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Carbocysteine: Clinical experience and new perspectives in the treatment of chronic inflammatory diseases
Expert Opinion on Pharmacotherapy
Abstract
Carbocysteine is a muco-active drug with free radical scavenging and anti-inflammatory properties. It is actually approved for clinical use as adjunctive therapy of respiratory tract disorders characterized by excessive, viscous mucus, including chronic obstructive airways disease (COPD).
The intriguing antioxidant and anti-inflammatory properties of carbocysteine, beyond its known mucolytic activity, are described to explain its therapeutic efficacy and suggest new clinical uses.
After reviewing physiology and preclinical studies, human studies on the use of carbocysteine in chronic inflammatory diseases, i.e., COPD and cancer cachexia, are reviewed.
Carbocysteine has been recently recognized as an effective and safe treatment for the long-term management of COPD, able to reduce the incidence of exacerbations and improve patient quality of life. Moreover, carbocysteine was effective in counteracting some symptoms associated with cancer cachexia. Preclinical and clinical studies have demonstrated that the antioxidant and anti-inflammatory properties of carbocysteine are more important than mucolysis itself for its therapeutic efficacy. Therefore, carbocysteine may be able to reverse the oxidative stress associated with several chronic inflammatory diseases, such as cardiovascular diseases and neurodegenerative disorders. Controlled, randomized studies in humans are warranted.
... Про-демонстрировано, что терапия карбоцистеином, которая продолжалась на протяжении шести месяцев, привела к значительному снижению 8-изопростана и провоспалительных цитокинов (интерлейкин (IL)-8 и IL-6) в выдыхаемом воздухе у больных с ХОБЛ [21,36]. Доклинические и клинические исследования продемонстрировали, что терапевтическую эффективность пролонгированной терапии карбоцистеином в большей степени определяет его антиоксидантное и противовоспалительное действие, чем муколитическая активность [8]. ...
... Исследования терапевтической эффективности карбоцистеина показали, что его пролонгированное применение у больных с ХОБЛ является целесообразным, позволяющим снизить частоту обострений заболевания [8,14,29]. ...
... Эрдостеин (2-[(2-оксотиолан-3-ил)карбамоилметилсульфанил]уксусная кислота) является лекарственным средством с выраженным антиоксидантным и противовоспалительным действием [8,16]. Согласно данным метаанализа, эрдостеин по своей терапевтической эффективности превосходит другие муколитические средства [9]. ...
В огляді літератури наведено сучасні дані щодо групи антиоксидантних лікарських засобів — сполук, що містять тіол. Показано їх дію на окислювально-відновний статус організму при захворюваннях органів дихання.
... Indeed, the tide appears to be turning for SCMC (Hooper and Calvert, 2008;Ishibashi et al., 2010;Maccio et al., 2009). A recent review effused, "Carbocysteine has been recently recognised as an effective and safe treatment for the long-term management of COPD [chronic obstructive pulmonary disease], able to reduce the incidence of exacerbations and improve patient quality of life. ...
... A recent review effused, "Carbocysteine has been recently recognised as an effective and safe treatment for the long-term management of COPD [chronic obstructive pulmonary disease], able to reduce the incidence of exacerbations and improve patient quality of life. … […] …studies have demonstrated that the antioxidant and anti-inflammatory properties of carbocysteine are more important than mucolysis itself for its therapeutic efficacy" (Maccio et al., 2009). Without doubt, these attributed antioxidant and -inflammatory activities are properties that SCMC has always possessed since its first interaction with human physiology, although they have been recognized and documented only recently. ...
... However, for the efficacy of SCMC, this may be crucial. It is now appreciated that some patients do respond very well to SCMC treatment, whereas others show little or no benefit (Maccio et al., 2009;Yasuda et al., 2006b). Advice given in medical texts reflects this situation: "In some patients with chronic obstructive pulmonary disease and a chronic productive cough, mucolytics can reduce exacerbations; mucolytic therapy should be stopped if there is no benefit after a 4-week trial" (BNF, 2007). ...
S-carboxymethyl-L-cysteine, the side-chain carboxymethyl derivative of the sulfur-containing amino acid, cysteine, has been known and available for almost 80 years. During this time, it has been put to a variety of uses, but it is within the field of respiratory medicine that, presently, it has found a clinical niche. Early studies indicated that this compound underwent a rather simplistic, predictable pattern of metabolism, whereas later investigations alluded to more subtle interactions with the pathways of intermediary metabolism, as may be expected for an amino acid derivative. In addition, suggestions of polymorphic influences and circadian rhythms within metabolic profiles have emerged. These latter factors may underlie the conflicting reports regarding the therapeutic efficacy of this compound: that it appears to work well in some patients, but has no measurable effects in others. The relevant literature pertaining to the fate of this compound within living systems has been reviewed and a comprehensive précis advanced. Hopefully, this article will serve as a vade mecum for those interested in S-carboxymethyl-L-cysteine and as a catalyst for future research.
... Carbocysteine can also markedly decrease the adherence of Streptococcus pneumoniae to pharyngeal epithelial cells [47]. In COPD patients, carbocysteine can decrease the occurrence of common colds and related exacerbations, a characteristic that can contribute to its capacity to reduce the expression of intercellular adhesion molecule 1 in the respiratory tract [191]. The effect of treatment with carbocysteine (250 mg, 3 times a day) has been assessed for 3 years in 709 Chinese COPD patients. ...
... Carbocysteine can also markedly decrease the adherence of Streptococcus moniae to pharyngeal epithelial cells [47]. In COPD patients, carbocysteine can de the occurrence of common colds and related exacerbations, a characteristic that can tribute to its capacity to reduce the expression of intercellular adhesion molecule 1 respiratory tract [191]. The effect of treatment with carbocysteine (250 mg, 3 times a has been assessed for 3 years in 709 Chinese COPD patients. ...
Chronic obstructive pulmonary disease (COPD) is an increasing and major global health problem. COPD is also the third leading cause of death worldwide. Oxidative stress (OS) takes place when various reactive species and free radicals swamp the availability of antioxidants. Reactive nitrogen species, reactive oxygen species (ROS), and their counterpart antioxidants are important for host defense and physiological signaling pathways, and the development and progression of inflammation. During the disturbance of their normal steady states, imbalances between antioxidants and oxidants might induce pathological mechanisms that can further result in many non-respiratory and respiratory diseases including COPD. ROS might be either endogenously produced in response to various infectious pathogens including fungi, viruses, or bacteria, or exogenously generated from several inhaled particulate or gaseous agents including some occupational dust, cigarette smoke (CS), and air pollutants. Therefore, targeting systemic and local OS with therapeutic agents such as small molecules that can increase endogenous antioxidants or regulate the redox/antioxidants system can be an effective approach in treating COPD. Various thiol-based antioxidants including fudosteine, erdosteine, carbocysteine, and N-acetyl-L-cysteine have the capacity to increase thiol content in the lungs. Many synthetic molecules including inhibitors/blockers of protein carbonylation and lipid peroxidation, catalytic antioxidants including superoxide dismutase mimetics, and spin trapping agents can effectively modulate CS-induced OS and its resulting cellular alterations. Several clinical and pre-clinical studies have demonstrated that these antioxidants have the capacity to decrease OS and affect the expressions of several pro-inflammatory genes and genes that are involved with redox and glutathione biosynthesis. In this article, we have summarized the role of OS in COPD pathogenesis. Furthermore, we have particularly focused on the therapeutic potential of numerous chemicals, particularly antioxidants in the treatment of COPD.
... According to the current findings, CRBST has exceptional free radical scavenging activities and can counteract the decrease in antioxidant enzyme activity. In accordance with the present results, previous in vitro, in vivo and clinical research have shown that CRBST can act as an antioxidant by decreasing oxidative stress and boosting antioxidative enzymes, independent of recognized mucolytic activity (Macciò et al., 2009;Nogawa et al., 2009;Choudhury and Macnee, 2017;Catanesi et al., 2021). ...
... The link between oxidative stress and inflammatory reactions in UC has received a lot of attention (Tian et al., 2017). Previous preclinical and clinical research have shown that CRBST has powerful antioxidant and antiinflammatory properties in several organs and disease models (Macciò et al., 2009). These studies, together with our findings, show that CRBST helps to modulate the interaction between oxidative stress and inflammation. ...
Ulcerative colitis (UC), an inflammatory bowel disease, is a chronic condition of a multifaceted pathophysiology. The incidence of UC is increasing internationally. The current therapies for UC lack relative effectiveness and are associated with adverse effects. Therefore, novel therapeutic options should be developed. It has been well documented that modulating the Nrf2/NFκB is a promising therapeutic target in inflammation. Carbocisteine is a mucoregulatory medication and its efficacy in COPD was found to be more closely related to its antioxidant and anti-inflammatory properties. Carbocisteine has not yet been examined for the management of UC. Hence, our approach was to investigate the potential coloprotective role of carbocisteine in acetic acid-induced colitis in rats. Our results revealed that carbocisteine improved colon histology and macroscopic features and subdued the disease activity as well. Additionally, carbocisteine attenuated colon shortening and augmented colon antioxidant defense mechanisms via upregulating catalase and HO-1 enzymes. The myeloperoxidase activity was suppressed indicating inhibition of the neutrophil infiltration and activation. Consistent with these findings, carbocisteine boosted Nrf2 expression along with NFκB inactivation. Consequently, carbocisteine downregulated the proinflammatory cytokines IL-6 and TNF-α and upregulated the anti-inflammatory cytokine IL-10. Concomitant to these protective roles, carbocisteine displayed anti-apoptotic properties as revealed by the reduction in the Bax: BCL-2 ratio. In conclusion, carbocisteine inhibited oxidative stress, inflammatory response, and apoptosis in acetic acid-induced UC by modulating the Nrf2/HO-1 and NFκB interplay in rats. Therefore, the current study provides a potential basis for repurposing a safe and a commonly used mucoregulator for the treatment of UC.
... Though COPD is not curable, a number of therapies, including treatment of exacerbations with mucolytic antioxidant agents, were offered to attenuate damaging effects of the chronic inflammation in lungs of COPD patients. S-Carboxymethyl-L-cysteine (CMC, carbocisteine) is an antioxidant and a mucolytic commonly prescribed to patients with COPD [3]. Although CMC has a long history of a clinical drug use, CMC metabolism has been a subject of debate for a number of years [4]. ...
... Although CMC is considered a mucolytic, this molecule lacks free thiol groups that are needed to break the S-S bonds in mucus proteins that stabilize the matrix. Rather, CMC is believed to relieve inflammation and decrease mucus secretion in the lower airways [3]. Our study compared the ability of CMC and CMCO to affect cell signaling pathways, which are sensitive to oxidative stress and pro-inflammatory stimuli, in human bronchial epithelial and alveolar cells. ...
S-Carboxymethyl-L-cysteine (CMC) is an antioxidant and mucolytic commonly prescribed to patients with chronic obstructive pulmonary disease. In humans, CMC is rapidly metabolized to S-carboxymethyl-L-cysteine sulfoxide (CMCO). In this study, we assessed structural and functional similarities between CMC and CMCO. X-Ray diffraction analysis provided detailed structural information about CMCO, which exists as a 1:1 mixture of epimers, due to the emergence of a new chiral center at the sulfur atom. Both CMC and CMCO epimers protected model DNA from copper-mediated hydroxyl free radical damage. Using an insulated transposable construct for reporting activity of the cellular stress-responsive transcription factors Nrf2, p53, NF-κB, and AP-1, we demonstrate that CMCO, especially its (4R)-epimer, is comparable to CMC in their ability to mitigate the effects of oxidative stress and pro-inflammatory stimuli in human alveolar (A549) and bronchial epithelial (BEAS-2B) cells. The results of these in vitro studies suggest that CMCO retains, at least partially, the antioxidant potential of CMC and may inform pharmacodynamics considerations of CMC use in clinics.
... 6 Both CMC and β-CEC are thioether-containing amino acids and, similarly to methionine, possess the antioxidant capacity that could be employed in clinics. 7 Recently, 8,9 we have demonstrated that CMC and β-CEC can protect DNA from oxidative degradation, protect airway and kidney cells from cytotoxic platinum drugs or copper oxide nanoparticles, mitigate pro-inflammatory signaling in the cells. In continuation of our studies on antioxidant amino acids, [8][9][10] we have synthesized CBC and report here its molecular and crystal structure. ...
C8H15NO4S, orthorhombic, P212121 (no. 19), a = 5.0215 (3) Å, b = 7.0392 (5) Å, c = 28.0593 (19) Å, V = 991.82 (11) ų, Z = 4, R gt(F) = 0.0462, wR ref(F ²) = 0.0899, T = 100 K.
