. or i.v., and plasma concentrations of thalidomide wer...

These studies were performed to characterize the contribution of the uridine diphosphate glucuronosyltransferase (UGT) enzymes to the clearance of 3'-azido-3'-deoxythymidine (AZT) in vivo and to assess the regulation of UGT activity [including the disposition of the cofactor uridine diphosphate glucuronic acid (UDPGA)] in the placenta. Transport of...

Thalidomide is increasingly important in clinical treatment, not only of various inflammatory conditions but also in multiple myeloma and other malignancies. Moreover, the metabolism of thalidomide varies considerably among different species, indicating a need to understand its mechanistic basis. Our previous in vivo studies showed the plasma half-...

The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is the drug of choice for preventing maternal-fetal HIV transmission during pregnancy. Our aim was to assess the cytotoxic effects of AZT on human placenta in vitro. The mechanisms of AZT-induced effects were investigated using JEG-3 choriocarcinoma cells and primary explant cultures from term and...

The rationale for this study was to assess the expression, activity and localization of the enzymes uridine diphosphate glucuronosyltransferase (UGT), beta-glucuronidase, cytochrome P450 1A (CYP1A) and cytochrome P450 2E1 (CYP2E1) in first trimester human placenta and to gauge the effects of maternal variables on placental metabolism. CYP1A, CYP2E1...

Purpose: Satraplatin is an orally administered platinum complex that has demonstrated clinical activity and manageable toxicity in phase II trials. The presence of several different platinum-containing species and very little intact parent drug in the systemic circulation indicates extensive biotransformation of satraplatin in vivo. To investigate...

1. Mouse studies have indicated that the antitumour effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) are dramatically potentiated in combination with other drugs, and it has been proposed that optimization of the therapeutic potential of DMXAA would exploit combination therapy. The aim was to identify the most appropriate animal model for fu...

The activity, expression and localization of the UDP-glucuronosyltransferases (UGTs) were investigated in human placenta at term. UGT activity (measured with the substrate 4-methylumbelliferone (4-MU)) was observed in all 25 placentas sampled and maximum velocity (V(max)) ranged 13-fold from 5.1+/-0.9 to 66.9+/-17.5 nmol/min/mg protein (mean+/-SD)....

There is increased interest in the treatment of cancer with thalidomide because of its antiangiogenic, immunomodulating and sedative effects. In animal models, the antitumour activity of thalidomide is dependent on the species, route of administration and coadministration of other drugs. For example, thalidomide has shown antitumour effects as a si...

Marked gender differences in the pharmacokinetics of many drugs have been reported. For the investigational anticancer drug, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), negligible gender differences in the plasma pharmacokinetics have been observed in mice. The gender effects on the plasma pharmacokinetics of DMXAA were further investigated using...

To investigate the effects of various anticancer drugs on the major metabolic pathways (glucuronidation and 6-methylhydroxylation) of DMXAA in human liver microsomes. The effects of various anticancer drugs at 100 and 500 microM on the formation of DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA) in...

The reversed-phase HPLC methods were developed to determinate the covalently bound protein adducts of the novel anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) via its glucuronides after releasing aglycone by alkaline hydrolysis in human plasma and human serum albumin (HSA). An aliquot of 75 microl of the mixture was injected onto a S...

The novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a highly protein bound drug with narrow therapeutic window. We report a simple HPLC method with fluorimetric detection for the determination of free DMXAA concentration in human plasma. Sample preparation involves the ultrafiltration of plasma by a Centrisart device for 30...

1. The novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is extensively metabolized by glucuronidation and 6-methylhydroxylation, resulting in DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA). 2. The major human urinary metabolite of DMXAA was isolated and purified by a solid-phase...

Purpose: Coadministration of thalidomide, cyproheptadine or diclofenac has been shown to increase the area under the plasma concentration-time curve (AUC) of the novel antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice. The aim of this study was to further investigate these pharmacokinetic DMXAA-drug interactions in the rat mode...

The plasma protein binding and distribution in blood cells of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) has been investigated in-vitro using filtration and an HPLC method to measure DMXAA. DMXAA (500 microM) was extensively bound in plasma from all species with an unbound fraction (fu) of 4.61+/-1.10 (mouse), 2.59+/-0...

Background: Previous studies have demonstrated that coadministration of L-thalidomide with the novel antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) results in an increased area under the plasma concentration-time curve (AUC) of DMXAA, suggesting an explanation for the observed increase in the antitumour activity. The aims of this st...

2-Amino-3-methyl-imidazo[4,5-f]quinoline (IQ) is a mutagen produced in cooked food. It is commonly present in the human diet and often used as a (pro)carcinogen for chemoprevention studies. Many foodstuffs act as chemopreventers by altering xenobiotic metabolising enzyme expression in favour of detoxication over bioactivation pathways. However, IQ...

