Showing papers in "Basic & Clinical Pharmacology & Toxicology in 2006"
TL;DR: Five reasons that favour use of propensity scores are discussed: the value of focus on indications for drug use; optimal matching strategies from alternative designs; improved control of confounding with scarce outcomes; ability to identify interactions between propensity of treatment and drug effects on outcomes; and correction for unobserved confounders via propensity score calibration.
Abstract: Use of propensity scores to identify and control for confounding in observational studies that relate medications to outcomes has increased substantially in recent years. However, it remains unclear whether, and if so when, use of propensity scores provides estimates of drug effects that are less biased than those obtained from conventional multivariate models. In the great majority of published studies that have used both approaches, estimated effects from propensity score and regression methods have been similar. Simulation studies further suggest comparable performance of the two approaches in many settings. We discuss five reasons that favour use of propensity scores: the value of focus on indications for drug use; optimal matching strategies from alternative designs; improved control of confounding with scarce outcomes; ability to identify interactions between propensity of treatment and drug effects on outcomes; and correction for unobserved confounders via propensity score calibration. We describe alternative approaches to estimate and implement propensity scores and the limitations of the C-statistic for evaluation. Use of propensity scores will not correct biases from unmeasured confounders, but can aid in understanding determinants of drug use and lead to improved estimates of drug effects in some settings.
517 citations
TL;DR: Results show that rutin exhibits antihyperglycaemic and antioxidant activity in streptozotocin-induced diabetic rats.
Abstract: Flavonoids are non-nutritive dietary components that are widely distributed in plants. The present study investigated the antihyperglycaemic and antioxidant effect of rutin, a polyphenolic flavonoid in normal and streptozotocin-induced diabetic Wistar rats. Diabetes as induced in rats by an intraperitoneal injection of streptozotocin. Rutin was orally administered to normal and diabetic rats for a period of 45 days. Fasting plasma glucose, glycosylated haemoglobin, thiobarbituric acid reactive substances and lipid hydroperoxides were significantly (P<0.05) increased, whereas insulin, C-peptide, total haemoglobin, protein levels, non-enzymic antioxidants (glutathione, vitamin C, vitamin E and ceruloplasmin) were decreased significantly (P<0.05) in diabetic rats. Oral administration of rutin to diabetic rats significantly (P<0.05) decreased fasting plasma glucose, glycosylated haemoglobin and increased insulin, C-peptide, haemoglobin and protein levels. Administration of rutin also decreased thiobarbituric acid reactive substances and lipid hydroperoxides and increased the non-enzymic antioxidants significantly (P<0.05). Treatment of normal rats with rutin did not significantly (P<0.05) alter any of the parameters studied. These results show that rutin exhibits antihyperglycaemic and antioxidant activity in streptozotocin-induced diabetic rats.
442 citations
TL;DR: Late toxic effects of sulfur mustard were most commonly found in lungs, skin and eyes, and natural killer cells were significantly lower 16 to 20 years after intoxication.
Abstract: Sulfur mustard is an alkylating agent that reacts with ocular, respiratory, cutaneous, and bone marrow tissues, resulting in early and late toxic effects. We compare these effects based on the experience in Iranian veterans exposed to the agent during the Iran-Iraq conflict (1983-88). The first clinical manifestations of sulfur mustard poisoning occurred in the eyes with a sensation of grittiness, lacrimation, photophobia, blepharospasm, and corneal ulceration. Respiratory effects appeared as rhinorhea, laryngitis, tracheobronchitis, and dyspnoea. Skin lesions varied from erythema to bullous necrotization. Initial leukocytosis and lymphopenia returned to normal within four weeks in recovered patients, but marked cytopenia with bone marrow failure occurred in fatal cases. Late toxic effects of sulfur mustard were most commonly found in lungs, skin and eyes. Main respiratory complications were chronic obstructive pulmonary disease, bronchiectasis, asthma, large airway narrowing, and pulmonary fibrosis. Late skin lesions were hyperpigmentation, dry skin, atrophy, and hypopigmentation. Fifteen of the severely intoxicated patients were diagnosed with delayed keratitis, having corneal vascularization, thinning, and epithelial defect. Respiratory complications exacerbated over time, while cutaneous and ocular lesions decreased or remained constant. Both the severity and frequency of bronchiectatic lesions increased during long-term follow-up. The only deteriorating cutaneous complication was dry skin. The maximum incidence of delayed kaeratitis was observed 15 to 20 years after initial exposure. Being suggested as the main cause ofassociated with malignancies and recurrent infections, natural killer cells were significantly lower 16 to 20 years after intoxication.
311 citations
TL;DR: The comet assay is a valuable method for detection of genotoxic exposure in humans and it is important that the performance of the assay is investigated in multi-laboratory validation trials.
Abstract: Generation of DNA damage is considered to be an important initial event in carcinogenesis. The single cell gel electrophoresis (comet) assay is a technically simple and fast method that detects genotoxicity in virtually any mammalian cell type without requirement for cell culture. This review discusses the strength of the comet assay in biomonitoring at its present state of validation. The simple version of the alkaline comet assay detects DNA migration caused by strand breaks, alkaline labile sites, and transient repair sites. By incubation with bacterial glycosylase/endonuclease enzymes, broad classes of oxidative DNA damage, alkylations, and ultraviolet light-induced photoproducts are detected as additional DNA migration. The most widely measured enzyme sensitive sites have been those detected by formamidopyrimidine DNA glycosylase (FPG) and endonuclease III (ENDOIII). Reports from biomonitoring studies show that the basal level of DNA damage in leukocytes is influenced be a variety of lifestyle and environmental exposures, including exercise, air pollution, sunlight, and diet. Although not all types of carcinogenic exposures should be expected to damage DNA in leukocytes, the comet assay is a valuable method for detection of genotoxic exposure in humans. However, the predictive value of the comet assay is unknown because it has not been investigated in prospective cohort studies. Also, it is important that the performance of the assay is investigated in multi-laboratory validation trials. As a tool in risk assessment the comet assay can be used in characterization of hazards.
