Population pharmacokinetics of fluconazole given for secondary prevention of oropharyngeal candidiasis in HIV-positive patients

Abstract.: Objectives: To determine fluconazole population pharmacokinetics and explore the relationships between fluconazole average concentration and treatment effectiveness or microbiological resistance induction during a study aimed at evaluating the efficacy, tolerability and resistance induction after secondary prevention with fluconazole (150mg weekly) versus placebo in human immunodeficiency virus-positive (HIV+) patients with oropharyngeal candidiasis. Methods: Population pharmacokinetic parameters of fluconazole determined from 458 serum drug concentration measurements obtained over 37months in 132 HIV+ patients not receiving highly active antiretroviral therapy. Mean estimates and variabilities were generated using non-linear regression analysis. Logistic and linear regression analyses were used to explore the relationships between the estimated average concentration of fluconazole and candidiasis relapse or fungal resistance towards fluconazole. Results: Fluconazole kinetics were best described by a one-compartment model with first-order oral absorption from the gastrointestinal tract. The pharmacokinetics were influenced only by body weight. No effect was observed for gender, age, height or lymphocyte CD4 counts. The mean apparent population clearance was 0.79l/h, the volume of distribution 57l and the absorption constant (ka) 0.93h-1. Inter-occasion variability in clearance (45%) was large relative to inter-subject variability (21%). Taking into account the average fluconazole concentration or the time above the minimal inhibitory concentrations did not clinically improve the prediction of the occurrence of oropharyngeal relapse or microbiological resistance. Conclusion: The relationship between fluconazole concentrations and preventive effectiveness was poor. Together with the rather large inter-occasion variability in fluconazole clearance, this suggests no role of therapeutic drug monitoring in optimising fluconazole treatment for secondary preventio

Incidence of drug-induced liver injury in medical inpatients

Objectives: Drug-induced liver injury (DILI) is a common concern. However, data on DILI epidemiology in inpatients are sparse. Methods: To investigate the incidence of DILI, we screened all patients in the pharmacoepidemiological inpatient database according to the CIOMS (Council for International Organisation of Medical Science) criteria, which consist of the evaluation of some clinical chemistry laboratory liver parameters (CIOMS laboratory criteria) and the exclusion of any disease-related causes for the liver injury. Thus, only cases with probable or certain causality according to the World Health Organization criteria were included. Results: Among a total of 6383 patients, liver parameters were determined in 4610, and 489 among them fulfilled the CIOMS laboratory criteria. However, 401 patients had to be excluded because of disease-related liver injury and, thus, the study cohort consisted of 4209 patients at risk for DILI. Among a total of 88 DILI cases, 31 had no documented normal baseline liver parameters and, thus, represented prevalent cases. The remaining 57 represented incident DILI cases. Thus, the incidence of DILI was 1.4% (95% CI 1.0, 1.7). The drug classes most frequently causing DILI were heparins, antibacterials, tuberculostatics and antineoplastic agents. Among those, antineoplastic agents and tuberculostatics showed the highest incidence. Liver injury was not mentioned among the diagnoses or in the physician's discharge letter in about 52-68% of all cases. Conclusion: Approximately 1 in 100 patients develops DILI during hospitalisation in a department of medicine. Incidences of DILI were highest for antineoplastic agents and tuberculostatics. DILI is frequently missed and, therefore, DILI detection by diagnoses will result in misleadingly low incidence rate

Blended Learning "Polypharmazie im Alter" im 4. Studienjahr Humanmedizin

Using deep two-color near-infrared HST imaging and unbiased grism spectroscopy, we present a detailed study of the z = 1.803 JKCS 041 cluster. We confirm, for the first time for a high-redshift cluster, a mass of log M ≳ 14.2 in solar units using four different techniques based on the X-ray temperature, the X-ray luminosity, the gas mass, and the cluster richness. JKCS 041 is thus a progenitor of a local system like the Coma cluster. Our rich dataset and the abundant population of 14 spectroscopically confirmed red-sequence galaxies allows us to explore the past star formation history of this system in unprecedented detail. Our most interesting result is a prominent red sequence down to stellar masses as low as log M/M☉ = 9.8, corresponding to a mass range of 2 dex. These quiescent galaxies are concentrated around the cluster center with a core radius of 330 kpc. There are only few blue members and avoid the cluster center. In JKCS 041 quenching was therefore largely completed by a look-back time of 10 Gyr, and we can constrain the epoch at which this occurred via spectroscopic age-dating of the individual galaxies. Most galaxies were quenched about 1.1 Gyr prior to the epoch of observation. The less-massive quiescent galaxies are somewhat younger, corresponding to a decrease in age of 650 Myr per mass dex, but the scatter in age at fixed mass is only 380 Myr (at log M/M☉ = 11). There is no evidence for multiple epochs of star formation across galaxies. The size-mass relation of quiescent galaxies in JKCS 041 is consistent with that observed for local clusters within our uncertainties, and we place an upper limit of 0.4 dex on size growth at fixed stellar mass (95% confidence). Comparing our data on JKCS 041 with 41 clusters at lower redshift, we find that the form of the mass function of red sequence galaxies has hardly evolved in the past 10 Gyr, both in terms of its faint-end slope and characteristic mass. Despite observing JKCS 041 soon after its quenching and the three-fold expected increase in mass in the next 10 Gyr, it is already remarkably similar to present-day clusters

Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans

Garlic extracts have been shown to decrease drug exposure for saquinavir, a P-glycoprotein and cytochrome P450 3A4 substrate. In order to explore the underlying mechanisms and to study the effects of garlic on pre-systemic drug elimination, healthy volunteers were administered garlic extract for 21 days. Prior to and at the end of this period, expression of duodenal P-glycoprotein and cytochrome P450 3A4 protein were assayed and normalized to villin, while hepatic cytochrome P450 3A4 function and simvastatin, pravastatin and saquinavir pharmacokinetics were also evaluated. Ingestion of garlic extract increased expression of duodenal P-glycoprotein to 131% (95% CI, 105-163%), without increasing the expression of cytochrome P450 3A4 which amounted to 87% (95% CI, 67-112%), relative to baseline in both cases. For the erythromycin breath test performed, the average result was 96% (95% CI, 83-112%). Ingestion of garlic extract had no effect on drug and metabolite AUCs following a single dose of simvastatin or pravastatin, although the average area under the plasma concentration curve (AUC) of saquinavir decreased to 85% (95% CI, 66-109%), and changes in intestinal P-glycoprotein expression negatively correlated with this change. In conclusion, garlic extract induces intestinal expression of P-glycoprotein independent of cytochrome P450 3A4 in human intestine and liver

[Pharmacotherapy of hyperthyreosis--adverse drug reactions]

The antithyroid drugs mainly include thioimidazole (carbimazole, methimazole=thiamazole) and propylthiouracil. After absorption, carbimazole is rapidly metabolized to methimazole and thus switching between these two drugs should not be considered in case of side effects. Furthermore, in case of side effects, sometimes even cross reactions between thioimidazoles and propylthiouracil occur. Common and typical adverse reactions of antithyroid drugs include dose dependent hypothyroidism and thus thyroid function should be repeatedly checked while the patient is on antithyroid drugs. Furthermore, pruritus and rash may develop. In this case, one might try to switch from thioimidazoles to propylthiouracil or vice versa. Antithyroid drugs may cause mild dose dependent neutropenia or severe allergy-mediated agranulocytosis, which typically occurs during the first three months of treatment, has an incidence of 3 per 10,000 patients and cross reactivity between thioimidazoles to propylthiouracil may occur. Rarely, antithyroid drugs can cause aplastic anemia. Mainly propylthiouracil, but sometimes also methimazole may lead to an asymptomatic transient increase in liver enzymes or to severe, even lethal liver injury of cholestatic or hepatocellular pattern. Since propylthiouracil associated liver injury was observed increasingly among children and adolescent, it has been suggested to prefer thioimidazoles for these patients. Because of these potential serious adverse effects, physicians should advise patients to immediately seek medical help if they get a fever or sore throat or malaise, abdominal complaints or jaundice, respectively. Furthermore, arthralgias may develop in 1-5% of patients under both antithyroid drugs. Since arthralgias may be the first symptom of more serious immunologic side effects, it is recommended to stop the antithyroid drug in this case. Drug induced polyarthritis mainly develops during the first month of therapy, whereas ANCA-positive vasculitis is generally observed only after long term exposure to propylthiouracil or very rarely with the thioimidazoles. The teratogenic risk of the thioimidazoles is somewhat higher (Aplasia cutis congenita), that is why one generally recommends preferring propylthiouracil during pregnancy. During breast feeding both, thioimidazoles or propylthiouracil, may be administered. Nowadays, perchlorate is only used short term in case of latent hyperthyroidism before administering iodine-containing contrast agents. Therefore, the known side effects, which usually are only observed after long term treatment, are not an issue any more

How much is too much? Oligosymptomatic presentation after 11.5 g of diphenhydramine

We report the case of a 47-year-old male obese Caucasian patient presenting 2 hours after ingestion of 11.5 g of diphenhydramine. Despite this excessive overdose, he showed only a few hours of impaired consciousness and no further symptoms. A diphenhydramine plasma concentration of 15,352 nmol/L was measured 8 hours after the overdose ingestion. A heterogeneous CYP2D6 extensive metabolizer genotype excludes a pharmacokinetic explanation for this unusually oligosymptomatic presentation. However, the patient suffered from longstanding, refractory depression despite numerous treatment attempts with various drugs, pointing to the possibility of decreased pharmacodynamic responsiveness for therapeutic and toxic effects

Oral heroin in opioid-dependent patients: Pharmacokinetic comparison of immediate and extended release tablets

In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Non-compartmental methods and deconvolution were applied for data analysis. Mean (+/-S.D.) immediate and extended release doses were 719+/-297 and 956+/-404mg, with high absolute morphine bioavailabilities of 56-61%, respectively. Immediate release diacetylmorphine caused rapid morphine absorption, peaking at 10-15min. Morphine absorption was considerably slower and more sustained for extended release diacetylmorphine, with only approximately 30% of maximal immediate release absorption being reached after 10min and maintained for 3-4h, with no relevant food interaction. The relative extended to immediate release bioavailability was calculated to be 86% by non-compartmental analysis and 93% by deconvolution analysis. Thus, immediate and extended release diacetylmorphine produce the intended morphine exposures. Both are suitable for substitution treatments. Similar doses can be applied if used in combination or sequentially

Probleme der Pharmakotherapie in der Hausarztpraxis : Pharmakotherapie konkret - Ein E-Learning für Medizinstudierende

Hintergrund Fehler in der Pharmakotherapie sind häufig und betreffen wahrscheinlich etwa 2-10% aller Verschreibungen. Direkt nach Abschluss des Studiums beschreibt sich nur eine Minderheit der jungen Ärzte als „kompetent zu Verordnen“. Unser Ziel ist es, die Medizinstudierenden in Ergänzung zu den Vorlesungen optimal auf die klinische Tätigkeit des Medikamente Verordnens vorzubereiten. Bereits umgesetzt sind die beiden blended learning Module „Arzneimittelrezepte korrekt schreiben“ und „Polypharmazie im Alter“