In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) isoenzyme involved in the 6-methylhydroxylation of 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) by using a human liver library (n = 14). The metabolite 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA) was determined by HPLC with fluorescence detection. The me...

Diets containing wheat bran (WB) protect against cancers of the colon or breast in rats, and may be beneficial in humans. In a previous study of rats treated with the carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), inclusion of 10% wheat bran in the diet led to an apparent reduction in IQ metabolites but not of intact IQ in plasma. In the...

The fluorescent compound 4-methylumbelliferone (4MU) can be used to detect uridine diphosphate glucuronosyl transferase activity by observing the fall in fluorescence as the compound is converted to 4-methylumbelliferone glucuronide. A microplate assay has been developed that has improved sensitivity and is faster and cheaper than the historical ex...

High-performance liquid chromatographic methods have been developed and validated for the glucuronidated and oxidative metabolites of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA), produced in human liver microsomal incubations. Calibration curves for DMXAA acyl glucuronide (DMXAA-Glu) and 6-hydroxymethyl-5-methylxantheno...

The use of the antimalarial agent amodiaquine has been curtailed due to drug-induced idiosyncratic reactions. These have been attributed to the formation of a protein-reactive quinoneimine species via oxidation of the 4-aminophenol group. Therefore, the effects of chemical modifications on the disposition of amodiaquine in relation to its metabolis...

The effect of 2,2'-substitution with fluorine, methyl or trifluoromethyl groups on the toxicity, metabolism and pharmacological activity of dapsone has been investigated in vitro and in vivo. There was marked inter-species variation in the bioactivation (N-hydroxylation) of the compounds, as determined by methemoglobin formation. However, the inclu...

The metabolism and toxicity of dapsone was compared in vitro and in vivo in rat, mouse and man. Metabolism was assessed by high-pressure liquid chromatography-mass spectrometry and methemoglobin formation has been used as a toxic endpoint. The greatest toxicity in vitro was seen in microsomes prepared from male Wistar rats (36.6 +/- 1.5% methemoglo...

The structural basis of dapsone (4,4'-diaminodiphenyl sulphone) haemotoxicity has been determined by investigation of the in vitro bioactivation of a series of 4-substituted arylamines. In the presence of rat liver microsomes, dapsone (100 microM) was the most potent former of methaemoglobin in human erythrocytes (44.8 +/- 6.7%). Substitution of th...

The purpose of this study was to investigate the use of human and animal subcellular liver fractions in an in vitro evaluation of carcinogenic risk. The bioactivation and bioinactivation of the known genotoxic carcinogen aflatoxin B1 by human, mouse and rat liver preparations was investigated using the SCE assay in human lymphocytes as a genotoxic...

To determine whether HIV-infected patients have a deficiency of intracellular glutathione (GSH) in peripheral blood mononuclear cells (PBMC) and erythrocytes. Initial experiments determining the stability of intracellular GSH preceded the measurement of GSH levels in 33 HIV-positive patients and 40 control subjects within 1 h of isolation of their...

1. The adverse reactions associated with the administration of dapsone are believed to be caused by metabolism to its hydroxylamine. Previous reports suggest that CYP3A4 is responsible for this biotransformation [1]. 2. Data presented in this paper illustrate the involvement of more than one cytochrome P450 enzyme in dapsone hydroxylamine formation...

Amodiaquine, a 4-aminoquinoline antimalarial, has been associated with hepatitis and agranulocytosis in humans. Drug hypersensitivity reactions, especially agranulocytosis, have been attributed to reactive intermediates generated by the oxidants discharged from stimulated polymorphonuclear leucocytes (PMN). The metabolism of amodiaquine to both sta...

5-Fluoro-6-methoxy-8-nitroquinoline was synthesised by a modified Skraup Reaction and was subsequently converted into 5-fluoroprimaquine in three steps. 5-Fluoroprimaquine 9 is less susceptible to in vitro bioactivation than primaquine 1 in a range of different species. However, significant bioactivation of 9 was observed with hepatic microsomes fr...

1 The ability of model stable epoxides and metabolites generated by human liver microsomes from benzo[a]pyrene, aflatoxin B 1 , naphthalene and tamoxifen to produce cytotoxicity and genotoxicity in human periph eral lymphocytes has been investigated. 2 The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100μM) and trans stilbene oxide (100μM) as...

We have previously shown that cimetidine, given concurrently for 2 weeks to patients on chronic dapsone therapy, reduced methaemoglobinaemia by inhibiting the formation of the toxic hydro-xylamine metabolite of dapsone. The aim of the present study was to examine the effect of this combination on the benefit/toxic ratio of dapsone over a longer per...

Adverse drug reactions that cannot be predicted from the pharmacological properties of the drug and which are not easily reproduced in laboratory animals are a major complication of drug therapy. It is necessary to investigate the mechanisms of such reactions in order to (1) define structural features within a given drug molecule which are responsi...