257 citations
TL;DR: A simple method to compare dynamic treatment regimes by artificially censoring subjects and then using inverse probability weighting (IPW) to adjust for any selection bias introduced by the artificial censoring is described.
Abstract: Appropriate analysis of observational data is our best chance to obtain answers to many questions that involve dynamic treatment regimes. This paper describes a simple method to compare dynamic treatment regimes by artificially censoring subjects and then using inverse probability weighting (IPW) to adjust for any selection bias introduced by the artificial censoring. The basic strategy can be summarized in four steps: 1) define two regimes of interest, 2) artificially censor individuals when they stop following one of the regimes of interest, 3) estimate inverse probability weights to adjust for the potential selection bias introduced by censoring in the previous step, 4) compare the survival of the uncensored individuals under each regime of interest by fitting an inverse probability weighted Cox proportional hazards model with the dichotomous regime indicator and the baseline confounders as covariates. In the absence of model misspecification, the method is valid provided data are available on all time-varying and baseline joint predictors of survival and regime discontinuation. We present an application of the method to compare the AIDS-free survival under two dynamic treatment regimes in a large prospective study of HIV-infected patients. The paper concludes by discussing the relative advantages and disadvantages of censoring/IPW versus g-estimation of nested structural models to compare dynamic regimes.
252 citations
TL;DR: Data suggest a small reduced risk for naproxen present only in non-users of aspirin, mainly people free of clinically apparent vascular disease.
Abstract: Whether non-aspirin non-steroidal antiinflammatory drugs (NSAIDs) affect the risk of myocardial infarction is unclear. Also, it is unknown whether the effect varies by individual NSAIDs. To summarize the evidence from published observational studies on the risk of myocardial infarction associated with both traditional NSAIDs (tNSAIDs) and selective inhibitors of cyclooxygenase-2 (Coxibs), the authors conducted a systematic review of cohort and case-control studies on NSAIDs and myocardial infarction published between 2000 and 2005. Sixteen original studies were selected according to predefined criteria. Two researchers independently extracted the data on individual study characteristics and results. The authors calculated pooled relative risk (RR) estimates of myocardial infarction for specific NSAIDs compared with no NSAID use, tested the heterogeneity of effects, and evaluated potential reasons for heterogeneity. The pooled RR of myocardial infarction was 0.98 (95% confidence interval (CI): 0.92-1.05) for naproxen, 1.07 (95% CI: 1.02-1.12) for ibuprofen, 1.44 (95% CI: 1.32-1.56) for diclofenac, 0.96 (95% CI: 0.90-1.02) for celecoxib, and 1.26 (95% CI: 1.17-1.36) for rofecoxib (all doses). The pooled RR for rofecoxib at doses >25 mg/day was 1.78 (95% CI: 1.36-2.34), and 1.18 (95% CI: 1.07-1.31) for doses < or =25 mg/day. The RR associated with naproxen was 0.83 (95% CI: 0.72-0.90) among non-users of low-dose aspirin. The RR associated with rofecoxib (all doses) was 1.39 (95% CI: 1.25-1.54) among subjects without a history of myocardial infarction. The risk of myocardial infarction varies with individual NSAIDs. An increased risk was observed for diclofenac and rofecoxib, the latter one with a clear dose-response trend. There was a suggestion of a small increased risk with ibuprofen. Also, data suggest a small reduced risk for naproxen present only in non-users of aspirin, mainly people free of clinically apparent vascular disease.
174 citations
TL;DR: In this article, the effect of different CYP isoform inhibitors on the elimination of a clinically relevant concentration of pioglitazone (1 microM) and the formation of the main primary metabolite M-IV were studied using pooled human liver microsomes.
Abstract: Our objective was to identify the cytochrome P450 (CYP) enzymes that metabolise pioglitazone and to examine the effects of the CYP2C8 inhibitors montelukast, zafirlukast, trimethoprim and gemfibrozil on pioglitazone metabolism in vitro. The effect of different CYP isoform inhibitors on the elimination of a clinically relevant concentration of pioglitazone (1 microM) and the formation of the main primary metabolite M-IV were studied using pooled human liver microsomes. The metabolism of pioglitazone by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5 was investigated using human recombinant CYP isoforms. In particular, the inhibitors of CYP2C8, but also those of CYP3A4, markedly inhibited the elimination of pioglitazone and the formation of M-IV by HLM. Inhibitors selective to other CYP isoforms had a minor effect only. Of the recombinant isoforms, CYP2C8 (20 pmol/ml) metabolised pioglitazone markedly (56% in 60 min.), and also CYP3A4 had a significant effect (37% in 60 min.). Montelukast, zafirlukast, trimethoprim and gemfibrozil inhibited pioglitazone elimination in HLM with IC50 values of 0.51 microM, 1.0 microM, 99 microM and 98 microM, respectively, and the formation of the metabolite M-IV with IC50 values of 0.18 microM, 0.78 microM, 71 microM and 59 microM, respectively. In conclusion, pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYP3A4 in vitro. CYP2C9 is not significantly involved in the elimination of pioglitazone. The effect of different CYP2C8 inhibitors on pioglitazone pharmacokinetics needs to be evaluated also in vivo because, irrespective of their in vitro CYP2C8 inhibitory potency, their pharmacokinetic properties may affect the extent of interaction.
