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Showing posts with label Clinical Articles. Show all posts
Showing posts with label Clinical Articles. Show all posts
Measurement of intestinal absorption and first pass metabolism
By Piscean | Saturday, March 10, 2012 | Posted in , , , | With 0 comments

Background

PKQuest, a new physiologically based pharmacokinetic (PBPK) program, is applied to human ethanol data. The classical definition of first pass metabolism (FPM) based on the differences in the area under the curve (AUC) for identical intravenous and oral doses is invalid if the metabolism is non-linear (e.g. ethanol). Uncertainties in the measurement of FPM have led to controversy about the magnitude of gastric alcohol metabolism. PKQuest implements a new, rigorous definition of FPM based on finding the equivalent intravenous input function that would produce a blood time course identical to that observed for the oral intake. This input function equals the peripheral availability (PA) and the FPM is defined by: FPM = Total oral dose – PA. PKQuest also provides a quantitative measurement of the time course of intestinal absorption.

Methods

PKQuest was applied to previously published ethanol pharmacokinetic data.

Results

The rate of ethanol absorption is primarily limited by the rate of gastric emptying. For oral ethanol with a meal: absorption is slow (≈ 3 hours) and the fractional PKQuest FPM was 36% (0.15 gm/Kg dose) and 7% (0.3 gm/Kg). In contrast, fasting oral ethanol absorption is fast (≈ 50 minutes) and FPM is small.

Conclusions

The standard AUC and one compartment methods significantly overestimate the FPM. Gastric ethanol metabolism is not significant. Ingestion of a coincident meal with the ethanol can reduce the peak blood level by about 4 fold at low doses. PKQuest and all the examples are freely available on the web at http://www.pkquest.com webcite. 

 
Diclofenac does not interact with codeine metabolism in vivo
By Piscean | | Posted in , , | With 0 comments

Background

Previously, we have demonstrated a marked inhibition of codeine glucuronidation by diclofenac in human liver tissue homogenate. We therefore aimed to investigate whether diclofenac inhibits glucuronidation of codeine also in vivo in healthy volunteers.

Methods

In a randomised, placebo-controlled, double-blind, cross-over study, 12 healthy volunteers received a singe of 100 mg codeine phosphate plus 50 mg diclofenac sodium or codeine phosphate plus placebo. Over a 36 hour period serum concentrations of codeine and its metabolites as well as urinary excretion were analysed using LC-mass spectrometry. Side effects were recorded and analgesic efficacy was determined using the cold pressor test (0–6 h).

Results

A single dose of diclofenac did not alter the formation of codeine-6-glucuronide in healthy volunteers. Metabolic clearance of codeine to morphine was not affected by diclofenac. In terms of side effects, both treatments were well tolerated. Diclofenac did not significantly influence the analgesic effects of codeine in the cold pressor test.

Conclusions

In contrast to recent in vitro data, a single oral dose of diclofenac did not alter the glucuronidation of codeine in healthy volunteers. 

 
prophylactic antibiotic use in the management of snakebite
By Piscean | | Posted in , , | With 0 comments

Background

Routine antibiotic prophylaxis following snakebite is not recommended but evidence suggests that it may be common practice in Zimbabwe. This study set out to determine and describe the extent of this practice at Parirenyatwa Hospital, a large teaching hospital in Zimbabwe

Methods

A retrospective case review (1996 to 1999 inclusive) of all cases of snakebite was undertaken at Parirenyatwa Hospital. Cases with a diagnosis of snakebite, presenting within 24 hours of the bite and with no complications or concurrent illness were defined as "routine prophylactic antibiotic use".

Results

From 78 cases which satisfied the inclusion criteria, 69 (88.5%) received antibiotics. Ten different antibiotics from 6 different classes were used with penicillins the most commonly prescribed (benzylpenicillin in 29% of cases, alone or in combination). Over 40% of antibiotics were given parenterally although all patients were conscious on admission. The total cost of antibiotics used was estimated at US$522.98.

Conclusion

Routine prophylactic use of antibiotics in snakebite at Parirenyatwa Hospital is common practice. This may highlight the lack of a clearly defined policy leading to wasteful inappropriate antibiotic use which is costly and may promote bacterial antibiotic resistance. Further work is required to investigate the reasons for this practice and to design appropriate interventions to counter it. 

adverse drug reactions in randomised controlled trials – a systematic survey
By Piscean | | Posted in , , | With 0 comments

Abstract

Background

Decisions on treatment are guided, not only by the potential for benefit, but also by the nature and severity of adverse drug reactions. However, some researchers have found numerous deficiencies in trial reports of adverse effects. We sought to confirm these findings by evaluating trials of drug therapy published in seven eminent medical journals in 1997.

