...this study aimed to find the prevalence of actual DDIs on admission to the hospital and compare the clinical usefulness of different DDI screening systems according to observed actual DDIs. The ...study team identified the patients with actual DDI-related adverse drug reactions (ADRs) on admission, the causality of which was...
Warfarin is an anticoagulant drug with narrow therapeutic index and high interindividual variability in dose requirement. S-warfarin is metabolized mainly by polymorphic cytochrome P450 (CYP) 2C9. We ...systematically quantified the influence of CYP2C9 genotype, demographic factors and concomitant drug treatment on warfarin metabolism and maintenance dose. The mean warfarin doses were lower in carriers of one (2.71 mg/day, 59 patients) and two polymorphic alleles (1.64 mg/day, 11 patients) than in carriers of two wild-type alleles (4.88 mg/day, 118 patients). Multiple regression analysis demonstrated that CYP2C9 genotype, age, concomitant treatment with warfarin metabolism inducers and lean body weight contributed significantly to interindividual variability in warfarin dose requirement (adjusted R(2)=0.37). The same factors, except for age, significantly influenced S-warfarin clearance (adjusted R(2)=0.42). These results can serve as a starting point for designing prospective studies in patients in the initiation phase of genotype-based warfarin therapy.
Prediction of in vivo drug dissolution from enteric coated pellets on the basis of in vitro drug dissolution and gastric emptying of pellets under fasting conditions, and correlation with absorption ...profiles.
The absorption and bioavailability of drugs can be substantially affected by the transit of dosage forms through the gastrointestinal (GI) tract. Gastric emptying is one of the most critical parameters contributing to this inter- and intra-individual GI transit variability. It is especially important for the delayed release dosage forms whose release depends on the local environment and begins when the dosage form passes pylorus and comes into contact with higher pH medium in small intestine. The purpose of our research work was to predict the in vivo dissolution from enteric coated pellets for population and establish a good in vitro/in vivo correlation (IVIVC) with mean in vivo absorption profiles, obtained in a pharmacokinetic study under fasting conditions. The dissolution tests were carried out on a USP 4 – flow-through cell with enteric coated pellets containing an acid-labile drug and formulated as orodispersible tablets. Using several residence times in an acidic medium, we simulated the gastric emptying of the pellets and the exposure of different fractions of the pellets to the gastric medium for different periods of time. The amount of drug released decreased with the increasing time of exposure to the acidic medium due to the drug’s degradation. The mean in vivo dissolution profiles, which were predicted on the basis of experimentally determined dissolution profiles and mathematical model of pellets’ gastric emptying, gave a very good IVIVC with the mean in vivo absorption profiles.
To estimate the relative risk reduction of the clinical outcomes (coronary events, strokes, cardiovascular, non-cardiovascular and all-cause mortality) associated with statin therapy in primary and ...secondary prevention.
A literature search of the Medline and Cohrane databases for articles published from 1985 to July 2002 was performed. The data on systematic reviews and preliminary reports were also included in this study. Primary and secondary prevention trials and regression trials were eligible. DATA EXTRACTION AND STATISTICAL METHOD: Data were extracted by 2 authors according to the defined inclusion criteria. Disagreements were resolved by consensus or by a third reviewer. Testing for heterogeneity was applied and on the basis of these results a fixed effect model or a random effect model was used for calculation of relative risk values (RR) and 95% confidence intervals (95% CI). Sensitivity analysis tested the impact of the individual study--duration of study, type of statin therapy and study size. The number of patients needed to treat was calculated as an absolute measure of clinical effectiveness of statin therapy when appropriate.
Data from 15 trials with 63,410 participants and mean duration of treatment of 3.6 years, were included in this overview. Tests for heterogeneity showed that the variability between study estimates is sufficiently small to assume that they are estimating the same underlying treatment effect. Statin therapy was associated with a 22% reduction in total cholesterol, 29% reduction in LDL cholesterol, 12% reduction in triglycerides and 6% increase in HDL cholesterol. Overall (primary and secondary studies) statin therapy significantly reduces relative risk of coronary events (RR, 0.73, 95% CI, 0.68, 0.77, *p < 0.0001), relative risk of cardiovascular disease mortality (RR, 0.78, 95% CI, 0.73, 0.84, *p < 0.0001), relative risk of non-fatal stroke (RR, 0.74, 95% CI, 0.67, 0.82, *p < 0.0001), relative risk of total (fatal and non-fatal) stroke (RR, 0.77, 95% CI, 0.70, 0.84, *p < 0.001) and relative risk of all-cause death (RR, 0.85, 95% CI, 0.81, 0.89, *p < 0.0001). There was a slight and insignificant reduction of relative risk in non-cardiovascular mortality (RR, 0.94, 95% CI, 0.86, 1.03, p = 0.1677) and fatal strokes (RR, 0.86, 95% CI, 0.70, 1.07, p = 0.1912). Sensitivity analysis showed the robustness of our results for all outcomes. The results were not altered if an individual study was removed from meta-analysis.
This overview indicates that statin treatment reduces the relative risk of occurrence of coronary events, cardiovascular disease mortality, non-fatal strokes and all-cause mortality. While secondary prevention with statins provides considerable improvement of cardiovascular morbidity/mortality, primary prevention with statins provides only small and clinically hardly relevant improvement of cardiovascular morbidity/mortality.