... Actually, adding SCMC to inhaled corticosteroids (ICS) in asthmatic patients can effectively ameliorate the clinical manifestations, such as cough and shortness of breath in asthmatic patients, and the improvement of PEF in patients after the addition of SCMC is more obvious when compared with the application of ICS alone, indicating that SCMC can effectively increase the effect of ICS and play a role in enhancing the lung function of asthmatic patients [18]. Moreover, SCMC is effective in scavenging hypochlorous acid and hydroxyl radicals, thus reducing the release of inflammatory factors (e.g., IL8) and exerting anti-inflammatory effects [19,20]. Besides, it also reduced the release of inflammatory factors such as TGF and VEGF in COPD mice [21]. ...
Background:
The alleviating effects of carbocisteine (S-carboxymethylcysteine, SCMC) have been implicated in chronic obstructive pulmonary disease; however, very little is known about its mechanisms in asthma. In this study, we aimed to investigate the effects of SCMC on airway remodeling in asthmatic mice induced by ovalbumin (OVA).
Methods:
The asthma mouse model was generated by OVA sensitization and stimulation and subsequently intervened by SCMC or dexamethasone. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected from each group of mice. The TGF-β1 levels in BALF were measured by ELISA. Masson's staining was used to detect collagen fiber deposition in mouse airway tissues, while immunohistochemistry and RT-qPCR were conducted to examine the protein and mRNA expression of TGF-β1 in mouse lung airway tissues, respectively. The correlation between TGF-β1 mRNA expression and the area of collagen fiber deposition in airway tissues was analyzed by Pearson's correlation coefficient.
Results:
The area of collagen fiber deposition in the airway tissues of asthmatic mice was significantly increased, while SCMC alleviated the collagen fiber deposition in the airway tissues. TGF-β1 expression was significantly elevated in BALF and airway tissues of asthmatic mice, while SCMC inhibited TGF-β1 expression. TGF-β1 expression was significantly and positively correlated with collagen fiber deposition in mouse airway tissues.
Conclusions:
SCMC intervention improves collagen fiber deposition in airway tissues and inhibits TGF-β1 expression in asthmatic mice.
... In addition, β-CEC structure is a homolog of S-carboxymethyl-L-cysteine (carbocisteine, CMC), a clinically approved drug prescribed to patients with chronic obstructive pulmonary disease. The therapeutic activity of CMC is believed to rely on its mucolytic and antioxidant mechanisms in the airways [14,15]. The protective potential of S-carboxymethyl-L-cysteine sulfoxide against oxidative stress agents in airway epithelial cells has been evaluated, as well [16]. ...
Insecticidal non-proteinogenic amino acid S-(2-carboxyethyl)-L-cysteine (β-CEC) and its assumed metabolite, S-(2-carboxyethyl)-l-cysteine sulfoxide (β-CECO), are present abundantly in a number of plants of the legume family. In humans, these amino acids may occur as a result of exposure to environmental acrylonitrile or acrylamide, and due to consumption of the legumes. The β-CEC molecule is a homolog of S-carboxymethyl-l-cysteine (carbocisteine, CMC), a clinically employed antioxidant and mucolytic drug. We report here detailed structural data for β-CEC and β-CECO, as well as results of in vitro studies evaluating cytotoxicity and the protective potential of the amino acids in renal tubular epithelial cells (RTECs) equipped with reporters for activity of seven stress-responsive transcription factors. In RTECs, β-CEC and the sulfoxide were not acutely cytotoxic, but activated the antioxidant Nrf2 pathway. β-CEC, but not the sulfoxide, induced the amino acid stress signaling, which could be moderated by cysteine, methionine, histidine, and tryptophan. β-CEC enhanced the cytotoxic effects of arsenic, cadmium, lead, and mercury, but inhibited the cytotoxic stress induced by cisplatin, oxaliplatin, and CuO nanoparticles and acted as an antioxidant in a copper-dependent oxidative DNA degradation assay. In these experiments, the structure and activities of β-CEC closely resembled those of CMC. Our data suggest that β-CEC may act as a mild activator of the cytoprotective pathways and as a protector from platinum drugs and environmental copper cytotoxicity.
... Carbocysteine (®-2-amino-3-(carboxymethylsulfanyl))propanoic acid) (41) ( Table 2) is a mucolytic agent with significant antioxidant and anti-inflammatory activities [217]. Pace et al. reported that carbocysteine reduces the production of ROS, increases HO-1, GSH, Nrf2, and HDAC-2 nuclear expression and activity in cigarette smoke extractstimulated cells [218]. ...
Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling has become a key pathway for cellular regulation against oxidative stress and inflammation, and therefore an attractive therapeutic target. Several organosulfur compounds are reportedly activators of the Nrf2 pathway. Organosulfur compounds constitute an important class of therapeutic agents in medicinal chemistry due to their ability to participate in biosynthesis, metabolism, cellular functions, and protection of cells from oxidative damage. Sulfur has distinctive chemical properties such as a large number of oxidation states and versatility of reactions that promote fundamental biological reactions and redox biochemistry. The presence of sulfur is responsible for the peculiar features of organosulfur compounds which have been utilized against oxidative stress-mediated diseases. Nrf2 activation being a key therapeutic strategy for oxidative stress is closely tied to sulfur-based chemistry since the ability of compounds to react with sulfhydryl (-SH) groups is a common property of Nrf2 inducers. Although some individual organosulfur compounds have been reported as Nrf2 activators, there are no papers with a collective analysis of these Nrf2-activating organosulfur compounds which may help to broaden the knowledge of their therapeutic potentials and motivate further research. In line with this fact, for the first time, this review article provides collective and comprehensive information on Nrf2-activating organosulfur compounds and their therapeutic effects against oxidative stress, thereby enriching the chemical and pharmacological diversity of Nrf2 activators.
... It is used to relieve the symptoms in people suffering from bronchiectasis and chronic obstructive pulmonary disorder (COPD) by allowing the easy expulsion of mucus [3]. In addition to its mucoregulatory activity, carbocisteine also shows anti-oxidative and antiinflammatory properties [4,5]. Its side effects include skin rashes, headache, dizziness, gastrointestinal bleeding, although it rarely shows any severe adverse effect [6]. ...
A fast, reproducible, and sensitive method is proposed for the kinetic determination of carbocisteine (CCys). The method depends on the inhibitory property of carbocisteine, which reduces the Hg²⁺ catalyzed substitution rate of cyanide from [Ru(CN)6]⁴⁻ with N-R-salt (1-Nitroso-2-naphthol-3,6-disulfonic acid disodium salt) via forming a stable complex with Hg²⁺. Spectrophotometric measurements were carried out by recording the absorbance at 525 nm (λmax of [Ru(CN)5 Nitroso-R-Salt]³⁻ complex) at a fixed time of 10 and 15 min under the optimized reaction conditions with [N-R-salt] = 4.5 × 10⁻⁴ M, I = 0.05 M (KNO3), Temp = 45.0 ± 0.2o C, pH = 7.0 ± 0.03, [Hg²⁺] = 8.0 × 10⁻⁵ M and [Ru(CN)6 4- ] = 4.25 × 10⁻⁵ M. With the proposed method, CCys can be determined quantitatively down to 3.0 × 10⁻⁶ M. This methodology can be effectively used for the rapid quantitative estimation of CCys in the pharmaceutical samples with good accuracy and reproducibility. The addition of common excipients in pharmaceuticals even up to 1000 times with [CCys] does not interfere significantly in the estimation of CCys.
... As endothelial dysfunction is an important hallmark of COPD, carbocysteine administration has been shown to exert protective effects by reducing inflammationassociated endothelial dysfunction (Macciò et al., 2009;Biswas et al., 2013). Oral administration of carbocysteine has also been reported to inhibit VEGF-induced angiogenesis and tumor growth in mice. ...
The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1β monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.
... Of relevance, Wu et al. [7] has reported the treatment of patients with severe COVID-19 with antioxidants like glutathione and N-acetyl cysteine. In this regard, we would like to mention our previous review on the role of carbocysteine, which focused primarily on the antiinflammatory properties of such an irreplaceable antioxidant agent [125]. ...
Improving early diagnosis along with timely and effective treatment of COVID-19 are urgently needed. However, at present, the mechanisms underlying disease spread and development, defined prognosis, and immune status of patients with COVID-19 remain to be determined. Patients with severe disease state exhibit a hyperinflammatory response associated with cytokine storm syndrome, hypercoagulability, and depressed cell-mediated immunity. These clinical manifestations, sharing similar pathogenesis, have been well-studied in patients with advanced ovarian cancer. The present review suggests treatment approaches for COVID-19 based on strategies used against ovarian cancer, which shares similar immunopathology and associated coagulation disorders.
The chronicization of the hyperinflammatory cytokine storm in patients with severe COVID-19 highlights a defective resistance phase that leads to aspecific chronic inflammation, associated with oxidative stress, which impairs specific T-cell response, induces tissue and endothelial damage, and thrombosis associated with systemic effects that lead to severe multi-organ failure and death. These events are similar to those observed in advanced ovarian cancer which share similar pathogenesis mediated primarily by Interleukin-6, which is, as well demonstrated in ovarian cancer, the key cytokine driving the immunopathology, related systemic symptoms, and patient prognosis.
Consistent with findings in other disease models with similar immunopathology, such as advanced ovarian cancer, treatment of severe COVID-19 infection should target inflammation, oxidative stress, coagulation disorders, and immunodepression to improve patient outcome. Correctly identifying disease stages, based on available laboratory data, and developing a specific protocol for each phase is essential for effective treatment.
... Chronic bronchitis patients treated with S-CMC lysine exhibited enhanced mucociliary transport and reduced mucus viscosity. 27,28 Carbocysteine has been shown to reduce human neutrophil elastase (HNE)induced mucus hypersecretion and decrease the level of ROS in NCI-H292 cell line. 29 A study revealed that carbocysteine promoted cell survival and inhibited the cell damage/apoptosis caused by H 2 O 2 by activating PI3K-AKT pathway. ...
Chronic obstructive pulmonary disease (COPD) is the most prevalent obstructive lung disease worldwide characterized by decline in lung function. It is associated with airway obstruction, oxidative stress, chronic inflammation, mucus hypersecretion, and enhanced autophagy and cellular senescence. Cigarette smoke being the major risk factor, other secondary risk factors such as the exposure to air pollutants, occupational exposure to gases and fumes in developing countries, also contribute to the pathogenesis of COPD. Conventional therapeutic strategies of COPD are based on anti-oxidant and anti-inflammatory drugs. However, traditional anti-oxidant pharmacological therapies are commonly used to alleviate the impact of COPD as they have many associated repercussions such as low diffusion rate and inappropriate drug pharmacokinetics. Recent advances in nanotechnology and stem cell research have shed new light on the current treatment of chronic airway disease. This review is focused on some of the anti-oxidant therapies currently used in the treatment and management of COPD with more emphasis on the recent advances in nanotechnology-based therapeutics including stem cell and gene therapy approaches for the treatment of chronic airway disease such as COPD and asthma.
... This variation in S-carboxymethyl-L-cysteine sulfoxidation capacity and the ability to remove differing proportions of the active dose after administration undoubtedly leads to the observations that some patients respond well to treatment whereas others show little or no improvement (Macci o et al., 2009;Yasuda et al., 2006). Indeed, general recommendations for the use of this drug state, "In some patients with chronic obstructive pulmonary disease and a chronic productive cough, mucolytics can reduce exacerbations; mucolytic therapy should be stopped if there is no benefit after a 4-week trial" (BNF, 2007). ...
1). Consistent differences in the proportion of an orally administered dose of S-carboxymethyl-L-cysteine subsequently excreted in the urine as S-oxide metabolites were reported 40 years ago. This observation suggested the existence of inter-individual variation in the ability to undertake the enzymatic S-oxygenation of this compound. Pedigree studies and investigations employing twin pairs indicated a genetically-controlled phenomenon overlaid with environmental influences. It was reproducible and not related to gender or age.
2). Studies undertaken in several healthy volunteer cohorts always provided similar results that were not significantly different when statistically analysed. However, when compared to these healthy populations, a preponderance of subjects exhibiting the characteristic of poor sulfoxidation of S-carboxymethyl-L-cysteine was found within groups of patients suffering from various disease conditions. The most striking of these associations were witnessed amongst subjects diagnosed with neurodegenerative disorders, although underlying mechanisms were unknown.
3). Exhaustive investigation has identified the enzyme responsible for this S-oxygenation reaction as the tetrahydrobiopterin-dependent aromatic amino acid hydroxylase, phenylalanine 4-monooxygenase classically assigned the sole function of converting phenylalanine to tyrosine. The underlying principle is discussed that enzymes traditionally associated solely with intermediary metabolism may have as yet unrecognised alternative roles in protecting the organism from potential toxic assault.