137 citations
TL;DR: The kinds of research questions that can be addressed using pharmacoepidemiologic databases are described, some differences between medical records and administrative databases are explained, and factors that should be considered when choosing a database for a particular study are discussed.
Abstract: Pharmacoepidemiology is the study of the use and effects of medications in populations. Large health care databases are often used to address research questions within pharmacoepidemiology. This paper briefly describes the kinds of research questions that can be addressed using pharmacoepidemiology databases, provides an overview of pharmacoepidemiologic databases, describes some differences between medical records and administrative databases, discusses factors that should be considered when choosing a database for a particular study, and considers what the future holds.
130 citations
TL;DR: Results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.
Abstract: Proton pump inhibitors are being increasingly used and for longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo-/achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.
128 citations
TL;DR: Alleged penicillin allergic patients are likely to be treated with more toxic, broad-spectrum, and more expensive antibiotics, with effects on microbial resistance patterns and public economy as a consequence.
Abstract: Suspected penicillin allergy is common among hospitalised patients, but the quality of the information given by the patient is often doubtful. Alleged penicillin allergic are likely to be treated with more toxic, broad-spectrum, and more expensive antibiotics, with effects on microbial resistance patterns and public economy as a consequence. We performed a cross-sectional case-control study with two visits to all clinical departments of a large university hospital in order to find in-patients with medical files labelled "penicillin allergy" or who reported penicillin allergy upon admission. Patient histories were obtained via a questionnaire, and they were offered investigation for penicillin allergy with specific IgE, basophil histamine release, skin prick tests, intradermal tests and drug challenge tests. Finally, the pharmaco-economical consequences of the penicillin allergy were estimated. In a cohort of 3642 patients, 96 fulfilled the inclusion criteria giving a point-prevalence of alleged penicillin allergy of 5% in a hospital in-patient population. Mean time elapsed since the alleged first reaction to penicillin was 20 years. The skin was the most frequently affected organ (82.2%), maculo-papular exanthema (35.4%) and urticaria (10.4%) being the most frequently reported reactions. 25% did not recall the time of their reaction. 82.2% did not remember the name of the penicillin they reacted to. 34.8% had been treated with penicillins after suspicion of penicillin allergy had been raised. None of these reacted to penicillins. 33.3% of the patients receiving antibiotics during their current hospitalisation were prescribed penicillins. 2% developed non-severe exanthema. The average acquisition costs for antibiotics to penicillin allergic patients were euro 278, compared to euro 119 had they been non-allergic. The prevalence of suspected penicillin allergy was lower than reported elsewhere. A substantial number of patients failed to recall basic information about their alleged allergy. Patients reporting penicillin allergy upon admission and labels stating penicillin allergy on medical files are ignored in almost a third of patients receiving antibiotics. The acquisition costs for antibiotics to penicillin allergic patients were higher, compared to the cost had the patients been non-allergic.
120 citations
TL;DR: In this article, the effect of R-citalopram on the association of escitaloprams with the high affinity primary site and on its dissociation from the serotonin transporter via an allosteric mechanism was investigated.
Abstract: Recent results on the in vivo and in vitro pharmacology of escitalopram are summarised. The exact molecular mechanism by which R-citalopram inhibits the effect of S-citalopram on the serotonin transporter remains to be elucidated. Preliminary evidence indicates an effect of R-citalopram on the association of escitalopram with the high affinity primary site, and on its dissociation from the serotonin transporter, via an allosteric mechanism. Escitalopram can be considered as an allosteric serotonin reuptake inhibitor. This serotonin dual action in binding to two sites on the serotonin transporter (both the primary site and the allosteric site) is hypothesised to be responsible for a longer binding to, and therefore greater inhibition of the serotonin transporter by escitalopram.
TL;DR: The present study demonstrates the effect of acute arsenic administration at three different doses in liver and brain of Wistar rats and observed significant changes in lipid peroxidation and glutathione peroxidase activity, as well as dose-dependent histopathological changes.
Abstract: Arsenic is a well established human carcinogen and is ubiquitous in the environment. The present study demonstrates the effect of acute arsenic administration at three different doses in liver and brain of Wistar rats. Sodium arsenite was administered orally at doses of 6.3 mg/kg, 10.5 mg/kg and 12.6 mg/kg of body weight on the basis of a lethal dose 50% (LD50) for 24 hr. After administration of arsenites, liver and brain were analyzed for various parameters of oxidative stress, histopathological changes and caspase-3 activity. Glutathione levels were decreased significantly in the liver at all doses. In liver the following biochemical changes were observed, a significant lipid peroxidation and cytochrome-P450 induction along with significant decrease in catalase and superoxide dismutase was observed at 10.5 mg/kg and 12.6 mg/kg. The activity of glutathione peroxidase was increased significantly at all doses. In brain, no significant change was observed at 6.3 mg/kg. However, a significant increase in lipid peroxidation and glutathione peroxidase activity along with significant decrease in the activity of glutathione, catalase and superoxide dismutase was observed at 10.5 mg/kg and 12.6 mg/kg. The activity of glutathione-S-transferase was decreased significantly in both liver and brain at 10.5 and 12.6 mg/kg. No significant alteration in the activity of glucose-6-phosphate dehydrogenase and glutathione reductase was observed in either liver or brain at any dose. Dose-dependent histopathological changes, observed in both liver and brain are also described. A significant increase in caspase-3 activity was observed at all doses in liver and at 10.5 and 12.6 mg/kg in brain. Sodium arsenite caused DNA cleavage into fragments and manifested as “DNA laddering”, a hallmark of apoptosis.