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The purpose of this research was to predict the in vivo dissolution of lansoprazole from enteric coated pellets in the fasted state using a biorelevant flow-through dissolution method ...with low flow rates and volumes close to those in vivo. Additionally, a novel rotating stirring element, composed from magnet inserted in a silicone tube, was used to produce the movement of the pellets and expose them to slightly increased physical stress. Obtained dissolution results were compared to the dissolution results of our previous work using the USP IV with higher flow rate (11ml/min). As drug release from enteric coated pellets usually starts in the small intestine, the influence of pellets’ residence time in the gastric medium and additionally the effect of different media on drug release was studied. Prolongation of residence time in an acidic medium had only minor effect on the release rate after initial lag time, but significantly reduced the total amount of the drug released from both tested formulations, which was attributed to the drug’s degradation in an acidic medium. The increased physical load on the pellets induced by the rotating stirring element compensated for the decrease of flow rate from 11ml/min using the USP IV to 3ml/min using the non-compendial system. Considering also gastric emptying kinetics good prediction of the in vivo release was achieved compared to in vivo absorption data obtained from a pharmacokinetic study under fasting conditions. Thus, using more physiologically relevant dissolution conditions, expressed through low volume and lower flow rate, and in combination with increased mechanical stress we obtained equally good in vitro/in vivo correlation as using USP IV and higher flow rates. Comparison of the dissolution results obtained with two different systems provided additional insight into product behaviour and improved prediction of in vivo performance.
Bazedoxifene is used for the prevention and treatment of osteoporosis. After peroral application, bazedoxifene is metabolized by UDP-glucuronosyltransferases (UGTs) to bazedoxifene-4'-glucuronide ...(M4) and bazedoxifene-5-glucuronide (M5). It has already been shown that a relatively common UGT1A1*28 polymorphism can considerably affect raloxifene pharmacokinetics and pharmacodynamics. As pharmacokinetics of bazedoxifene and raloxifene are very similar, the influence of UGT1A1*28 polymorphism on metabolism of bazedoxifene was investigated by genotyped microsomes. Our results indicate an influence of UGT1A1*28 allele on the formation clearance of both bazedoxifene metabolites. The decreased metabolic clearance was most pronounced in microsomes from polymorphic homozygote (*28/*28) where a 7 to 10-fold lower metabolic clearance was observed for both metabolites compared to other genotypes. In conclusion, the significant UGT1A1*28 genotype effect on bazedoxifene intrinsic metabolic clearance indicates that this subject is worth further exploration in vivo and provides valuable information research in this field.
Summary
Aims: The aim of the present analysis was to evaluate the cost‐effectiveness of alternative treatments for outpatients with chronic schizophrenia from the healthcare payer's perspective.
...Methods: Decision analysis was used to evaluate the cost‐effectiveness of the following antipsychotic drugs: amisulpride, aripiprazole, haloperidol (oral formulation), haloperidol (depot formulation), olanzapine, quetiapine, risperidone (oral formulation), risperidone (depot formulation) and ziprazidone. Clinical and economic outcomes were modelled over 1‐year time horizon. Effectiveness was measured as a percentage of patients in remission. Clinical parameters used in the model included compliance rates, rehospitalisation rates for compliant and non‐compliant patients, duration and frequency of hospitalisation, and adverse event rates. One‐way sensitivity analysis was performed to test the robustness of the model.
Results: The most effective treatment was treatment with olanzapine where 64.1% of patients remained in remission. The least effective treatment was treatment with quetiapine where 32.7% of patients remained in remission. Overall costs ranged from 3726.78€ for haloperidol to 8157.03€ for risperidone in depot formulation. Inpatient costs represented the major part of costs for most of antipsychotic drugs. Typical antipsychotic drugs had substantially smaller outpatient costs (6.5%) compared with atypical antipsychotics (37.9%). In the base case scenario the non‐dominated treatment strategies were haloperidol, haloperidol decanoate and olanzapine. Additionally, risperidone can also be considered to be part of the efficient frontier based on the sensitivity analysis results.
Conclusion: Among second‐generation antipsychotics, which have a better safety profile than first‐generation antipsychotics, olanzapine and risperidone showed to be the most cost‐effective treatment strategies for outpatient treatment of chronic schizophrenia.
Intravesical administration of cytotoxic agents is commonly used in urological practice for treatment of superficial bladder cancer. The leading motive is optimisation of drug delivery near the site ...of action and reduction of systemic toxicity. Bladder pharmacokinetics is complicated by several mechanisms. The objectives of this work were to develop a kinetic model of drug distribution in the bladder wall following intravesical instillation and to study the effect of various parameters on tissue and systemic drug exposure and explore the potential benefits of permeability enhancing effects of chitosan (CH) and polycarbophil (PC) through simulation. Key elements of the model are variable urinary drug concentration due to urine formation and voiding, biphasic diffusion in the bladder tissue and systemic absorption. Model parameters were estimated from bladder-tissue concentration profiles obtained in previous
in vitro experiments with pipemidic acid (PPA) as a model drug. The results support further investigations on application of CH and PC in intravesical drug delivery. Both polymers increase permeability of the bladder wall by diffusion enhancement in the urothelium and presumably by improving the contact with the bladder surface. The developed mathematical model could serve for optimisation of intravesical drug delivery and future development of intravesical drug delivery systems.
In the present work mathematical modeling of individual gastric emptying (GE) profiles of pellets in the fed state was performed. Twenty two profiles from healthy subjects obtained by gamma ...scintigraphy were collected by literature search. A variety of shapes were found: linear, exponential, as a series of small boluses, two phase as fast GE followed by slow GE and the opposite, and curves containing one or more intervals with no GE. The Elashoff, Siegel, and double Weibull models were fitted to each of the individual GE profiles. Additionally, the values of parameters reflecting the time when GE of pellets started were calculated on the basis of the models and were compared to the experimentally determined values. The double Weibull model was proven to be the most capable of fitting various GE patterns and could be thus implemented in biorelevant dissolution testing and in prediction of in vivo dissolution profiles.
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