... Помимо NF-kB изучается влияние ацетилцистеина и на другие провоспалительные пути, такие как p38, ERK1/2, SAPK/JNK, c-Jun и c-Fos [42,43]. Карбоцистеин и амброксол, возможно, также обладают антиоксидантными свойствами [36,37], однако эти свойства пока мало изучены. ...
... Oxidative stress plays an important role in several elements of the lung physiology and the development of COPD, such as oxidative inactivation of antiproteases and surfactants, mucus hypersecretion, membrane lipid peroxidation, alveolar epithelial injury, and remodeling of extracellular matrix. Therefore, targeting oxidative stress with antioxidants may be effective in the treatment of stable COPD [15][16][17][18][19][20][21]. ...
BACKGROUND: The recent epidemiological and experimental evidence suggest possible antioxidant effect of carbocysteine in patients with chronic obstructive pulmonary disease (COPD).AIM: To assess efficacy and tolerability of carbocysteine in the management of stable COPD.METHODS: We performed an observational, non-randomized, open study (a real life study) including 87 patients with stable COPD (group B and D by combined COPD assessment) divided in two groups, examined group (EG) and control group (CG). All participants were treated with the regular treatment of the stable disease, but in the participants of the EG carbocysteine 1,500 mg daily was added to their regular treatment during the period of two months. The study protocol included completion of the COPD Assessment Test (CAT) and spirometric measurements at initial visit and at the end of the mentioned period.RESULTS: We found significantly lower mean value of the overall CAT score in the EG at the end of the study as compared to its mean value registered at initial visit (26.9 vs. 24.3; P = 0.007). In regard to certain CAT items, we found significantly lower values of the mean scores related to cough phlegm and sleep disturbances as compared to their mean scores at initial visit. In addition, the mean values of the overall CAT scores at initial visit and at the end of the study in controls were similar. In EG we found significantly higher mean value of the MEF 25-75 at the end of the study as compared to its mean value registered at initial visit (59.3% vs. 67.2%; P = 0.003). There was no significant difference in the mean values of other spirometric parameters at the end of the study as compared to their mean values at initial visit. In controls we registered similar values of all measured spirometric parameters at the end of the study as compared to their values registered at initial visit. Mild gastrointestinal manifestations were registered in 13.3% of the participants of the EG during the examined period.CONCLUSION: Our findings indicate positive effects of carbocysteine regarding the symptoms and lung function, as well as its good tolerability in the patients with stable COPD.
... Карбоцистеина лизиновая соль (Флуифорт) хорошо водорастворима, что обеспечивает быстрое и полное всасывание, а также способствует нейтрализации кислотности (с pH3,0 до pH6,8), что существенно снижает риск побочных эффектов со стороны желудочно-кишечного тракта. Помимо этого, карбоцистеина лизиновая соль характеризуется быстрым фармакодинамическим действием, в короткие сроки приводит к нормализации количества, состава и реологических свойств секрета, способствует положительным сдвигам функциональных параметров, улучшает общее состояние больного [12,16,17]. Быстрота воздействия позволяет использовать этот мукорегулятор при острых формах воспалительных заболеваний респираторного тракта для максимального ограничения или предотвращения гиперсекреторных нарушений. ...
The paper gives information on current mucoactive therapy with carbocysteine for acute and chronic bronchopulmonary diseases. The author’s observations during a multicenter study and the data available in the literature provide evidence that carbocysteine lysine salt (Fluifort) shows high clinical and immunological efficacies as a mucoregulatory and mucolytic agent used in children aged 2 to 17 years with acute and chronic bronchopulmonary diseases. The highest efficacy of carbocysteine lysine salt has been found in schoolchildren, which is attributable to the age-related features of the formation of the bronchial secretory apparatus and local immune system, as well as in the children with protracted and chronic inflammatory processes, including those associated with smoking.
... It can significantly inhibit IL-8 production from peripheral neutrophils. 33 It also inhibits conversion of xanthine dehydrogenase to xanthine oxidase to exert antiinflammatory effects. 34,35 Anti-infective activity Carbocysteine reduces bacterial colonization by decreasing the expression of adhesion molecule-1, especially for Streptococcus pneumoniae. ...
Airway mucus hypersecretion is a frequent symptom associated with acute and chronic airway disease. Inhibition of mucus production or promotion of mucolysis not only relieved symptoms but also improved disease outcomes. There are numerous available mucoactive medicines for prescription, and how to select them properly for different diseases is important for clinical practice. So far, there is no one consensus or guideline reported. A group of Chinese pulmonary physicians worked together to complete this consensus based on literature review, summarized mechanism and usage of each classical mucoactive medicine. In general, antioxidant mucoactive medicines play an important role in chronic airway disease, including but not limited to airway mucus clearance, reduced acute exacerbation and improved pulmonary function.
... В нескольких рандомизированных клинических исследованиях длительная поддерживающая тера пия карбоцистеином привела к снижению числа обострений ХОБЛ и улучшению КЖ, связанного со здоровьем [136][137][138][139]. В исследовании PEACE изуче но влияние терапии карбоцистеином (в дозе 500 мг в сутки) в течение 3 лет на развитие обострений ХОБЛ (в основном III и IV стадий по GOLD). ...
Acute exacerbation is a typical event in the natural course of chronic obstructive pulmonary disease (COPD). Acute exacerbation of COPD (AECOPD) is one of the most frequent causes for seeking the emergency aid by patients. Frequent AECOPD could deteriorate lung function and gaz exchange, cause more rapid progression of the disease and significant worsening of the patient's quality of life for long time (up to several weeks). AECOPD is associated with severe economic burden. Current therapeutic approaches can greatly reduce the risk of AECOPD. Effect of the basic therapy on exacerbation rate are related to such factors as the exacerbation cause (infection, spontaneous deterioration of inflammation, bronchoconstriction, etc.), severity of the disease (usually, therapy can decrease the risk of exacerbation in more severe patients), COPD phenotype, etc. Results of clinical trials aimed at the reduction of exacerbation rate are also related to many of factors such as patients' population involved in the study, the previous rate of exacerbations, the study length, etc. Currently, no one therapeutic approach can completely eliminate the risk of exacerbations. The efficacy of different therapeutic methods in preventing AECOPD is 15% to 50%. Methods for preventing AECOPD can be divided to pharmacological and non-pharmacological ones. There is a need to search for target pharmacological approaches for preventing AECOPD including currently available drugs.
... The efficacy of bromhexine is as follows: 1) promoting serous secretion, 2) dissolving content of acid glycoprotein fibers, and 3) increasing the ciliary movement. In addition, it has been reported that expectorant agents have anti-inflammatory effects [17,18]. Therefore, a possible explanation for the efficacy of bromhexine in this case was that the activated ciliary movement and reduced inflammation facilitated removal of the dissolved mucoid impaction. ...
An 80-year-old Japanese woman with wet cough and dyspnea was diagnosed with pneumonia at a clinic. Antibiotics did not improve her symptoms; therefore, she was referred to our hospital one month after symptom onset. Chest radiograph findings revealed complete collapse of the left lung. Bronchoscopy showed white mucus plug in the left main bronchus, which could not be removed. She was initially treated with bromhexine. Subsequently, culture results of the mucus plug specimen obtained during bronchoscopy yielded Schizophyllum commune. After three weeks, improvement of the collapsed lung was observed on chest radiograph.
... Apart from eliminating or, at least, reducing the exposition to irritants, expectorants and mucolytic drugs decrease the viscosity of bronchial secretion thus facilitating its release. Acetylcysteine, for instance, is able to break disulfide bonds in mucoproteins, whereas other drugs, ambroxol or carbocysteine, can modulate the viscoelastic properties of the mucus [97,98]. Menthol increases the excitability threshold in peripheral reflexogenic areas, distending peripheral blood vessels and alleviating bronchoconstriction [99]. ...
Caffeine, theophylline and theobromine are the most known methylxanthines as they are present in coffee, tea and/or chocolate. In the last decades, a huge experimental effort has been devoted to get insight into the variety of actions that these compounds exert in humans. From such knowledge it is known that methylxanthines have a great potential in prevention, therapy and/or management of a variety of diseases. The benefits of methylxanthine-based therapies in the apnea of prematurity and their translational potential in pediatric affections of the respiratory tract are here presented.
... Установлено, что карбоцистеин ингибирует адгезию патогенных бактерий к эпителию дыхательных путей, что может способствовать снижению бактериального обсеменения респираторного тракта при хронических бронхолегочных заболеваниях [2,11]. ...
Inflammatory diseases of the respiratory tract are characterized by changes in rheological properties of the phlegm and lower of the mucociliary clearance. Adjustment of mucoregulatory agents is of a special significance in treatment of diseases of the lower respiratory tract in children. Aim: to assess efficacy of carbocysteine lysine salt monohydrate as a mucokinetic agent in children with respiratory tract diseases. Patients and methods: 65 children (31 girls and 34 boys) aged from 5 to 16 years old with acute respiratory tract diseases received treatment in Belgorod pediatric out-patient clinic № 4 were included into the study. The results of the clinical follow-up of these children are shown in the article. Results: carbocysteine lysine salt monohydrate was found to be effective and safe in treatment of acute and chronic inflammatory diseases of the respiratory tract in children. The authors observed quicker convalescence of the patients and possibility of combination of this drug with other medicines used in pediatric practice. Conclusions: the above-mentioned drug when used in combination with antibacterial agents intensifies penetration of the latter into the bronchial secretion and bronchial mucous membrane thereby increasing their efficacy. The drug does not have toxicity, is well-tolerated even when prolonged using and can be recommended for treatment of cough in children both under out- and in-patients conditions.Keywords: children, respiratory tract diseases, carbocysteine.
... This initial investigation has indicated that only a small proportion of an oral dose of SCMC had undergone Table 2. Pharmacokinetic data for SCMC and SCMC (R/S) sulfoxides in beagle plasma following a single oral dose (10 mg/kg) of S-carboxymethyl-Lcysteine. conversion to the inactive sulfoxide metabolites and that over the first eight hour period following intake the plasma concentration of the parent compound remained considerably higher than those of the major sulfoxide metabolites. Hence, following oral administration, sufficient SCMC should remain in the active sulfide form thereby serving as a free radical scavenging agent to assist in the potential treatment of COPD in this animal species, as it has done so effectively in man (Macció et al., 2009). ...
1. Incubation of beagle hepatic cytosol, under conditions promoting phenylalanine hydroxylase activity, led to the formation of the sulfoxide derivatives of S-carboxymethyl-l-cysteine, N-acetyl-S-carboxymethyl-l-cysteine, S-methyl-l-cysteine and N-acetyl-S-methyl-l-cysteine. Thiodiglycolic acid was not a substrate. Enzyme kinetic parameters (Km, Vmax) were derived indicating S-carboxymethyl-l-cysteine had the greatest clearance; no enantioselective preference was observed for this S-oxygenation reaction. 2. Following oral administration of S-carboxymethyl-l-cysteine to beagle dogs, the parent substance and its sulfoxide were the only compounds identified in the plasma. Pharmacokinetic data have been obtained indicating that the small amount of sulfoxide formed persisted within the body for longer than the parent material, but that the majority of the ingested dose remained in the administered sulfide form. 3. The sulfide moiety within the muco-regulatory drug, S-carboxymethyl-l-cysteine, is thought to be vital as it acts as a free radical scavenger, resulting in the inactive sulfoxide. Additional extensive enyzme-mediated sulfoxidation would decrease the amount of active sulfide available. In the dog this appears to not be an issue, signalling possible exploitation for therapeutic benefit in treating airway disease.
... However, they are potentially toxic and, therefore, the human body has a complex system of endogenous antioxidants to protect against the oxidative damage mediated by ROS. Endogenous antioxidants include both enzymes such as glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD), as well as nonenzymatic defenses, such as glutathione, histidine peptides, the iron-binding proteins transferrin and ferritin, lipoic acid, reduced Coenzyme Q10 (CoQ10), melatonin, urate, and plasma protein thiols [4]. Oxidative stress (OS) occurs when there is an imbalance between the production of pro-oxidant molecules and the antioxidant system in favor of the oxidants. ...