TL;DR: Significant differences exist in the inhibitory potency of protease inhibitors for different CYP3A forms, and ritonavir, nelfinavir, saquinavir and amprenavir seem to be prone to drug-drug interactions by inhibiting both CYP1A4 and CYP2A5.
Abstract: The effects of five HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) on cytochrome P450 (CYP) 3A4, 3A5 and 3A7 activities were studied in vitro using testosterone 6beta-hydroxylation in recombinant CYP3A4, CYP3A5 and CYP3A7 enzymes. The protease inhibitors showed differential inhibitory effects on the three CYP3A forms. Ritonavir and saquinavir were non-selective and preferential inhibitors of CYP3A4 and CYP3A5 (K(i) 0.03 microM and 0.6-0.8 microM for ritonavir and saquinavir, respectively), and weaker inhibitors of CYP3A7 (K(i) 0.6 microM and 1.8 microM, respectively). Nelfinavir was a potent and non-selective inhibitor of all three CYP3A forms (K(i) 0.3-0.4 microM). Amprenavir and indinavir preferentially inhibited CYP3A4 (K(i) 0.1 microM and 0.2 microM, respectively), with weaker inhibitory effects on CYP3A5 (K(i) 0.5 microM and 2.2 microM, respectively) and CYP3A7 (K(i) 2.1 microM and 10.6 microM, respectively). In conclusion, significant differences exist in the inhibitory potency of protease inhibitors for different CYP3A forms. Ritonavir, nelfinavir, saquinavir and amprenavir seem to be prone to drug-drug interactions by inhibiting both CYP3A4 and CYP3A5. Especially nelfinavir and ritonavir also have a potential to inhibit foetal CYP3A7-mediated drug metabolism and some endogenous pathways that may be crucial to normal foetal development, while indinavir has the lowest potential to inhibit CYP3A5 and CYP3A7.
TL;DR: Subjective heroin effect was rated more positively in heroin inhaling than in injecting patients, despite the lower C(max) levels following heroin inhalation, according to a pharmacokinetics and pharmacodynamics study performed in opioid-dependent patients in the Netherlands.
Abstract: A pharmacokinetic-pharmacodynamic study was performed in opioid-dependent patients in the Netherlands, who were currently treated with high doses of pharmaceutically prepared heroin on medical prescription. Besides intravenous heroin, heroin was prescribed for inhalation by "chasing the dragon" method. In this technique, heroin base is heated on aluminium foil, and heroin vapours are inhaled into the lungs. Not much is known about the pharmacokinetics profile and bioavailability of this specific administration method. Therefore, a study was performed on pharmacokinetics and pharmacodynamics of heroin inhalation and intravenous use. Eleven patients who injected heroin and 9 patients who inhaled heroin entered the study. They were on steady-state heroin treatment for at least 12 months. For safety reasons, there was no crossing-over between heroin injection or inhalation. In a double-blind randomised study, 67-100-150% of the regular heroin maintenance dose was administered to each patient. Maximal single heroin dose was 450 mg. Plasma concentrations of heroin and its metabolites 6-monoacetylmorphine, morphine and morphine-glucuronides were analysed using LC-MS-MS. Blood pressure, heart rate, skin temperature and reaction time were assessed. Furthermore, visual analogue scales regarding craving and appreciation of heroin effect were scored by the subjects. Both in inhaling and injecting patients, the areas under curve of heroin and all measured metabolites were linearly related to heroin dose. Mean C(max) of heroin and its metabolites were 2-6 times lower after inhalation, than after intravenous injection. Bioavailability (F) of heroin inhalation was estimated as 52% (95% CI 44-61%). Heroin was rapidly cleared from plasma. Cl/F was 930 l/hr (95% CI 799-1061 l/hr) after intravenous administration, and 1939 l/hr (95% CI 1661-2217 l/hr) after inhalation. Heroin Cl and Vd were correlated to body weight (R(2) 15-19%). Morphine-glucuronides levels were inversely related to creatinine clearance. After heroin administration, the reaction time was significantly prolonged with 28+/-5.3 msec. in injecting and 13+/-4.9 msec. in inhaling patients. Cardiovascular changes were only mild after heroin administration. Craving-scores declined immediately after heroin administration in both administration groups. Subjective heroin effect was rated more positively in heroin inhaling than in injecting patients, despite the lower C(max) levels following heroin inhalation. In both groups, in this blinded study heroin dose increments were more appreciated than dose reductions. Increments of 50% of the regular heroin dose did not cause any serious side effect.
TL;DR: The solution-containing citrate as buffer caused more pain after subcutaneous injection than the solution with histidine as buffer, suggesting that it seems advisable to employ histidine-buffered solution rather than citrate- Buffered solution for dispensing recombinant human growth hormone by daily sub cutaneous injections.