Methods

Literature review to determine whether the definition, recording and reporting of adverse drug reactions in clinical trials were in accordance with published recommendations on structured reporting.

Results

Of the 185 trials reviewed, 25 (14%) made no mention of adverse drug reactions. Data in a further 60 (32%) could not be fully evaluated, either because numbers were not given for each treatment arm (31 trials), or because a generic statement was made without full details (29 trials). When adverse drug reactions such as clinical events or patient symptoms were mentioned in the reports, details on how they had been recorded were given in only 14/95 (15%) and 18/104 (17%) trials respectively. Of the 86 trials that mentioned severity of adverse drug reactions, only 42 (49%) stated how severity had been defined. The median amount of space used for safety data in the Results and Discussion sections was 5.8%.

Conclusions

Trial reports often failed to provide details on how adverse drug reactions were defined or recorded. The absence of such methodological information makes comparative evaluation of adverse reaction rates potentially unreliable. Authors and journals should adopt recommendations on the structured reporting of adverse effects. 

three anti-seizure medications in hair: the effects of hair color, controlling for dose and age
By Piscean | | Posted in , , | With 0 comments

Abstract

Background

This paper assess the relationship between the quantity of three anti-seizure medications in hair and the color of the analyzed hair, while controlling for the effects of dose, dose duration, and patient age for 140 clinical patients undergoing anti-seizure therapy. Three drugs are assessed: carbamazepine (40 patients), valproic acid (40 patients), and phenytoin (60 patients). The relationship between hair assay results, hair color, dose, dose duration, and age is modeled using an analysis of covariance. The covariance model posits the hair assay results as the dependent variable, the hair color as the qualitative categorical independent variable, and dose, dose duration, and age as covariates. The null hypothesis assessed is that there is a no relationship between hair color and the quantity of analyte determined by hair assay such that darker colored hair will demonstrate higher concentrations of analyte than lighter colored hair.

Results

The analysis reveals that there is a significant relationship between dose and concentration for all hair color categories independent of the other covariates or the categorical independent variable.

Conclusion

There does not appear to be any relationship between carbamazepine concentration and hair color. There is a weak relationship between hair color and valproic acid concentration, which the data suggest may be mediated by age. There is a significant, moderate relationship between phenytoin concentration and hair color such that darker colored hair has greater concentration values than lighter colored hair. 

Upper gastrointestinal bleeding risk and perforation associated with low-dose aspirin as simple formulations and enteric-coated
By Piscean | | Posted in , , | With 0 comments

Abstract

Background

The use of low-dose aspirin has been reported to be associated with an increased risk of upper gastrointestinal complications (UGIC). The coating of aspirin has been proposed as an approach to reduce such a risk. To test this hypothesis, we carried out a population based case-control study.

Methods

We identified incident cases of UGIC (bleeding or perforation) aged 40 to 79 years between April 1993 to October 1998 registered in the General Practice Research Database. Controls were selected randomly from the source population. Adjusted estimates of relative risk (RR) associated with current use of aspirin as compared to non use were computed using unconditional logistic regression.

Results

We identified 2,105 cases of UGIC and selected 11,500 controls. Among them, 287 (13.6%) cases and 837 (7.3%) controls were exposed to aspirin, resulting in an adjusted RR of 2.0 (1.7-2.3). No clear dose-effect was found within the range of 75-300 mg. The RR associated with enteric-coated formulations (2.3, 1.6-3.2) was similar to the one of plain aspirin (1.9, 1.6-2.3), and no difference was observed depending on the site. The first two months of treatment was the period of greater risk (RR= 4.5, 2.9-7.1). The concomitant use of aspirin with high-dose NSAIDs greatly increased the risk of UGIC (13.3, 8.5-20.9) while no interaction was apparent with low-medium doses (2.2, 1.0-4.6).

Conclusions

Low-dose aspirin increases by twofold the risk of UGIC in the general population and its coating does not modify the effect. Concomitant use of low-dose aspirin and NSAIDs at high doses put patients at a specially high risk of UGIC. 