Cachexia influences morbidity, mortality and quality of life of cancer patients at advanced stage of disease. Therefore, the knowledge of its pathophysiology is critical to develop effective therapies to be integrated in the comprehensive approach of cancer patients. Oxidative stress, unless counteracted by effective antioxidant therapies, contributes to the development of anorexia and cachexia in cancer patients. In the present review the potential role of targeting oxidative stress in the treatment of cachexia is reported. Efficacy data on the use of antioxidants in advanced cancer patients are promising. However, the optimal dosage and route of administration as well as the timing and the most effective combination are not well established. Moreover, since cachexia is a multifactorial syndrome, targeting only oxidative stress as a contributing factor would be inadequate and likely to achieve a limited clinical therapeutic benefit. According to this rationale, antioxidants should be included as essential components of a multitargeted combined treatment of cancer cachexia, which has been shown to be the most successful approach for this syndrome.
... In addition to demonstrating beneficial effects in vitro, SCMC is also recognised to provide benefit to patients. SCMC has been shown to be an effective and safe drug for the treatment of COPD in randomised clinical trials, reducing the incidence of exacerbations and improving patient quality of life [35][36][37][38]. However, it should be noted for the PEACE study that subjects were Chinese (25% nonsmokers) who had limited access to other drugs that target exacerbations (e.g. ...
Mucus hypersecretion is a clinical feature of severe respiratory diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Airway mucosal infection and/or inflammation associated with these diseases often gives rise to inflammatory products, including neutrophil-derived DNA and filamentous actin, in addition to bacteria, apoptotic cells and cellular debris, that may collectively increase mucus production and viscosity. Mucoactive agents have been the medication of choice for the treatment of respiratory diseases in which mucus hypersecretion is a clinical complication. The main purpose of mucoactive drugs is to increase the ability to expectorate sputum and/or decrease mucus hypersecretion. Many mucoactive drugs are currently available and can be classified according to their putative mechanism of action. Mucoactive medications include expectorants, mucoregulators, mucolytics and mucokinetics. By developing our understanding of the specific effects of mucoactive agents, we may result in improved therapeutic use of these drugs. The present review provides a summary of the most clinically relevant mucoactive drugs in addition to their potential mechanism of action.
Aging is a natural process in which the structural integrity of an organism declines over time. The in vivo anti-aging activities in Caenorhabditis elegans (C. elegans) of 5 different in vitro edible fungal polysaccharides (EFPs) fermented by human feces were compared. The metabolites and microbial structure within the selected fermented polysaccharide solution were further analyzed using 16S rDNA sequencing and non-targeted metabolomics. The results showed that the fermented EFPs exhibited different anti-aging activities, and fermented Lanmaoa asiatica polysaccharides (FLAP) and Hohenbuehelia serotina polysaccharides (FHSP) were the best two. Beneficial bacteria (Romboutsia and Weissella) and metabolites with antioxidant, anti-inflammatory and immune-protective effects (ergothioneine, oleic acid and notoginsenoside R10) were positively correlated and enriched in FLAP and FHSP. These metabolites might have been generated by those bacteria and could be responsible for a significant anti-aging effect. Therefore, the anti-aging potency of the fermented EFPs correlates with metabolites during fermentation using human fecal intestinal microflora.
Практическое пособие посвящено вопросам ведения пациентов с кашлем. Представлены эпидемиология кашля, его клиническая классификация, анализ актуальных причин, перечень необходимых методов диагностики и направления фармакотерапии. Уделено внимание дифференциальной диагностике различных патологических состояний и заболеваний, включая COVID-19, ведущим клиническим признаком которых является кашель.
Авторами приводится подробная характеристика лекарственных препаратов для лечения кашля, принципы применения мукоактивных препаратов, практические рекомендации по ведению больных с острым и хроническим кашлем.
The article presents data on the etiology, modern methods for diagnosis and treatment of respiratory system diseases and examines in detail cough as the main symptom. Particular attention is paid to hypertussivity, which is defined as a cough that occurs in the absence of obvious reasons. In addition, the emphasize was put on the role of anatomical and physiological features in the development and characteristics of cough, especially in young children. The authors draw attention to the complex mechanism of the cough, which development involves many body systems such as nervous, immune, endocrine and respiratory. The article describes the main treatment methods, drugs prescribed to the patients with cough, which are divided into «antitussive» drugs used as cough suppressants and «protussive» drugs used in situations, in which mobilization of secretions is desired, combined drugs. The role of new combined drugs, in particular, Rengalin, which affects the central and peripheral links of the cough reflex, was noted.
Актуальность. В настоящее время наблюдается тенденция к пролонгированному течению острых респираторных инфекций, что требует разработки медикаментозных способов предупреждения его развития. Цель работы — изучение клинико-иммунологической эффективности экстракта листьев плюща обыкновенного при лечении острого простого бронхита у детей. Материалы и методы. Под наблюдением находились 40 детей в возрасте 2–6 лет, больных острым простым бронхитом, 14 детей получали препарат Пектолван Плющ. При проведении работы использовались клинические и лабораторные методы исследования. Тяжесть состояния больного оценивалась по шкале BSS (Bronchitis severity score). Лабораторное исследование включало в себя: общий анализ крови, мочи, назоцитологические, иммуноферментные методы. Этиологический диагноз устанавливался на основании вирусологических методов обследования. При определении концентрации лактоферрина использовался набор Нuman Lactoferrin NK 329 Edition 06-16 производства компании Hycult Biotech (США), нейтрофильных a-дефензинов (1–3) — реактивы Нuman HNP NK317 Edition 08-16 производства компании Hycult Biotech (США). Результаты. Острый бронхит у наблюдавшихся больных вызван вирусными агентами. У всех детей, больных острым простым бронхитом, заболевание начиналось остро и проявлялось катаральным и общевоспалительным синдромами. Применение в терапии отхаркивающего препарата Пектолван Плющ способствовало более быстрому уменьшению клинических проявлений заболевания, предупреждению затяжного течения, сопровождалось достоверным снижением количества лейкоцитов в слизи носовой полости и увеличением содержания лактоферрина в ротоглотковой жидкости к периоду реконвалесценции. Выводы. Экстракт листьев плюща является не только симптоматическим отхаркивающим, но и патогенетическим лекарственным средством, которое можно считать препаратом выбора при лечении острого простого бронхита у детей.
N-acetylcysteine in combination with urea is effective for the treatment of congenital ichthyosis. Although it is well tolerated, its foul smell may compromise treatment adherence. Carbocysteine is a similar molecule without that bad odor. Thus, we have tried a new formula with carbocysteine for the treatment of 4 patients with ichthyosis, with positive results.
Cancer cachexia is increasingly becoming a critical component in the comprehensive approach to cancer patients influencing morbidity, mortality, and quality of life. Therefore, its pathophysiology and the main contributing factors have been investigated with the aim of developing effective therapies. Reported findings indicate that increased production of reactive oxygen species and reduced activity of antioxidant enzymes contribute to development of anorexia and cachexia in cancer. Oxidative stress, almost always accompanying cancer cachexia, may be counteracted by effective antioxidant treatments: in this review, the most relevant recent clinical approaches addressing this target are reported. Fairly advanced clinical data on efficacy of and antioxidants in advanced cancer patients are promising, but the best way to administer and combine them with other agents, the optimal dose, and timing remain uncertain. However, because cachexia is a multifactorial syndrome, therapeutic approaches targeting a single contributing factor may be inadequate: targeting oxidative stress only one determinant is addressed, thereby limiting clinical efficacy. Therefore, antioxidants should be included in developing a therapeutic approach for cachectic cancer patients, however, they cannot encompass all symptoms of cancer cachexia. Recent evidence seems to confirm that the treatment of cancer cachexia, a multifactorial syndrome, is more likely to yield success with a multitargeted approach.
Introduction
The current pharmacological treatment of COPD provides only partial beneficial effects on symptoms, exercise tolerance, frequency of exacerbations and quality of life. This could be related to poor targeting of the distal airways by current treatments, yet these airways are particularly involved in airflow obstruction and its consequences such as hyperinflation.
Background
Many treatments used in COPD could have effects on distal airways, including bronchodilators, corticosteroids, mucolytics and antibiotics. However, these possible effects remain poorly understood.
Viewpoints
New treatments targeting more specifically the mechanisms of inflammation, oxidative stress and tissue remodeling that characterize COPD, could prove useful in its management, but most are still only in the early stages of their development. Advances could also come from improvements in inhalation devices, delivering more of the medication to the distal airways.
Conclusions
Improvement in the management of COPD could come from progress in terms of both molecules and their mode of administration.
The current pharmacological treatment of COPD provides only partial beneficial effects on symptoms, exercise tolerance, frequency of exacerbations and quality of life. This could be related to poor targeting of the distal airways by current treatments, yet these airways are particularly involved in airflow obstruction and its consequences such as hyperinflation.
Many treatments used in COPD could have effects on distal airways, including bronchodilators, corticosteroids, mucolytics and antibiotics. However, these possible effects remain poorly understood.
New treatments targeting more specifically the mechanisms of inflammation, oxidative stress and tissue remodeling that characterize COPD, could prove useful in its management, but most are still only in the early stages of their development. Advances could also come from improvements in inhalation devices, delivering more of the medication to the distal airways.
Improvement in the management of COPD could come from progress in terms of both molecules and their mode of administration.
Carbocysteine (S-carboxymethylcysteine) is a mucoactive drug with in vitro free radical scavenging and anti-inflammatory properties. Several clinical trials have indicated that carbocysteine reduces exacerbation rates in COPD. In the present study, the effect of carbocysteine on the airway load of Haemophilus influenzae was assessed in rats chronically exposed to cigarette smoke (CS). In addition, the effects of carbocysteine on airway mucus hypersecretion and mucociliary clearance (MCC) associated with the adherence and clearance of H. influenzae were investigated.
Wistar rats were randomly divided into control, carbocysteine vehicle, CS exposure and carbocysteine treatment groups. After 12 weeks, rats were selected for quantitative inoculation of H. influenzae. BAL fluid and lungs were collected aseptically after 3 h for quantitative culture of H. influenzae. MCC was measured by quantifying the clearance of (99m)Tc-Sc. Goblet cell metaplasia and the presence of mucoid matter were evaluated by Alcian blue/periodic acid-Schiff staining. Mucin 5AC (Muc5AC) expression was detected by western blotting and real-time reverse transcription-PCR.
Exposure to CS increased airway H. influenzae load, aggravated mucus hypersecretion and delayed MCC. Treatment with carbocysteine decreased airway H. influenzae load, and attenuated airway mucus hypersecretion, with improved MCC associated with adherence and clearance of H. influenzae.
These results suggest that carbocysteine may be beneficial in patients with COPD by increasing the clearance of bacteria and decreasing bacterial load.
Chronic obstructive pulmonary disease (COPD) and asthma are the major causes of pulmonary disability in the United States, with at least 10 million Americans suffering from COPD and up to 5% of the population afflicted with asthma. Over the past 20 years, major strides have been made in our understanding of the pathophysiology of these two disorders, although there are still large gaps in our knowledge. While a number of position papers and statements have been promulgated by the American Thoracic Society concerning various aspects of the diagnosis and treatment of COPD and asthma, it was felt that a review of the overall topic was timely. This statement represents the combined efforts of a Task Group appointed by the Scientific Assembly on Clinical Problems of the American Thoracic Society to accomplish this task. Clearly, we could not cover every aspect of this broad topic nor even provide a detailed review of those areas addressed. We elected instead to concentrate on clinically relevant topics and to provide sufficient data to be useful as a guide as well as to include selected, but in no way exhaustive, references. The first two chapters define the entities and set forth recommendations for diagnosis, hospital admission, and discharge. The remaining four chapters critically review the various facets of therapy. We have noted controversial areas and those where conclusive experimental data are not yet available. In these situations, the committee often decided to take a position on one side or the other based upon the best available information.
The hydroxyl radical (OH.) scavenger dimethyl sulfoxide (DMSO) was found to dose-dependently inhibit interleukin 8 (IL-8) production in LPS-stimulated human whole blood. At a concentration of 1% (vol/vol), DMSO blocked IL-8 release by approximately 90% in the presence of 1 microgram/ml LPS at a 24-h time point, but did not affect cell viability or reduce the production of tumor necrosis factor (TNF), interleukin 6, or interleukin-1 beta (IL-1 beta). DMSO was found to directly inhibit IL-8 expression at the level of transcription. Furthermore, this effect was not LPS-specific, in that IL-8 production was reduced by DMSO to a similar extent upon stimulation of blood with phytohemagglutinin, aggregated immune complexes, TNF, or IL-1 beta. Other oxygen radical scavengers that have been shown to inhibit OH.-dependent reactions (dimethyl thiourea, thiourea, mannitol, and ethanol) also inhibited IL-8 production. Conversely, addition of H2O2 caused a dose-dependent stimulation of IL-8 release. These results provide evidence that reactive oxygen metabolites play an important role in the regulation of IL-8 production and suggest that reduction of IL-8 release may contribute to the beneficial effects of antioxidants in experimental models of inflammation and ischemia/reperfusion injury.