Abstract: Several hormones are administered by daily subcutaneous injections. Pain caused by subcutaneous injection is an unpleasant condition, which can limit patient compliance. The objective of the present study was to evaluate the perception of pain by subcutaneous injection of two different and commercially available solutions for dispensing recombinant human growth hormone. The solutions are characterised by pH, conservation, and buffer. Isotonic saline was used as reference solution. Fifty-four healthy volunteers (mean age (+/-S.E.M.): 35.5+/-1.1 years) were recruited to the double-blind, randomised study. All injections were performed pairwise (right and left thigh) in one day by the same experienced nurse. Perception of pain was evaluated by the volunteers immediately after injection and 2 min. after injection into the thigh of three formulations, which differed with respect to pH and buffers (histidine, citrate and saline, respectively). Significantly more participants (38/54) found than the citrate buffer caused more pain than the histidine buffer immediately after injection (P=0.002). Histidine buffer did not cause more pain than saline (P=0.996). After 2 min., there was no difference between the histidine and the citrate buffer (P=1.00), nor between the histidine buffer and saline (P=1.00). In summary, the solution-containing citrate as buffer caused more pain after subcutaneous injection than the solution with histidine as buffer. Considering patient compliance, it seems advisable to employ histidine-buffered solution rather than citrate-buffered solution for dispensing recombinant human growth hormone by daily subcutaneous injections.
TL;DR: The results indicate that the antioxidant ellagic acid might have a protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat, but not enough to inhibit cisplat-induced renal dysfunction.
Abstract: The aim of this study was to investigate the possible protective role of antioxidant treatment with ellagic acid on cisplatin-induced nephrotoxicity using biochemical and histopatological approaches. Adult male Sprague-Dawley rats were randomly divided into four groups. The control group received 0.9% saline; animals in the ellagic acid group received only ellagic acid (10 mg/kg); animals in the cisplatin group received only cisplatin (7 mg/kg); animals in the cisplatin + ellagic acid group received ellagic acid for 10 days after cisplatin. The effects of ellagic acid on cisplatin-induced nephrotoxicity were evaluated by plasma creatinine, urea, sodium and calcium concentrations; kidney tissue malondialdehyde, reduced glutathione (GSH), glutathione peroxidase (GSH peroxidase) and catalase activities and histopatological examinations. Administration of cisplatin to rats induced a marked renal failure, characterized by significant increases in plasma creatinine, urea and calcium concentrations. Cisplatin also induced oxidative stress, as indicated by increased kidney tissue concentrations of malondialdehyde, and reduced activities of GSH peroxidase and catalase. Furthermore, treatment with cisplatin caused a marked tubular necrosis, degeneration and desquamation, luminal cast formation, karyomegaly, tubular dilatation, interstitial mononuclear cell infiltration and inter-tubular haemorrhagia. Ellagic acid markedly reduced elevated plasma creatinine, urea and calcium levels and counteracted the deleterious effects of cisplatin on oxidative stress markers. In the same way, ellagic acid ameliorated cisplatin-induced pathological changes including tubular necrosis, degeneration, karyomegaly, tubular dilatation when compared to the cisplatin alone group. These results indicate that the antioxidant ellagic acid might have a protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat, but not enough to inhibit cisplatin-induced renal dysfunction.
TL;DR: Rooibos tea possesses a combination of dominant K(ATP) channel activation and weak Ca(++) antagonist mechanisms and hence justifies its use in hyperactive gastrointestinal disorders.
Abstract: Rooibos tea has been widely used for abdominal spasm and diarrhoea. The aim of the present study was to explore the possible mechanism for its use in such ailments. Its aqueous extract (RT) at 0.3-10 mg/ml produced relaxation of spontaneous and low K(+) (25 mM)-induced contractions of rabbit jejunum, with weak effect on high K(+) (80 mM)-induced contractions. In the presence of glibenclamide, relaxation of low K(+)-induced contractions was prevented. Cromakalim inhibited contractions induced by low K(+), but not high K(+), while verapamil did not differentiate in its inhibitory effect on contractions produced by the two concentrations of K(+). RT also exhibited antidiarrhoeal and antisecretory activities in mice. The spasmolytic effect was concentrated in organic fractions. Its constituents, chrysoeriol, orientin and vitexin showed a similar pattern of spasmolytic effects to the extract, while rutin was more like verapamil. So Rooibos tea possesses a combination of dominant K(ATP) channel activation and weak Ca(++) antagonist mechanisms and hence justifies its use in hyperactive gastrointestinal disorders.
TL;DR: This review presents three non-specific analytic templates that may be applied to individual-level prescription data, including the Lorenz curve, which provides a reasonable ranking of drugs with respect to their retention in users.
Abstract: The advent of large population-based prescription databases has enabled us to study drug use with the individual user as our unit of analysis. This review presents three non-specific analytic templates that may be applied to individual-level prescription data. The ratio of prevalence odds to incidence rate can estimate the average duration for drug use. Limitations and pitfalls are discussed. Although it should be cautiously interpreted, it provides a reasonable ranking of drugs with respect to their retention in users. The Lorenz curve is an analytic tool to express skewness in drug use. It shows the proportion of drug use that is accounted for by percentiles of drug users, ranked according to their volume of drug intake. It may express the extent of heavy users as well as sporadic small-volume users and may, for example, be used to screen for an unsuspected abuse potential of a drug. The waiting-time distribution is a frequency distribution of first occurrences of drug use within a time-window. It forms the basis for a theoretical model for robust estimates of prevalence and incidence rate. On an intuitive level, it displays visual correlates of epidemiological prescribing parameters such as period prevalence, point prevalence, incidence rate, duration, prescription renewal rate, relapse of treatments and seasonality. Each measure may be incorporated into an integral matrix that reflects various traits in utilization of every drug or drug class, thereby possibly finding abnormalities that suggest sub-optimal prescribing.