This article is taken from biomedcentral.com, to read full article please go to original website
sulfonylureas consensus statement published on diabetes care
By Piscean | Saturday, July 16, 2011 | Posted in , | With 0 comments

Below is a transcript of the latest statement (December 2008) published on Diabetes Care about the role of sulfonylureas in the medical management of hyperglycemia in type 2 diabetes.
Sulfonylureas.
Sulfonylureas lower glycemia by enhancing insulin secretion (see mechanism of action). In terms of efficacy,  they appear to be similar to metformin, lowering A1C levels by 1.5 percentage points (26,49). The major adverse side effect is hypoglycemia, which can be prolonged and life threatening, but such episodes, characterized by a need for assistance, coma, or seizure, are infrequent. However, severe episodes are relatively more frequent in the elderly.
Chlorpropamide and glibenclamide (known as glyburide in the U.S. and Canada), are associated with a substantially greater risk of hypoglycemia than other second-generation sulfonylureas (gliclazide, glimepiride, glipizide, and their extended formulations), which are preferable (Table 1) (53,54). In addition, weight gain of 2 kg is common following the initiation of sulfonylurea therapy.
Although the onset of the glucose lowering effect of sulfonylurea monotherapy is relatively rapid compared with, for example, the thiazolidinediones (TZDs), maintenance of glycemic targets over time is not as good as monotherapy with a TZD or metformin (55). Sulfonylurea therapy was implicated as a potential cause of increased CVD mortality in the University Group Diabetes Program (UGDP) study (56). Concerns raised by the UGDP that sulfonylureas, as a drug class, may increase CVD mortality in type 2 diabetes were not substantiated by the UKPDS or ADVANCE study (6,12). The glycemic benefits of sulfonylureas are nearly fully realized at half-maximal doses, and higher doses should generally be avoided.

Source: http://pharmacologycorner.com/sulfonylureas-consensus-statement-published-on-diabetes-care/
By Piscean | Saturday, July 9, 2011 | Posted in | With 0 comments

Healing Effects of Rebamipide and Omeprazole in Helicobacter pylori-Positive Gastric Ulcer Patients after Eradication Therapy: A Randomized Double-Blind, Multinational, Multi-Institutional Comparative Study
Digestion, 07/08/2011  Clinical Article

Song KH et al. – Rebamipide is as effective as omeprazole in treating of Helicobacter pylori(H)– positive gastric ulcer after eradication therapy.
Methods
  • After completion of 1 week of eradication therapy, 132 patients with H. pylori-positive gastric ulcer were enrolled in 5 Chinese and 4 Korean institutions.
  • Patients were randomly assigned to take either 20 mg of omeprazole (n = 63) or 300 mg of rebamipide (n = 65) daily for 7 weeks
  • Healing was defined as complete recovery and S1 and S2 stage ulcer according to the Sakita-Miwa classification.
Results
  • Healing rates at 12 weeks were 81.5% (53/65) and 82.5% (52/63) in the rebamipide and omeprazole groups, respectively.
  • There was no significant difference in treatment efficacy, as evidenced by gastric ulcer healing rates (absolute difference -1.0%; 95% confidence interval -10.7 to 8.7; p = 0.88).
  • H. pylori eradication rate and ulcer healing rate did not differ between the groups, the latter regardless of eradication outcome.
Colon salvage therapy for acute severe colitis: cyclosporine or infliximab
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Colon salvage therapy for acute severe colitis: cyclosporine or infliximab
Current Opinion in Gastroenterology, 07/08/2011  Clinical Article

Burger DC et al. – Optimal salvage therapy will depend on detailed results of randomized controlled trials. Meanwhile, patients with acute severe colitis(ASC) should receive either cyclosporine or infliximab before surgery as long as there is specialist expertise that allows early decision–making.
  • ASC affects 25% of patients with ulcerative colitis and is associated with measurable morbidity and mortality.
  • Simple clinical and laboratory measures predict steroid refractoriness (such as stool frequency 3-8/day and C-reactive protein > 45 mg/l on day 3) and salvage therapy is appropriate at this stage.
  • Preliminary data from randomized controlled trials suggest that early (7 and 98 day) response to cyclosporine and infliximab are comparable.
  • Serum trough infliximab concentrations may correlate with outcome.
  • Sequential therapy cannot usually be recommended due to limited response (70% colectomy at 3 years) and high rate of serious adverse events.
Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study
By Piscean | Friday, July 8, 2011 | Posted in | With 0 comments