Neutrophil migration into the airspaces of the lung is thought to contribute to the alveolar damage and subsequent fibrosis in idiopathic pulmonary fibrosis (IPF). Interleukin 8 (IL-8), a monocyte- and macrophage-derived cytokine, displays potent chemotactic and activating properties towards neutrophils and thus may contribute to the pathogenesis of IPF. The objective of this investigation was to quantify the spontaneous expression of IL-8 transcripts by alveolar macrophages from normal healthy volunteers and individuals with IPF. A quantitative assay employing reverse transcription of mRNA and the polymerase chain reaction was utilized. The level of IL-8 mRNA in alveolar macrophages was found to be significantly elevated in individuals with lone IPF or with lung fibrosis associated with connective tissue disorders compared to normal healthy controls. Moreover, the level of IL-8 mRNA in the 23 individuals with IPF correlated with the number of neutrophils per milliliter in their bronchoalveolar lavage (BAL) and with the degree of disease severity. In addition, the level of IL-8 protein in BAL was found to reflect the pattern of IL-8 mRNA expression by alveolar macrophages. These data suggest that IL-8 derived from alveolar macrophages may significantly contribute to neutrophil involvement in the pathogenesis of IPF.
Regulation of proliferation of normal human T lymphocytes (T cells) by glutathione (GSH) was explored with T-cell activation models that do not require accessory cell signals. L-Buthionine-(S,R)-sulfoximine (BSO), which inactivates gamma-glutamylcysteine synthetase and therefore inhibits GSH synthesis, inhibited proliferation elicited by monoclonal antibodies directed at cluster designation 2 (CD2) and CD3 antigens, or by sn-1,2-dioctanoylglycerol and ionomycin. L-Buthionine-(R)-sulfoximine, which does not inactivate gamma-glutamylcysteine synthetase, did not affect proliferation. BSO-induced inhibition of accessory cell-independent T-cell proliferation was not reversed by recombinant human interleukin 2, despite activation-dependent expression of interleukin 2 receptor alpha by T cells treated with BSO. However, BSO-associated inhibition of T-cell proliferation was reversed by GSH or GSH ester. These studies, which show that GSH can directly modulate proliferation of highly purified T cells, suggest that GSH is essential for steps close to or at DNA synthesis. The availability of methods for decreasing and for increasing GSH levels suggest therapies to produce (i) immunosuppression (of value in organ transplantation), and (ii) immunopotentiation (of potential value in treatment of immunodeficiency states such as AIDS).
Ion transport by the airway epithelium contributes to the regulation of the quantity and composition of respiratory tract fluid, thereby affecting mucociliary clearance. We have investigated the effect of the mucoactive drug S-carboxymethylcysteine-lysine salt (S-CMC-Lys) on the transepithelial bioelectric properties of isolated rabbit trachea. Transepithelial potential difference (Vms), short-circuit current (Isc) and resistance (R) were measured in the isolated rabbit trachea mounted between flux half-chambers, in the presence and in the absence of S-CMC-Lys (100 microM), added to the mucosal or submucosal chamber. In some experiments, tissues were also exposed to ion channel-inhibitors, in order to evaluate the contribution of Na+ and Cl- active transport to Isc. The excised rabbit trachea expressed transepithelial bioelectric properties based on an active ion transport supported by the Na(+)-K(+)-adenosine triphosphatase (ATPase) activity, since ouabain (500 microM) completely abolished the transepithelial potential difference. In control preparations, Vms and Isc declined significantly during 300 min recording, whereas R remained constant. The Isc decline was essentially attributable to a decrease in Cl- transport. Bumetanide (100 microM) almost completely abolished the Isc fraction related to Cl- transport. Treatment of the tissues with S-CMC-Lys reduced the progressive fall in Isc, with the most clear-cut and significant effect observed for the mucosal treatment. In parallel, S-CMC-Lys significantly lowered R, without affecting Vms. Either mucosal or submucosal exposure to S-CMC-Lys significantly increased Cl- secretion to normal values, whilst Na+ absorption was not modified.(ABSTRACT TRUNCATED AT 250 WORDS)
Glutathione (GSH) is an important intracellular peptide with multiple functions ranging from antioxidant defense to modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, gamma-glutamylcysteine synthetase (GCS). In the liver, major factors that determine the availability of cysteine are diet, membrane transport activities of the three sulfur amino acids cysteine, cystine and methionine, and the conversion of methionine to cysteine via the trans-sulfuration pathway. Many conditions alter GSH level via changes in GCS activity and GCS gene expression. These include oxidative stress, activators of Phase II detoxifying enzymes, antioxidants, drug-resistant tumor cell lines, hormones, cell proliferation, and diabetes mellitus. Since the molecular cloning of GCS, much has been learned about the regulation of this enzyme. Both transcriptional and post-transcriptional mechanisms modulate the activity of this critical cellular enzyme.--Lu, S. C. Regulation of hepatic glutathione synthesis: current concepts and controversies.
Airway inflammation leads to secretion of abnormal mucous glycoprotein and ciliary injury. To investigate the possible usefulness of carbocisteine against airway inflammation and events related to it, we conducted a study in SO2-exposed rats of the effects of carbocisteine and ambroxol, as an active control drug, on components of mucous glycoprotein (fucose, sialic acid and protein) in bronchoalveolar lavage fluid (BALF); on infiltration and activation of inflammatory cells in BALF; on tracheal and bronchial-ciliary lesions; and on cAMP levels in tracheal and alveolar tissues. Carbocisteine inhibited or improved all SO2-induced changes tested, and dosages of 125 and 250 mg/kg b.i.d. reduced fucose, sialic acid and protein contents, inflammatory cells (as markers of inflammation), free radicals, and elastase activity in BALF, and suppressed the development of ciliary lesions of the tracheal and bronchial mucosa, while ambroxol (10 mg/kg b.i.d.) showed no such effects. In addition, carbocisteine improved cAMP levels in the tracheal and alveolar tissues. These results indicate that carbocisteine is able to prevent the development of inflammation-related respiratory disease in this rat model, and that this remission of airway inflammation may be associated with carbocisteine-induced normalization of cAMP levels in tracheal and alveolar tissues as well as with its mucoregulant and anti-inflammatory effects. In conclusion, carbocisteine has a unique mucoregulant action and inhibits SO2-induced airway inflammation in a manner different from that of ambroxol.
Reactive oxygen radicals are involved in many respiratory diseases, including chronic obstructive pulmonary disease (COPD). Carbocysteine lysine salt monohydrate (CLS) is a mucoactive drug effective in the treatment of bronchopulmonary diseases characterized by mucus alterations, including COPD. In the present study, the antioxidant activity of CLS was studied in vitro in three different oxygen radical producing systems, i.e. bronchoalveolar lavages (BAL) from patients affected by COPD, ultrasound treated human serum and cultured human lung endothelial cells challenged with elastase.
BAL, exposed or not to different concentrations of CLS (1.5-30 mM), was assayed for free radical content by fluorometric analysis of DNA unwinding (FADU) or by cytochrome c reduction kinetics. Human serum was treated with ultrasound in the presence or absence of CLS (1.5, 2.5 mM) or N-acetyl cysteine (NAC; 4, 5 mM) and assayed for free radical content by FADU. Human endothelial cells cultured in vitro from pulmonary artery were incubated with elastase (0.3 IU/mL), in the presence or absence of glutathione (GSH; 0.65 mM) or CLS (0.16 mM). The supernatant was tested for cytochrome c reduction kinetics whereas cell homogenates were assessed for xanthine oxidase (XO) content by SDS-PAGE.
Results showed that CLS is more effective as an in vitro scavenger in comparison to GSH and NAC. CLS reduced the damage of DNA from healthy donors exposed to COPD-BAL and was able to quench clastogenic activity induced in human serum by exposure to ultrasound at concentrations as low as 2.5 mM. NAC protect DNA from radical damage, starting from 5 mM. In human lung endothelial cells cultured in presence of elastase, CLS (0.16 mM) decreased xanthine oxidase activity.
These results suggest that CLS could act by interfering with the conversion of xanthine dehydrogenase into superoxide-producing xanthine oxidase. The antioxidant activity of CLS could contribute to its therapeutic activity by reducing radical damage to different lung structures.
So far, it is not well established whether oxidative stress found in cancer patients results from an increased production of oxidants in the body or from a failure of physiological antioxidant systems. To further investigate this question we have assessed the blood levels of reactive oxygen species as a marker of free radicals producing oxidative stress and the most relevant of the physiological body enzymes counteracting reactive oxygen species, namely glutathione peroxidase and superoxide dismutase. Serum levels of proinflammatory cytokines and IL-2 were also investigated. All these parameters were studied in relation to the clinically most important index of disease progression, namely Performance Status (ECOG PS). We also tested the reducing ability of different antioxidant agents on reactive oxygen species levels by measuring the increase in glutathione peroxidase activity, and the reduction of serum levels of IL-6 and TNF.
We carried out an open non randomized study on 28 advanced stage cancer patients (stage III, 10.7%, and stage IV, 89.3%) with tumours at different (8) sites: all were hospitalized in the Medical Oncology Dept, University of Cagliari Interventions. The patients were divided into 5 groups and a different antioxidant treatment was administered to each group. The selected antioxidants were: alpha lipoic acid 200 mg/day orally, N-acetylcysteine 1800 mg/day i.v. or carboxycysteine-lysine salt 2.7 g/day orally, amifostine 375 mg/day i.v., reduced glutathione 600 mg/day i.v., vitamin A 30000 IU/day orally plus vitamin E 70 mg/day orally plus Vitamin C 500 mg/day orally. The antioxidant treatment was administered for 10 consecutive days.
Our results show that all but one of the antioxidants tested were effective in reducing reactive oxygen species levels and 2 of them (cysteine-containing compounds and amifostine) had the additional effect of increasing glutathione peroxidase activity. Comprehensively, the "antioxidant treatment" was found to have an effect both on reactive oxygen species levels and glutathione peroxidase activity. The antioxidant treatment also reduced serum levels of IL-6 and TNF. Patients in both ECOG PS 0-1 and ECOG PS 2-3 responded to antioxidant treatment.
Carbocysteine is prescribed for conditions characterized by the accumulation of excessive mucus. Although often described as a mucolytic, its function is probably that of mucoregulation, which results in physical changes in accumulated secretions that are favorable in terms of clearance. The chemistry, pharmacology, pharmacokinetics, clinical applications, and toxicology of carbocysteine are reviewed.
Background. Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer. Methods. We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years. Results. Among the 876 new cases of lung cancer diagnosed during the trial, no reduction in incidence was observed among the men who received alpha-tocopherol (change in incidence as compared with those who did not, -2 percent; 95 percent confidence interval, -14 to 12 percent). Unexpectedly, we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not (change in incidence, 18 percent; 95 percent confidence interval, 3 to 36 percent). We found no evidence of an interaction between alpha-tocopherol and beta carotene with respect to the incidence of lung cancer. Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than among those who did not. Beta carotene had little or no effect on the incidence of cancer other than lung cancer. Alpha- tocopherol had no apparent effect on total mortality, although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not. Total mortality was 8 percent higher (95 percent confidence interval, 1 to 16 percent) among the participants who received beta carotene than among those who did not, primarily because there were more deaths from lung cancer and ischemic heart disease. Conclusions. We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects.
In advanced cancer patients, the oxidative stress could take place either at the onset of disease or as a function of disease progression. To test this hypothesis, the following parameters were investigated: the erythrocyte activity of the enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), the serum activity of glutathione reductase (GR) and the serum total antioxidant status (TAS). The total antioxidant capacity of plasma LMWA was evaluated by the cyclic voltammetry methodology. We further determined the serum levels of proinflammatory cytokines (IL-6 and TNFα), IL-2, leptin and C-reactive protein (CRP). All of these parameters have been correlated with the most important clinical indices of patients such as Stage of disease, ECOG PS and clinical response. Eighty-two advanced stage cancer patients and 36 healthy individuals used as controls were included in the study. Our findings show that SOD activity was significantly higher in cancer patients than in controls and GPx activity was significantly lower in cancer patients than in controls. Serum values of IL-6, TNFα and CRP were significantly higher in patients than in controls. Serum leptin values of cancer patients were significantly lower than controls. SOD activity increased significantly from Stage II/ECOG 0-1 to Stage IV/ECOG 0–1, whereas it decreased significantly in Stage IV/ECOG 3. GPx activity decreased significantly in Stage IV/ECOG 2–3. An inverse correlation between ECOG PS and serum leptin levels was found. Serum levels of IL-2 decreased from Stage II/ECOG 0–1 to Stage IV/ECOG 2–3. A direct correlation between Stage/ECOG PS and serum levels of both IL-6 and CRP was observed. Cisplatin administration induced a significant increase of GPx after 24 hr. In conclusion, this is the first study that shows that several “biological” parameters of cancer patients such as antioxidant enzyme activity, cytokines, leptin and CRP strictly correlate with the most important clinical parameters of disease such as Stage and ECOG PS. © 2001 Wiley-Liss, Inc.