TL;DR: The whole evidence supports the hypothesis that antidepressants with a relevant blockade action on serotonin reuptake mechanism increase the risk of bleeding, and may be of particular relevance when the SSRIs are associated with NSAIDs as well as low-dose aspirin.
Abstract: Selective serotonin reuptake inhibitors (SSRIs) are nowadays the most widely used antidepressants in the world, mainly because they have a better adverse reaction profile and a higher safety margin in overdoses, when compared to other antidepressants. These drugs recently have been the target of important debates concerning safety issues, among them the possibility that they may increase the risk of bleeding. Over the 1990s, an increasing number of individual cases of bleeding disorders were reported in the literature and to the pharmacovigilance programmes which prompted several epidemiological and pharmacological studies. In this review we have examined all available data. The whole evidence supports the hypothesis that antidepressants with a relevant blockade action on serotonin reuptake mechanism increase the risk of bleeding. Such disorders may have different degrees of severity and may be located anywhere in the body. The epidemiological evidence is, however, more robust for upper gastrointestinal bleeding. It has been estimated that upper gastrointestinal bleeding may occur at a frequency ranging from 1 in 100 to 1 in 1,000 patient-years of exposure to high-affinity drugs (the SSRIs), with the very old patients being in the highest part of the range. The increased risk may be of particular relevance when the SSRIs are associated with NSAIDs as well as low-dose aspirin.
TL;DR: It is shown that resveratrol potently relaxed rat aortic rings with denuded endothelium, and it seems that 4-aminopiridine and margatoxin-sensitive K(+) channels located in the smooth muscle of ratAorta mediated this relaxation.
Abstract: Resveratrol, a phenolic substance present in grapes and a variety of medical plants, has been reported to induce vasorelaxation, however the mechanisms are uncertain. In this paper we investigate the possible participation of K(+) channels in the endothelium-independent vasodilatation of rat aorta induced by resveratrol. Resveratrol induced concentration-dependent relaxation of rings with endothelium and without endothelium. We used different potassium channel inhibitors to determine whether the K(+) channels mediated endothelium-independent relaxation of rat aorta induced by resveratrol. Highly selective blocker of ATP-sensitive K(+) channels, glibenclamide, as well as non-selective blockers of K(+) channels, tetraethylammonium, did not block resveratrol-induced relaxation of rat aortic rings. Charybdotoxin, a blocker of calcium-sensitive K(+) channels did not affect the resveratrol-induced relaxation. 4-Aminopiridine, non-selective blocker of voltage-gated K(+) (Kv) channels, and margatoxin that inhibits Kv1 channels abolished relaxation of rat aortic rings induced by resveratrol. In conclusion, we have shown that resveratrol potently relaxed rat aortic rings with denuded endothelium. It seems that 4-aminopiridine and margatoxin-sensitive K(+) channels located in the smooth muscle of rat aorta mediated this relaxation.
TL;DR: The results suggest that ginsenoside Rh(2) is able to enhance the antitumour activity and decrease the genotoxic effect of cyclophosphamide.
Abstract: Ginsenoside Rh 2 , a panoxadiol saponins, possesses various antitumour properties. Cyclophosphamide, an alkylating agent, has been shown to possess various genotoxic and carcinogenic effects, however, it is still used extensively as an antitumour agent and immunosuppressant in the clinic. Previous reports reveal that cyclophosphamide is involved in some secondary neoplasmas. In this study, the antitumour activity and genotoxic effect of oral intake of ginsenoside Rh 2 combined with intraperitoneal injection of cyclophosphamide was investigated. Meanwhile, C57BL/6 mice bearing B16 melanoma and Lewis lung carcinoma cells were respectively used to estimate the antitumour activity in vivo. The clastogenic activity in bone marrow polychromatic erythrocytes was assayed by frequency of micronucleus. The DNA damage in peripheral white blood cells was assayed by single cell gel electrophoresis as well. The results indicated that oral administration of Rh 2 (5, 10 and 20 mg/kg body weight) alone has no obvious antitumour activity and genotoxic effect in mice, while Rh 2 synergistically enhanced the antitumour activity of cyclophosphamide (40 mg/kg body weight) in a dose-dependent manner. Rh 2 decreased the micronucleus formation in polychromatic erythrocytes and DNA strand breaks in white blood cells in a dose-dependent way. Our results suggest that ginsenoside Rh 2 is able to enhance the antitumour activity and decrease the genotoxic effect of cyclophosphamide.
TL;DR: It is demonstrated that naringenin exhibited antioxidant property and decrease the lipid peroxidation against oxytetracycline-induced oxidative stress in liver.
Abstract: Naringenin is a naturally occurring citrus flavanone, which has been reported to have a wide range of pharmacological properties. The present work was carried out to evaluate the effect of naringenin on antioxidant and lipid peroxidation status in liver of oxytetracycline-intoxicated rats. Intraperitonial administration of oxytetracycline 200 mg/kg for 15 days resulted a significant elevation in serum hepatospecific markers such as aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and bilirubin and the levels of lipid peroxidation markers (thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides) in liver. Oxytetracycline also caused a significant reduction in the activities of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione (GSH), vitamin C and vitamin E in liver. Oral administration of naringenin (50 mg/kg b.w.t.) with oxytetracycline significantly decreased the activities of serum aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase and the levels of bilirubin along with significant decrease in the levels of lipid peroxidation markers in the liver. In addition, naringenin significantly increased the activities of superoxide dismutase, catalase and GSH peroxidase as well as the level of GSH, vitamin C and vitamin E in liver of the oxytetracycline-treated rats. Our results demonstrate that naringenin exhibited antioxidant property and decrease the lipid peroxidation against oxytetracycline-induced oxidative stress in liver.