British Medical Journal, 05/26/2011  Clinical Article

Charlot M et al. – In aspirin treated patients with first time myocardial infarction, treatment with proton pump inhibitors was associated with an increased risk of adverse cardiovascular events.
Methods
  • Retrospective nationwide propensity score matched study based on administrative data.
  • All aspirin treated patients surviving 30 days after a first myocardial infarction from 1997 to 2006, with follow–up for one year.
  • Patients treated with clopidogrel were excluded.
  • The risk of the combined end point of cardiovascular death, myocardial infarction, or stroke associated with use of proton pump inhibitors was analysed using Kaplan–Meier analysis, Cox proportional hazard models, and propensity score matched Cox proportional hazard models.
Results
  • 3366 of 19 925 (16.9%) aspirin treated patients experienced recurrent myocardial infarction, stroke, or cardiovascular death.
  • The hazard ratio for the combined end point in patients receiving proton pump inhibitors based on the time dependent Cox proportional hazard model was 1.46 (1.33 to 1.61; P<0.001) and for the propensity score matched model based on 8318 patients it was 1.61 (1.45 to 1.79; P<0.001).
  • A sensitivity analysis showed no increase in risk related to use of H2 receptor blockers (1.04, 0.79 to 1.38; P=0.78).
Blood Pressure and Cardiovascular Outcomes in Patients Taking Nonsteroidal Antiinflammatory Drugs
By Piscean | | Posted in | With 0 comments

Cardiovascular Drug Reviews, 06/03/2011  Clinical Article

Krum H et al. – Baseline blood pressure (BP), but not change in BP, was significantly associated with risk of thrombotic CVEs through 18 months. The cardiovascular (CV) risk of COX–2s and NSAIDs did not appear to be related to the BP–elevating effects of these agents, although such analyses, i.e., from randomized controlled trials, are unable to definitively exclude such a relationship.
Results
  • Authors found that baseline systolic BP (SBP) was associated with significantly higher risk of all events (P < 0.001).
  • Baseline diastolic BP (DBP) was inversely and significantly associated with risk of all events (P < 0.001 to P= 0.016) except CV/CHF mortality (P= 0.054).
  • There was no significant differential effect between etoricoxib and diclofenac in relation to CVEs, except for confirmed CHF, for which the risk was significantly higher with etoricoxib (P= 0.019). Only CHF risk (P= 0.020 for both SBP and DBP change), but not thrombotic endpoints, was significantly associated with change in BP from months 0 to 4.
  • These findings were not meaningfully altered after covariate adjustment for baseline CV risk.
Effect of Aspirin on Mortality in the Primary Prevention of Cardiovascular Disease
By Piscean | | Posted in | With 0 comments

American Journal of Medicine, 06/21/2011  Clinical Article

Raju N et al. – Aspirin prevents deaths, myocardial infarction, and ischemic stroke, and increases hemorrhagic stroke and major bleeding when used in the primary prevention of cardiovascular disease.
Methods
  • Eligible articles were identified by searches of electronic databases and reference lists.
  • Outcomes of interest were all–cause mortality, cardiovascular mortality, myocardial infarction, stroke, and bleeding.
  • Data were pooled from individual trials using the DerSimonian–Laird random–effects model, and results are presented as relative risk (RR) and 95% confidence intervals (CIs).
Results
  • Nine randomized controlled trials enrolling 100,076 participants were included.
  • Aspirin reduced all–cause mortality (RR 0.94; 95% CI, 0.88–1.00), myocardial infarction (RR 0.83; 95% CI, 0.69–1.00), ischemic stroke (RR 0.86; 95% CI, 0.75–0.98), and the composite of myocardial infarction, stroke, or cardiovascular death (RR 0.88; 95% CI, 0.83–0.94), but did not reduce cardiovascular mortality (RR 0.96; 95% CI, 0.84–1.09).
  • Aspirin increased the risk of hemorrhagic stroke (RR 1.36; 95% CI, 1.01–1.82), major bleeding (RR 1.66; 95% CI, 1.41–1.95), and gastrointestinal bleeding (RR 1.37; 95% CI, 1.15–1.62).
  • A lack of availability of patient–level data precluded exploration of benefits and risks of aspirin in key subgroups.