Glutathione (gamma-glutamyl-cysteinyl-glycine, GSH) is the most abundant intracellular antioxidant thiol and is central to redox defense during oxidative stress. GSH metabolism is tightly regulated and has been implicated in redox signaling and also in protection against environmental oxidant-mediated injury. Changes in the ratio of the reduced and disulfide form (GSH/GSSG) can affect signaling pathways that participate in a broad array of physiological responses from cell proliferation, autophagy and apoptosis to gene expression that involve H(2)O(2) as a second messenger. Oxidative stress due to oxidant/antioxidant imbalance and also due to environmental oxidants is an important component during inflammation and respiratory diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and asthma. It is known to activate multiple stress kinase pathways and redox-sensitive transcription factors such as Nrf2, NF-kappaB and AP-1, which differentially regulate the genes for pro-inflammatory cytokines as well as the protective antioxidant genes. Understanding the regulatory mechanisms for the induction of antioxidants, such as GSH, versus pro-inflammatory mediators at sites of oxidant-directed injuries may allow for the development of novel therapies which will allow pharmacological manipulation of GSH synthesis during inflammation and oxidative injury. This article features the current knowledge about the role of GSH in redox signaling, GSH biosynthesis and particularly the regulation of transcription factor Nrf2 by GSH and downstream signaling during oxidative stress and inflammation in various pulmonary diseases. We also discussed the current therapeutic clinical trials using GSH and other thiol compounds, such as N-acetyl-l-cysteine, fudosteine, carbocysteine, erdosteine in environment-induced airways disease.
Carbocysteine is prescribed for conditions characterized by the accumulation of excessive mucus. Although often described as a mucolytic, its function is probably that of mucoregulation, which results in physical changes in accumulated secretions that are favorable in terms of clearance. The chemistry, pharmacology, pharmacokinetics, clinical applications, and toxicology of carbocysteine are reviewed.
The review examines the relationship between alpha1-antitrypsin (α
1AT) and emphysema. Although other defects occur in subjects with alpha1-antitrypsin deficiency, it seems likely that a reduction in inhibition due to loss of this inhibitor explains their emphysema.
There is a great deal of controversy, however, concerning the role of alpha1-antitrypsin in subjects without inherited deficiency. There is uncertainty about the presence and function of other elastase
inhibitors in the peripheral lung. The function of lungα
1AT and the presence of elastase activity are dependent upon the techniques used and this probably accounts for different results
between research groups. In addition, other relevant factors such as which enzymes cause lung elastolysis, control of neutrophil
chemotaxis, and mechanisms of elastin synthesis and repair are less well studied. The overall conclusion is that many aspects
of the elastase/antielastase hypothesis of emphysema are poorly understood. Without further information the true role ofα
1AT will remain largely speculative.
An impaired sulfoxidation pathway has been implicated in the pathogenesis of chlorpromazine-induced hepatotoxicity. Since some patients with chronic chlorpromazine-induced cholestasis may have features of primary biliary cirrhosis, we studied the ability to sulfoxidate the amino acid analogue S-carboxymethyl-cysteine in 44 patients with primary biliary cirrhosis and in two control groups--one without liver disease and one with a variety of liver diseases other than primary biliary cirrhosis. Poor sulfoxidation was observed in 84 percent of the patients with primary biliary cirrhosis, as compared with 24 percent of patients with other liver diseases and 22 percent of normal controls (P less than 0.0005 for both comparisons). Poor sulfoxidation did not correlate with the degree of hyperbilirubinemia or histologic severity of liver disease in any of the groups studied. There was an inverse correlation with age only in the patients with primary biliary cirrhosis (r = -0.44, P less than 0.001). Liver transplantation was performed in six of the patients and improved sulfoxidation in five; in the four with primary biliary cirrhosis, sulfoxidation improved from poor to good or intermediate. We conclude that poor sulfoxidation is closely associated with primary biliary cirrhosis but not with the other liver diseases we studied.
A picture is emerging of the complex interorgan regulation of cysteine and GSH metabolism. The liver appears to play a critical role in this process by exporting nearly all the GSH produced in hepatic cytosol at a rapid rate, mainly into plasma. The liver is also unique in its ability to generate cysteine from methionine. In this way, the capacity of the liver to synthesize GSH is not limited by the availability of dietary cysteine. Thus, the liver has the ability to maintain or increase GSH export in the face of limited dietary precursors. This may serve a critical role in supplying extrahepatic tissues with GSH or its component amino acids. The interorgan cycle seems to be completed by a quantitatively important reutilization of these amino acids in the liver for GSH synthesis. Key steps in the cycle are the cystathionine pathway in the liver, carrier-mediated GSH transport (efflux) in the liver, and mechanisms for tissue utilization of plasma GSH. A great deal more needs to be learned about the regulation of these events and their interactions.
The metabolism of 14C- and 35S-labeled S-carboxymethylcysteine (SCMC) has been compared. The majority of the dose appeared in urine in the first 24 hr; no activity was detectable in feces. Use of 25S-labeled compound gave small amounts of inorganic 35S-sulfate, whereas 14C-labeled material was degraded to give some [14C]urea. Peak excretion of the parent compound occurred first after administration of SCMC; metabolites requiring one chemical modification for their formation were maximally excreted 1-4 hr after the dose and those involving more metabolic processes appeared later (4-8 hr).
This review is concerned with current progress in unraveling the biochemical bases of the physiological roles of this important compound. Detailed information is now available about glutathione synthesis and its metabolism by the reactions of the γ-glutamyl cycle, and its function in reductive processes that are essential for the synthesis (and the degradation) of proteins, formation of the deoxyribonucleotide precursors of DNA, regulation of enzymes, and protection of the cell against reactive oxygen compounds and free radicals. In addition, glutathione is a coenzyme for several reactions; it conjugates with foreign compounds (e.g. drugs) and with compounds formed in metabolism (e.g. estrogens, prostaglandins, leukotrienes), and thus participates in their metabolism. An important recent finding is that cellular turnover of glutathione is associated with its transport, in the form of GSH, out of cells. The functions of such GSH transport include formation by membrane-bound γ-glutamyl transpeptidase of γ-glutamyl amino acids, which can be transported into certain cells, and thus serve as one mechanism of amino acid transport. Transported GSH probably also functions in reductive reactions that may involve the cell membrane and the immediate environment of the cell. In the mammal, such transported GSH may enter the blood plasma and be transferred to other cells. Glutathione thus appears to be a storage form and a transport form of cysteine. Much of the new information about glutathione has arisen through studies with selective inhibitors of the enzymes involved in its metabolism. Thus, inhibition in vivo of γ-glutamyltranspeptidase, γ-glutamyl cyclotransferase, 5-oxoprolinase, and glutathione synthesis has been achieved, and the effects observed have contributed importantly to the understanding of glutathione metabolism and function. Studies on the inhibition of γ-glutamyl transpeptidase have elucidated the transport of GSH and the formation and transport of γ-glutamyl amino acids. Inhibition of glutathione synthesis by sulfoximine compounds that inactivate γ-glutamylcysteine synthetase has also contributed to such knowledge, as well as to information about the roles of glutathione in protection against both free radicals and reactive oxygen compounds, and in metabolism. These enzyme inhibitors, and other compounds that increase in vivo glutathione synthesis have opened the way to selective modulation of glutathione metabolism; this has made several new therapeutic approaches possible.
Interindividual variation in the sulphoxidation of S-carboxymethyl-L-cysteine (750 mg p.o.) was investigated in 200 healthy volunteers. Nearly a 100-fold difference was observed between individuals with respect to the amount of sulphoxide metabolites detected in their 0-8 h urine (0.6 to 59.1% recovery). Such a difference was shown to be reproducible over several months in 40 subjects who spanned the entire range of capacities. Cumulative plots and maximum likelihood analysis of the distribution indicated that a bimodal model was most probable. Analysis of pedigree data obtained from 12 families suggested a genetic effect with overlying environmental influences.
To test the hypothesis that adult respiratory-distress syndrome (ARDS) is related to increased activity of the proteolytic enzyme elastase released from neutrophils in the lung, we determined the differential white-cell count, the elastolytic activity, the source of elastase, and the concentration and activity of the endogenous protease inhibitor alpha-1-antiprotease (alpha-1-AP) in bronchoalveolar lavage fluid from 23 patients with ARDS and from 55 patients without this syndrome. Neutrophil predominance (> 80 per cent) was observed in 18 of 23 patients with ARDS. High elastolytic activity of neutrophil origin was found in 12 of 23 patients with ARDS (52 per cent), in none of 16 normal nonsmokers (P < 0.01), in two of 17 normal smokers, and in three of 22 patients with chronic obstructive pulmonary disease. Although there were no significant differences in alpha-1-AP concentrations, its activity was reduced in eight of nine patients with ARDS and high elastolytic activity. We conclude that in many patients with ARDS, high levels of neutrophil elastolytic activity in the lungs are associated with reduced alpha-1-AP function.
A mass fragmentographic technique was used to study the pharmacokinetic behavior of SCMC-Lys in patients with acute exacerbations of chronic bronchitis and with dense expectoration. Serum and urine levels, as well as bronchial mucus levels and their correlations, were determined. The data suggest that SCMC-Lys diffuses well into bronchial mucus, a useful feature for a mucolytic drug.
Among reactive oxygen species generated by human neutrophils during inflammatory disorders, hypochlorous acid and hydroxyl radical are especially involved in many diseases such as arteriosclerosis or emphysema. It was shown in vitro that two thiol-containing drugs, mesna and N-acetylcysteine, have antioxidant properties towards these oxidants. The 50% inhibitory concentrations (IC50s) of mesna and N-acetylcysteine for hypochlorous acid production by stimulated neutrophils were 29 and 30 mcM, respectively, and for hydroxyl radical production, IC50s were 520 and 480 mcM, respectively. With this in vitro demonstrated effectiveness, both mesna and N-acetylcysteine have been considered as therapeutic antioxidants to decrease tissue damage inflicted by an excess of activated neutrophils by scavenging hypochlorous acid and hydroxyl radical.
Some antioxidants, including butylated hydroxyanisole (BHA), tetrahydropapaveroline (THP), nordihydroguiauretic acid, and 10,11-dihydroxyaporphine (DHA), were found to be potent inhibitors of the production of tumor necrosis factor (TNF)-alpha, IL-1 beta, and IL-6 by human peripheral blood mononuclear cells (PBMC) stimulated by lipopolysaccharide (LPS) (IC50s in the low micromolar range). Inhibition of cytokine production was gene selective and not due to general effects on protein synthesis. Inhibition of cytokine production by PBMC was observed also when other inducers were used (staphylococci, silica, zymosan). Much higher concentrations of other antioxidants--including ascorbic acid, trolox, alpha-tocopherol, butylated hydroxytoluene, and the 5-lipoxygenase inhibitor zileuton--did not affect the production of these cytokines. The active compounds did not inhibit IL-1-induced production of IL-6 in fibroblasts, showing the cell selectivity of the effect. Antioxidant-mediated inhibition of cytokine production was correlated with low levels of the corresponding messenger RNAs. Nuclear run-on experiments showed that THP inhibited transcription of the IL-1 beta gene. THP decreased the concentration of the transcription factors NF-kappa B and AP-1 detected in nuclear extracts of PBMC cultured in the presence or absence of LPS. THP and DHA markedly decreased the levels of TNF-alpha and IL-1 beta in the circulation of mice following LPS injection. Thus antioxidants vary widely in potency as inhibitors of the activation of transcription factors and of the transcription of genes for pro-inflammatory cytokines. Coordinate inhibition of the transcription of genes for inflammatory cytokines could provide a strategy for therapy of diseases with inflammatory pathogenesis and for septic shock.