TL;DR: Results suggest that the laboratory's approach is suited for the in silico identification of adverse effects triggered by drugs and chemicals and encouraged us to compile an Internet Database for the virtual screening of drugs andchemicals for toxic effects.
Abstract: Poor pharmacokinetics, side effects and compound toxicity are frequent causes of late-stage failures in drug development. A safe in silico identification of adverse effects triggered by drugs and chemicals would be highly desirable as it not only bears economical potential but also spawns a variety of ecological benefits: sustainable resource management, reduction of animal models and possibly less risky clinical trials. In computer-aided drug discovery, both existing and hypothetical compounds may be studied; the methods are fast, reproducible, and typically based on human bioregulators, making the question of transferability obsolete. In the recent past, our laboratory contributed towards the development of in silico concepts (--> multi-dimensional QSAR) and validated a series of "virtual test kits" based on the oestrogen, androgen, thyroid, and aryl hydrocarbon receptor (endocrine disruption, receptor-mediated toxicity) as well as on the enzyme cytochrome P450 3A4 (metabolic transformations, drug-drug interactions). The test kits are based on the three-dimensional structure of their target protein (i.e. ER(alphabeta), AR, TR(alphabeta), CYP450) or a surrogate thereof (AhR) and were trained using a representative selection of 362 substances. Subsequent evaluation of 107 compounds different therefrom showed that binding affinities are predicted close to experimental uncertainty. These results suggest that our approach is suited for the in silico identification of adverse effects triggered by drugs and chemicals and encouraged us to compile an Internet Database for the virtual screening of drugs and chemicals for toxic effects.
TL;DR: The introduction of the genomics technology is a promising emerging area in developmental toxicity testing in vitro, and future application of alternatives in testing strategies for developmental toxicity may significantly gain from the inclusion of gene expression studies, given the unique programme of geneexpression changes in embryonic and foetal development.
Abstract: Alternatives to animal testing in developmental toxicology have been the subject of three decades of research. The aims of these investigations have been to reduce animal experimentation, to refine effect assessment and mechanistic studies, and to accelerate and simplify safety testing in an area of toxicology that uses relatively many animals. Many alternatives have been developed over the years with different compexities, using biologic material ranging from continuous cell lines to complete embryos. The validation of alternatives and their application in testing strategies is still in its infancy, although significant steps towards these aims are currently being made. The introduction of the genomics technology is a promising emerging area in developmental toxicity testing in vitro. Future application of alternatives in testing strategies for developmental toxicity may significantly gain from the inclusion of gene expression studies, given the unique programme of gene expression changes in embryonic and foetal development.
TL;DR: The model proved to be feasible, showing stable means except for the mechanical and thermal stimulation in viscera, which showed decreasing pain thresholds when the tests were repeated with 30 min. intervals.
Abstract: Experimental pain models for assessment of analgesic effect needs to be reproducible, valid and responding in a uniform way to changes in pain level. The pain system differs in various tissue types and analgesics may have different effects in different tissues. This study assessed the reproducibility of an experimental model using mechanical, thermal and electrical stimulations. Pain was evoked in three tissues: Skin, muscle and viscera. Pain was evoked and assessed in 24 healthy volunteers. The experiment was repeated three times with 30 min. intervals and twice with a weekly interval. Systematic bias, intra-class correlation (ICC) and coefficient of variation (CV) and valid sample sizes for analgesic testing were assessed. The model proved to be feasible. Most tests were unbiased, showing stable means except for the mechanical and thermal stimulation in viscera, which showed decreasing pain thresholds when the tests were repeated with 30 min. intervals. Generally the pain tests showed relatively high CV (mean 71%, range 8-145%). The pain tests showed high ICC's (>0.80) when repeated on the same day. When the tests were repeated with an interval of one week, ICC was smaller (mean 0.79 range 0.49-0.96). This means that these tests are useful for analgesic testing recruiting useful sample sizes in a crossover (mean 31 range 2-84) and a parallel study (mean 59 range 3-164) design. Application of this experimental pain model in a cross-over study design with appropriate base-line recordings offers a unique opportunity of revealing analgesic effects on pain arising from different tissues.
TL;DR: It is implied a possibility that ROS may participate in the whole process of dependence and withdrawal of heroin, and strategies of blocking oxidative stress may be useful in the development of therapy for opiate abuse.