We investigated the possible effects of the mucoactive drug Carbocysteine lysine salt monohydrate (CLS.H2O) on experimentally-induced airway inflammation and hyperresponsiveness. CLS.H2O given by the oral route (300 mg kg(-1)) significantly reduced neutrophil infiltration into the airway lumen induced by intratracheal injection of IL-1 beta in rats. In addition, CLS.H2O inhibited dose-dependently (100-300 mg kg(-1) p.o.) the formation of pleural exudate and leukocyte recruitment induced by intrapleural injection of carrageenan in rats. Because of the close interaction between the inflammatory process and the development of airway hyperresponsiveness we also tested CLS.H2O on cigarette-smoke-induced inflammation and hyperreactivity in anaesthetized guinea-pigs. The drug, given either by oral (300 mg kg(-1)) or aerosol route (30-100 mg ml(-1)), was able to reduce the increase in airway responsiveness induced by smoke and the associated cell recruitment detected in the bronchoalveolar lavage (BAL) fluids. These results suggest that CLS.H2O can exert an anti-inflammatory action in addition to its mucoregulatory activity. The anti-inflammatory and anti-hyperreactivity effect of the drug within the airways may be of advantage in the treatment of inflammatory lung diseases where mucus secretion together with airway inflammation and hyperreactivity contribute to airway obstruction.
The efficacy and safety of carbocysteine lysine salt monohydrate (SCMC-Lys) in the prevention of acute exacerbations associated with chronic obstructive bronchitis were evaluated in a multicenter double-blind, placebo-controlled, parallel group trial in 662 outpatients. After a 1-month run-in period, patients were randomized to three groups and assigned to receive one of the following oral treatments: continuous SCMC-Lys 2.7 g once daily, intermittent SCMC-Lys at the same dosage (1-week courses alternating with 1-week intervals on placebo) or placebo. Each treatment lasted for 6 months and spanned the cooler months of the year. Evaluation was based on a daily recording of relevant clinical symptoms and signs and subsequent evaluation of the collected data by three blinded independent physicians. A total of 146 patients (23%) failed to complete the 6-month treatment (mostly due to difficulties in complying with protocol requirements), without clear-cut differences in the dropout rate in the three groups. An intention-to-treat analysis revealed that the incidence of patients without exacerbations in the group assigned to continuous SCMC-Lys treatment was significantly higher than in the placebo-treated group (p
Recent evidence suggests that bradykinin (BK) plays a role in regulating neointimal formation after vascular injury. The present study examined the mechanism whereby BK regulates platelet-derived growth factor (PDGF) AB-induced mitogenesis in smooth muscle cells from rat mesenteric artery. BK, but not other activators of phosphoinositidase C (e.g., angiotensin II), inhibited PDGF-stimulated mitogenesis. The B1 receptor agonist des-Arg9-BK (DABK) was more potent than the B2 agonist BK; smaller BK fragments had no activity. In studies in which the B2 receptor antagonist HOE-140 {D-Arg0[Hyp3,beta-(2-thienyl)-Ala5,D-Tic7,Oic 8]BK} and the B1 receptor antagonist DHOE [[D-Arg0,Hyp3,beta-(2-thienyl)-Ala5,D-Tic7,Oi c8,des-Arg9]BK] were used, both receptors independently mediated inhibition of PDGF-induced mitogenesis. There was no evidence for metabolism of BK to DABK. The rank potency for activating phosphoinositidase C and increasing intracellular Ca2+ (BK > DABK) was opposite that for inhibiting mitogenesis (DABK > BK). Inhibition of cyclooxygenase did not prevent the kinin-mediated inhibition. Kinetic analysis of the cell cycle effects of kinins on PDGF-stimulated mitogenesis revealed that continuous exposure to DABK or BK was inhibitory even when added shortly before the cells initiated DNA synthesis (S phase). However, short-term exposure (5-60 min) to DABK or BK was inhibitory only when added after exposure to PDGF. These data suggest that the B1 and B2 receptors potently inhibited PDGF-stimulated mitogenesis and proliferation by activating an alternative signal transduction cascade not involving phosphoinositidase C or prostaglandins. The inhibition occurred at a point late in progression of the cell cycle from G1 to S and was dependent on the presence of kinins after exposure to PDGF.
Mitochondria generate reactive oxygen species (ROS) as byproducts of molecular oxygen consumption in the electron transport chain. Most cellular oxygen is consumed in the cytochrome-c oxidase complex of the respiratory chain, which does not generate reactive species. The ubiquinone pool of complex III of respiration is the major site within the respiratory chain that generates superoxide anion as a result of a single electron transfer to molecular oxygen. Superoxide anion and hydrogen peroxide, derived from the former by superoxide dismutase, are precursor of hydroxyl radical through the participation of transition metals. Glutathione (GSH) in mitochondria is the only defense available to metabolize hydrogen peroxide. A small fraction of the total cellular GSH pool is sequestered in mitochondria by the action of a carrier that transports GSH from the cytosol to the mitochondrial matrix. Mitochondria are not only one of the main cellular sources of ROS, they also are a key target of ROS. Mitochondria are subcellular targets of cytokines, especially tumor necrosis factor (TNF); depletion of GSH in this organelle renders the cell more susceptible to oxidative stress originating in mitochondria. Ceramide generated during TNF signaling leads to increased production of ROS in mitochondria. Chronic ethanol-fed hepatocytes are selectively depleted of GSH in mitochondria due to a defective operation of the carrier responsible for transport of GSH from the cytosol into the mitochondrial matrix. Under these conditions, limitation of the mitochondrial GSH pool represents a critical contributory factor that sensitizes alcoholic hepatocytes to the prooxidant effects of cytokines and prooxidants generated by oxidative metabolism of ethanol. S-adenosyl-L-methionine prevents development of the ethanol-induced defect. The mitochondrial GSH carrier has been functionally expressed in Xenopus laevis oocytes microinjected with mRNA from rat liver. This critical carrier displays functional characteristics distinct from other plasma membrane GSH carriers, such as its ATP dependency, inhibitor specificity, and the size class of mRNA that encode the corresponding carrier, suggesting that the mitochondrial carrier of GSH is a gene product distinct from the plasma membrane transporters.
Accumulating evidence suggests that the early pulmonary inflammation pathogenesis in cystic fibrosis (CF) may be associated with an abnormal increase in the production of pro-inflammatory cytokines in the CF lung, even in the absence of infectious stimuli. We have postulated that if baseline abnormalities in airway epithelial cell production of cytokines occur in CF, they should be manifested in the CF bronchial submucosal glands, which are known to express high levels of CFTR (cystic fibrosis transmembrane conductance regulator) protein, the gene product mutated in CF disease. Immunohistochemical analyses showed that CF bronchial submucosal glands in patients homozygous for the deltaF508 deletion expressed elevated levels of the endogenous chemokine interleukin (IL)-8 but not the pro-inflammatory cytokines IL-1beta and IL-6, compared with non-CF bronchial glands. Moreover, basal protein and mRNA expression of IL-8 were constitutively up-regulated in cultured deltaF508 homozygous CF human bronchial gland cells, in an unstimulated state, compared with non-CF bronchial gland cells. Furthermore, the exposure of CF and non-CF bronchial gland cells to an elevated extracellular Cl- concentration markedly increased the release of IL-8, which can be corrected in CF gland cells by reducing the extracellular Cl- concentration. We also found that, in contrast to non-CF gland cells, dexamethasone did not inhibit the release of IL-8 by cultured CF gland cells. The selective up-regulation of bronchial submucosal gland IL-8 could represent a primary event that initiates early airway submucosal inflammation in CF patients. These findings are relevant to the pathogenesis of CF and suggest a novel pathophysiological concept for the early and sustained airway inflammation in CF patients.
Inflammatory cytokine activity is increased in many forms of experimental and clinical liver injury including alcoholic liver disease (ALD). Monocytes and Kupffer cells produce cytokines such as tumor necrosis factor (TNF), interleukin (IL)-8, and IL-6 in response to stimuli such as endotoxin (lipopolysaccharide [LPS]). This cytokine production is regulated by the oxidative stress-sensitive transcription factor NFkappaB. Glutathione (GSH) prodrugs such as oxathizolidine-4-carboxylic acid (OTZ) can inhibit activation of NFkappaB and subsequent cytokine production in monocytes and Kupffer cells in vitro. The objective of this study was to treat stable cirrhotic patients with OTZ in vivo to evaluate its effects on monocyte cytokine production (TNF, IL-8, and IL-6) and whole blood GSH levels.
Nine patients with stable cirrhosis received OTZ (70 mg/kg IV every 8 hours) for 9 days. Peripheral blood monocytes were obtained on study days 1 and 9, using density gradient centrifugation and adherence to plastic, and were stimulated with LPS (5 microg/mL). TNF, IL-8, and IL-6 were measured in culture supernatants by enzyme-linked serum immunosorbent assay. Whole blood GSH levels were measured by high-performance liquid chromatography.
There was a significant decrease in monocyte TNF, IL-8, and IL-6 production after OTZ therapy. Patients with cirrhosis had significantly lower admission whole blood GSH levels compared with controls and GSH normalized with OTZ administration.
Treatment with the GSH prodrug OTZ inhibited monocyte cytokine production and increased whole blood GSH. This may have important therapeutic implications for multiple cytokine-mediated disease processes.
The routes of metabolism of S-carboxymethyl-L-cysteine in humans are dependent on the time of dosing. Administration of 750 mg of S-carboxymethyl-L-cysteine (Day 1) during the day at 8:00 AM followed by a 8:00 AM to 4:00 PM urine collection revealed that S-carboxymethyl-L-cysteine S-oxide was the major urinary metabolite produced. The 4:00 PM to midnight urine collection resulted in S-(carboxymethylthio)-L-cysteine being identified as the major urinary metabolite. However, the administration of 750 mg of S-carboxymethyl-L-cysteine (day 15) during the night at midnight and analysis of the midnight to 8:00 AM urine collection found that thiodiglycolic acid was the major urinary metabolite, whereas thiodiglycolic S-oxide was identified as the major urinary metabolite in the 8:00 AM to 4:00 PM urine collection. A diurnal variation in the metabolism of S-carboxymethyl-L-cysteine was seen and, in particular, the timing of S-carboxymethyl-L-cysteine administration had a profound effect on the identity of urinary S-oxide metabolites produced. After administration at 8:00 AM the urinary S-oxides produced were S-carboxymethyl-L-cysteine S-oxide and S-methyl-L-cysteine S-oxide but at midnight the major urinary S-oxide metabolite produced was thiodiglycolic acid S-oxide.
In addition to its well-known antioxidant effects, glutathione apparently has an additional double role in the central nervous system as a neurotransmitter and neuromodulator. A number of recent neurochemical, neuropharmacological and electrophysiological studies have yielded evidence on both functions. As an excitatory neurotransmitter, glutathione depolarizes neurons by acting as ionotropic receptors of its own which are different from any other excitatory amino acid receptors. As a neuromodulator, it displaces ionotropic glutamate receptor ligands from their binding sites and regulates calcium influx through N-methyl-D-aspartate receptor-governed ionophores. In brain slices glutathione has been shown to regulate the release of other transmitters, e.g., gamma-aminobutyrate and dopamine, mediated by N-methyl-D-aspartate receptors. In the present article, we review recent findings on the neuromodulatory actions of glutathione and discuss possible physiological and pathophysiological consequences.
In spontaneously hypertensive rats (SHRs), excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes and normalizing membrane Ca2+ channels and cytosolic free calcium. The aim of the present study was to investigate whether a dietary supplementation of an endogenous fatty acid, alpha-lipoic acid, another thiol compound that is known to increase tissue cysteine and glutathione, can lower blood pressure and normalize associated biochemical and histopathological changes in SHRs.
Starting at 12 weeks of age, animals were divided into three groups of six animals each. Animals in the Wistar- Kyoto (WKY) rat control group and the SHR control group were given a normal diet, and the SHR-lipoic acid group was given a diet supplemented with lipoic acid (500 mg/kg feed) for the next 9 weeks. After 9 weeks, systolic blood pressure, platelet [Ca2+]i, plasma insulin and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared with WKY rat controls and the SHR lipoic acid group. SHR controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys.
Dietary alpha-lipoic acid supplementation in SHRs lowered the systolic blood pressure, cytosolic [Ca2+]i, blood glucose and insulin levels, and tissue aldehyde conjugates, and attenuated adverse renal vascular changes.
The ability of Alpha-Lipoic Acid (ALA) and N-Acetyl Cysteine (NAC), two active antioxidant agents, to correct in vitro the most significant functional defects of peripheral blood mononuclear cells (PBMC) isolated from advanced stage cancer patients was studied. The proliferative response of PBMC isolated from cancer patients to anti-CD3 monoclonal antibody (MAb) and the expression of CD25 (IL-2R) and CD95 (Fas) on unstimulated and anti-CD3 MAb-stimulated PBMC were studied, and the serum levels of proinflammatory cytokines IL-1, IL-6, TNFalpha as markers of pro-cachectic activity in cancer patients, and the serum levels of IL-2 and sIL-2R were assessed. Twenty patients (mean age 64.6 years) with cancer of lung, ovary, endometrium, and head and neck, all in advanced (III, IV) stage of disease, were studied. The serum levels of IL-1beta, IL-2, IL-6, TNFalpha, and sIL-2R were significantly higher in cancer patients than in normal subjects. The response of PBMC isolated from cancer patients to anti-CD3 MAb was significantly lower than that of controls. The addition of either ALA 0.001 mM or NAC 0.004 mM in the PBMC cultures stimulated with anti-CD3 MAb significantly increased the response of PBMC isolated from cancer patients and normal subjects. After 24 and 72 hr of culture with anti-CD3 MAb, the expression of CD25 and CD95 on PBMC isolated from cancer patients was significantly lower than that of PBMC isolated from normal subjects. The addition of either ALA or NAC into cultures of PBMC isolated from cancer patients significantly increased the percentage of cells expressing CD25 as well as those expressing CD95. The results of the present study show a favorable effect of antioxidant agents ALA and NAC on several important T-cell functions in vitro in advanced-stage cancer patients.
Exercise appears to increase reactive oxygen species, which can result in damage to cells. Exercise results in increased amounts of malondialdehyde in blood and pentane in breath; both serve as indirect indicators of lipid peroxidation. However, not all studies report increases; these equivocal results may be due to the large intersubject variability in response or the nonspecificity of the assays. Some studies have reported that supplementation with vitamins C and E, other antioxidants, or antioxidant mixtures can reduce symptoms or indicators of oxidative stress as a result of exercise. However, these supplements appear to have no beneficial effect on performance. Exercise training seems to reduce the oxidative stress of exercise, such that trained athletes show less evidence of lipid peroxidation for a given bout of exercise and an enhanced defense system in relation to untrained subjects. Whether the body's natural antioxidant defense system is sufficient to counteract the increase in reactive oxygen species with exercise or whether additional exogenous supplements are needed is not known, although trained athletes who received antioxidant supplements show evidence of reduced oxidative stress. Until research fully substantiates that the long-term use of antioxidants is safe and effective, the prudent recommendation for physically active individuals is to ingest a diet rich in antioxidants.
Increased levels of interleukin 8 (IL-8) are found in bronchoalveolar lavage (BAL) fluids from patients with the acute respiratory distress syndrome (ARDS). However, IL-8 is not an efficient predictor of the course of ARDS. Our prior studies demonstrated that IL-8 present in lung fluids from patients with ARDS is associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 complexes). These data led us to hypothesize that the complexes might better predict the development of acute lung injury. Accordingly, we measured concentrations of free and complexed IL-8 in BAL fluids from 19 patients at risk and 45 with established ARDS on Days 1, 3, 7, 14, and 21 after the onset of ARDS. The concentrations of anti-IL-8:IL-8 complexes in patients with ARDS on Day 1 were significantly higher than in patients at risk (p < 0.05). There was a significant association between anti-IL-8:IL-8 complex concentrations and the onset of ARDS (p = 0.03). Similarly, anti-IL-8:IL-8 complex concentrations were significantly higher in patients on Day 1 of ARDS who later died (p < 0.05), and the association between high anti-IL-8: IL-8 complex concentrations and the probability of dying was significant (p = 0.03). The presence of anti-IL-8:IL-8 complexes in BAL fluids of patients with ARDS is an important prognostic indicator for the development and outcome of ARDS.
Carbocysteine is a mucoactive drug and is being used for both acute and chronic infectious airway diseases. Although carbocysteine can repair the damage of epithelial cells caused by exposure to various agents, the effects of this agent on allergic airway diseases such as asthma and eosinophilic bronchitis with an isolated chronic cough, in both of which epithelial damage may be characteristic, is not clear. We investigated the effects of carbocysteine on antigen-induced cough hypersensitivity to inhaled capsaicin at 48 h and bronchial hyperresponsiveness to inhaled methacholine at 72 h after challenge with an aerosolized antigen in actively sensitized guinea pigs. After measuring bronchial responsiveness, we examined neutral endopeptidase (NEP) activity in the tracheal tissue. Carbocysteine (10, 30, or 100 mg/kg) was given intraperitoneally every 12 h for 3 days after antigen challenge. The number of coughs elicited by an aerosol of capsaicin (10(-4) M) was significantly (p < 0.01) decreased in carbocysteine groups (6.13 +/- 0.59 at 10 mg/kg, 4.88 +/- 0.67 at 30 mg/kg, and 4.50 +/- 0.33 at 100 mg/kg during 3 min measurement) compared with the control group (9.75 +/- 0.53). Furthermore, carbocysteine dose dependently repaired the antigen-induced decrease of NEP activity in the tracheal tissue, but it did not influence the bronchial hyperresponsiveness or bronchoalveolar lavage cell component. These findings suggest that carbocysteine promotes the repair of damaged epithelium by allergic reaction and may be useful in allergic airway diseases accompanied by isolated chronic coughing, especially eosinophilic bronchitis without asthma and tracheobronchitis with cough hypersensitivity.
Patients with chronic obstructive pulmonary disease (COPD) exhale more hydrogen peroxide (H2O2) and lipid peroxidation products than healthy subjects. This may reflect oxidative stress in the airways that plays important role in the development and progression of COPD. N-acetylcysteine (NAC), a mucolytic drug, possesses antioxidant properties as it is a precursor of reduced glutathione that together with glutathione peroxidase may decompose H2O2 and lipid peroxides. We aimed to determine the effect of NAC, 600 mg effervescent tablets (Fluimucil), once a day for 12 months, and placebo on the concentration of H2O2 and thiobarbituric acid reactive substances (TBARs) in expired breath condensate and serum levels of two lipid peroxidation products (TBARs, lipid peroxides) in patients with COPD. The study was performed as a double-blind, double-dummy comparison between active drug and placebo in two parallel groups. Forty-four outpatients with stable COPD (22 in the NAC group and 22 in the placebo group) completed the study. Specimens of expired breath condensate and serum were collected at the randomization visit and then every 3 months over 1 year. The concentration of TBARs and H2O2 in expired breath condensate was measured spectrofluorimetrically by the thiobarbituric acid and homovanillic acid methods, respectively. Serum levels of lipid peroxides were determined spectrophotometrically after extraction with butanol and pyridine. Initially, H2O2 exhalation did not differ between the placebo and NAC groups up to 6 months of treatment. After this the significant differences were observed. After 9 and 12 months of treatment NAC group exhaled 2.3-fold (0.17+/-0.33 microM vs. 041+/-0.26 microM, P<0.04) [median 0.01 microM, quartile range (qr)=0.22 vs. median 0.15 microM, qr =0.43] and 2.6-fold (0.15+/-0.23 microM vs. 0.40+/-0.25 microN, P<0.05) median = 0.00 microM, qr = 0.23 vs. median = 0.36 microM, qr = 0.51] less H2O2 than placebo receivers, respectively. No significant effect of NAC administration on TBARs exhalation and serum levels of TBARs and lipid peroxides were noted over the whole treatment period. Also no significant associations between exhaled H2O2 and concentrations of lipid peroxidation products were noted in both treatment groups at any time-point. These results indicate that long-term oral administration of NAC attenuates H2O2 formation in the airways of COPD subjects and prove anti-oxidant action of drug. However, further studies are necessary to estimate the clinical significance of this finding.
Chemioxyexcitation [deltapO2/reactive oxygen species (ROS)] constitutes a potential signaling mechanism for regulating an inflammatory signal associated with oxidative stress. Exposure of fetal alveolar type II epithelial cells to an ascending deltaPO2 regimen with or without the hydroxyl radical (OH) or the superoxide radical anion (O2*-) induces a dose-dependent release of pro-inflammatory cytokines. Similarly, the Escherichia coli-derived lipopolysaccharide (LPS) upregulates cytokine biosynthesis in a dose- and time-dependent manner. Irreversible inhibition by L-buthionine-(S,R)-sulfoximine (BSO) of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of glutathione (GSH), induces intracellular accumulation of ROS and augments chemioxyexcitation and LPS-mediated release of interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha). Analysis of the molecular mechanism implicated reveals an inhibitory kappaB (IkappaB-alpha)/nuclear factor kappaB (NF-kappaB)-independent pathway mediating the redox-dependent regulation of inflammatory cytokines. Although BSO stabilizes cytosolic IkappaB-alpha and downregulates its phosphorylation, thereby blockading NF-kappaB activation, it augments cytokine biosynthesis in a dose-dependent manner. These results indicate that glutathione depletion is associated with augmentation of an oxidative stress-mediated pro-inflammatory state in an ROS-dependent mechanism and that the IkappaB-alpha/NF-kappaB pathway is otherwise not necessarily indispensable for redox-mediated regulation of cytokines.
S-nitrosothiols are biological metabolites of nitric oxide. It has often been suggested that they represent a more stable metabolite of nitric oxide that can either be stored, or transported, although the evidence for this is sparse. There are many unanswered questions concerning how S-nitrosothiols are formed, how they are metabolized and how they elicit biological responses. These questions are highlighted by the fact that the known chemistry of nitric oxide, thiols, and S-nitrosothiols cannot serve to explain their proposed biological activities. This review attempts to highlight the gulf between our chemical understanding of S-nitrosothiols and the proposed biological activities of these compounds with respect to guanylyl cyclase-independent nitric oxide bioactivity and also the control of vascular tone.
Mucus hypersecretion is a hallmark of chronic obstructive pulmonary disease (COPD) and is regarded as contributing to airflow limitation in these patients. The value of mucolytic therapy is still a matter for debate. We investigated the short-term influence of an inhalative mucolytic drug mercapto-ethane sulfonate (Mesna) on the lung function, respiratory mechanics and viscous respiratory load in patients with COPD in a randomized, placebo controlled, double-blind, cross-over study in 10 patients with moderate, stable COPD. Resistance, static compliance and frequency dependent dynamic compliance and viscous respiratory work, FVC, FEV(1), PEFR, MEF(75), MEF(50), MEF(25), TLC and RV were measured. These lung function parameters did not show any significant differences between the treatment groups. In conclusion, an inhalative treatment with an active mucolytic drug of patients with mild COPD does not improve respiratory mechanics and respiratory load.
In this study, the possible mechanisms of action for the inhibitory effects of S-carboxymethylcysteine on the activation of human neutrophils by N-formyl-methionyl-leucyl-phenylalanine (FMLP) were investigated. Preincubation of neutrophils with more than 10 microg/ml of S-carboxymethylcysteine was found to impair neutrophil chemotactic activity toward FMLP, and to inhibit FMLP-mediated neutrophil adherence to pulmonary vascular endothelial cells. Preincubation of neutrophils with 10 and 100 microg/ml of S-carboxymethylcysteine decreased in the production of inositol 1,4,5-triphosphate (IP(3)) and diacylglycerol in neutrophils stimulated with FMLP, respectively. Preincubation of neutrophils with S-carboxymethylcysteine did not affect the cellular cyclic AMP (cAMP) levels in neutrophils stimulated with FMLP. S-carboxymethylcysteine inhibited the enzymatic activity of phosphatidyl inositol-specific phospholipase C in vitro in a concentration-dependent manner. These findings indicate that S-carboxymethylcysteine attenuates FMLP-stimulated neutrophil activation at least in part by inhibiting phosphatidyl inositol-specific phospholipase C-mediated signal transduction.
Patients with end-stage renal failure have increased oxidative stress and show elevated cardiovascular mortality. Whether increased cardiovascular events can be prevented by the administration of antioxidants is unknown.
We evaluated the effects of acetylcysteine, a thiol-containing antioxidant, on cardiovascular events in patients undergoing hemodialysis. A prospective, randomized, placebo-controlled trial was conducted between October 1, 1999, and September 30, 2001, in 134 patients (76 male and 58 female) with a mean age of 62+/-16 years (mean+/-SD) who had been undergoing maintenance hemodialysis for a minimum of 3 months 3 times weekly in an ambulatory center. Median (range) follow-up was 14.5 (1 to 24) months. Patients were randomly assigned either to receive acetylcysteine (600 mg BID) or placebo. The primary end point was a composite variable consisting of cardiac events including fatal and nonfatal myocardial infarction, cardiovascular disease death, need for coronary angioplasty or coronary bypass surgery, ischemic stroke, peripheral vascular disease with amputation, or need for angioplasty. Secondary end points included each of the component outcomes, total mortality, and cardiovascular mortality. A total of 18 (28%) of the 64 hemodialysis patients assigned to acetylcysteine group and 33 (47%) of the 70 hemodialysis patients assigned to control group had a primary end point (relative risk, 0.60 [95% CI, 0.38 to 0.95], P=0.03). No significant differences in secondary end points or total mortality were detected.
In hemodialysis patients, treatment with acetylcysteine (600 mg BID) reduces composite cardiovascular end points.