Abstract: Heroin has been shown to elevate dopamine (DA) level. It is well known that an increase in DA oxidative metabolism leads to increased reactive oxygen species (ROS) formation, and thus, ROS have been frequently associated with neuronal cell death due to damage to carbohydrates, amino acids, phospholipids, and nucleic acids. This study investigated whether there are oxidative stress and effects of exogenous antioxidants in heroin-administered mice. The heroin-dependent mice model was made via intraperitoneal injection. Oxidative damage of DNA, protein, and lipid was measured by analysis of single cell electrophoresis, the 2,4-dinitrophenylhydrazine method, and thiobarbituric acid method respectively. The activities of antioxidative enzymes and total antioxidant capacity were assayed by spectrophotometry. After administration with heroin, the mice not only showed decrease of total antioxidant capacity in serum and antioxidant enzymes such as superoxide dismutase, catalase, and glutathione (GSH) peroxidase in brain, but also exhibited the oxidative damages of DNA, protein and lipid. On the other hand, exogenous antioxidants could restrain the oxidative stress, even alleviate withdrawal syndrome in heroin-administered mice. Our results also imply a possibility that ROS may participate in the whole process of dependence and withdrawal of heroin. Therefore, strategies of blocking oxidative stress may be useful in the development of therapy for opiate abuse.
TL;DR: The present review critically analyzes the reasons of failure of anti-TNF-a therapy in heart failure and the potential approaches for the development of new anti- TNF- a therapy has been discussed which may open new vista of the management of heart failure.
Abstract: The elevated level of tumour necrosis factor-a (TNF-a) in patients with heart failure has triggered interest in investigating the role of TNF-a in the pathogenesis of heart failure. Both clinical and experimental evidence has suggested that high levels of TNF-a occur in heart failure and lead to progression of left ventricular dysfunction. In addition, it has been documented that inhibition of TNF-a reverses its deleterious effects in heart failure. A number of clinical trials have been initiated to investigate the effect of anti-TNF-a therapy in patients with heart failure. The discouraging results of recent clinical trials of anti-TNF-a therapy in patients with heart failure have raised a number of questions about the role of TNF-a in heart failure. The present review critically analyzes the reasons of failure of anti-TNF-a therapy in heart failure. Moreover the potential approaches for the development of new anti-TNF-a therapy has been discussed which may open new vista of the management of heart failure.
TL;DR: Results indicated that ginsenoside 20(S)-protopanaxadiol is able to inhibit the invasiveness of HT1080 cells significantly in vitro and this action may be primarily due to down-regulating the expression of matrix metalloproteinase-2.
Abstract: Ginsenoside 20(S)-protopanaxadiol, one of metabolites of ginseng saponins, has been well characterized to possess the pleiotropic anticancer capabilities in several cancer cell lines. The object of this study was to investigate the effects of ginsenoside 20(S)-protopanaxadiol on the invasion in vitro and the expression of matrix metalloproteinase-2 in human fibrosarcoma HT1080 cells in absence of cytotoxicity. Our results showed that ginsenoside 20(S)-protopanaxadiol exerted a concentration-dependent inhibitory effect on the proliferation of HT1080 cells (IC50 was 76.78+/-2.24 microM, 48 hr). Treatment with 20(S)-protopanaxadiol significantly declined the invasive capacity of HT1080 cells compared to the control cells (P<0.01) in the in vitro invasion assay. Further analysis with gelatin zymography and western blotting revealed that both the activity and the expression of matrix metalloproteinase-2 decreased dramatically in a concentration-dependent manner (P<0.01). Taken together, these results indicated that ginsenoside 20(S)-protopanaxadiol is able to inhibit the invasiveness of HT1080 cells significantly in vitro and this action may be primarily due to down-regulating the expression of matrix metalloproteinase-2. Ginsenoside 20(S)-protopanaxadiol, a metabolite of ginseng, may be applied as a potential therapeutic agent in the prevention and treatment of cancer.
TL;DR: The results from the chronic toxicity studies demonstrated that the toxicity targets in the experimental animals were liver and kidney and provide the theoretical foundation for clinical applications of this promising natural anticancer agent.
Abstract: Acute and chronic toxicity of gambogic acid, a promising novel anticancer agent, was determined using albino mice and Beagle dogs as model animals. Histopathological examination and viscera parameter investigation were also carried out after autopsy. The LD50 of gambogic acid was found to be 45 approximately 96 mg/kg and the 95% confidence limit was determined to be 43.18 approximately 48.45 mg/kg. The results from the chronic toxicity studies demonstrated that the toxicity targets in the experimental animals were liver and kidney. The innocuous dose was established to be 4 mg/kg after administration to dogs for a total of 13 weeks at a frequency of one injection every other day. This dose (4 mg/kg) was approximately 9.6 (body weight) or 5.1 (body surface area) times the dosage (25 mg/60 kg, every other day) recommended for human trials. Our results provide the theoretical foundation for clinical applications of this promising natural anticancer agent and will likely bring about considerable economic and social benefits.
TL;DR: Cinnamaldehyde has an effect on the antioxidant status of rat kidney and its effect is time- and dose-dependent.
Abstract: Cinnamaldehyde, a food flavour, has a high potential for human consumption in India. In this study, we evaluated the effect of cinnamaldehyde on the antioxidant status of the rat kidney. Rats were given cinnamaldehyde orally by gavage at dose levels of 2.14, 6.96, 22.62 and 73.5 mg/kg body weight/day for the period of 10, 30 and 90 days. The non-enzymatic antioxidants ascorbic acid, α-tocopherol and reduced glutathione were decreased while the antioxidant enzymes, superoxide dismutase, glutathione peroxidase and glutathione-s-transferase were increased. Catalase was decreased and thiobarbituric acid-reactive substances were increased only in the kidney of rats treated with cinnamaldehyde at the dose level of 73.5 mg/kg body weight/day during an exposure period of 90 days and not in the kidney of other cinnamaldehyde-treated rat groups. Thus, cinnamaldehyde has an effect on the antioxidant status of rat kidney and its effect is time- and dose-dependent.