CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients.

It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 -24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67+/-0.3 and 1.36+/-0.73 x 10(3) l (P<0.00001) for tacrolimus and 0.42+/-0.17 and 0.84+/-0.46 x 10(3) l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)(0-12) was 106.8+/-17.5 ng/ml x h compared with 133.3+/-42.2 ng/ml x h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC(0-24) of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles.

The selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056) reduces the incidence of reflux episodes in dogs and patients with moderate to severe gastroesophageal reflux disease.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) induced by gastric distension are modulated by the metabotropic glutamate receptor 5 (mGluR5) that influences the vagal reflex loop. We therefore aimed to examine the effects of the selective mGluR5 antagonist mavoglurant (AFQ056) on the number of TLESRs in dogs and reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: In a dog model, the number of meal-induced TLESRs was determined after intravenous (0.03, 0.1, 0.3, and 1 mg kg-1 ) and oral (1, 3, and 10 mg kg-1 ) doses of mavoglurant with reference to vehicle. In a multicenter, randomized, double-blind, placebo-controlled, three-period crossover study, the incidence of meal-induced reflux episodes was assessed by esophageal impedance monitoring after single, oral doses of mavoglurant (50 and 400 mg) or baclofen (40 mg) in 30 patients with moderate to severe GERD. KEY RESULTS: In dogs, mavoglurant reduced the number of TLESRs after intravenous and oral administration. In patients with GERD, the incidence of postprandial reflux episodes was significantly lower at a dose of 400 mg mavoglurant (-37.5% ; 90% confidence interval [CI]: -57.8, -17.2), whereas there was no significant difference at 50 mg of mavoglurant compared to placebo. A significantly lower incidence of reflux episodes was also noted with the active comparator baclofen (-50.3%; 90% CI: -66.2, -34.3), thereby validating this study. CONCLUSIONS AND INFERENCES: These data suggest a potential clinical benefit of mGluR5 antagonists such as mavoglurant in patients with GERD, particularly in those with persisting symptoms despite treatment with proton pump inhibitors.

Influence of CYP3A4, CYP3A5, and ABCB1 genotype and expression on budesonide pharmacokinetics: a possible role of intestinal CYP3A4 expression.

Budesonide treatment of chronic inflammatory bowel disease commonly leads to non-response or adverse reactions, possibly because of alterations in efflux transport mediated by the ABCB1 gene product P-glycoprotein or metabolism by CYP3A isoenzymes. Two groups, each consisting of nine healthy volunteers, one with the CYP3A5(*)1/(*)3 genotype (expressors) and the other with the CYP3A5(*)3/(*)3 genotype (non-expressors), were given a single oral dose of 9 mg budesonide. Plasma and urine concentrations of budesonide and its major metabolites were determined using liquid chromatography-tandem mass spectrometry. Subsequently, rectosigmoidal biopsies were taken for analysis of messenger RNA (mRNA) expression. Budesonide pharmacokinetics did not differ between genotype groups. However, intestinal CYP3A4 expression was shown to correlate directly with partial metabolic clearances of 16-hydroxy-prednisolone (r(2) = 0.30; P = 0.010) and 6-hydroxy-budesonide (r(2) = 0.25; P = 0.016), but inversely with budesonide AUC(0-24 h) (r(2) = 0.18; P = 0.040). Interestingly, a strong correlation was found between CYP3A5 and ABCB1 expression in CYP3A5 expressors (r(2) = 0.79; P = 0.001). This study suggests that intestinal CYP3A4 expression has an impact on budesonide pharmacokinetics. Moreover, CYP3A5 and ABCB1 expression appears to be coregulated.

Patterns and prevalence of antidepressant drug use in the German state of Baden-Wuerttemberg: a prescription-based analysis.

PURPOSE: Population-based data about patterns and prevalence of antidepressant drug use is limited in Europe and presently unavailable for Germany. Therefore, we have identified patterns and prevalence of antidepressant use among outpatients on a population-based scale in the German state of Baden-Wuerttemberg. METHODS: We conducted a historical cohort study using a computerised prescription database referring to all members of the major German public health insurance company AOK. We assessed the prevalence of antidepressant drug use over a 3-year period, calculated the number of prescription items purchased per patient and compared first-line and second-line treatments. RESULTS: The 1-year prevalence of antidepressant drug use among more than 4,000,000 health insurance members was 7.4% (male: 4.3%; female: 10.2%). Importantly, almost 40% of the patients received only a single prescription item from 2000 to 2002. Though the use of serotonin-reuptake inhibitors (SSRIs) markedly increased by about 65% within the study period, these are primarily used as second-line drugs and still much less frequently than St. John's wort or tricyclic antidepressants such as amitryptiline or doxepin. CONCLUSIONS: The prevalence of antidepressant drug use is higher than previously reported for other European countries. The preferred use of St. John's wort and tricyclics over SSRIs and other modern-type antidepressants in Germany is quite unique in Europe and different from the US. The identified drug use pattern leaves a major room for improvement in view of the numerous single prescription items purchased.

No benefit of 3,4-diaminopyridine in essential tremor: a placebo-controlled crossover study.

3,4-Diaminopyridine (3,4-DAP) is a potassium channel blocker that has recently demonstrated an antioscillatory effect in humans by significantly reducing downbeat nystagmus. Based on the presumed role of intrinsic oscillations in the pathophysiology of essential tremor (ET), the authors conducted a double-blind, placebo-controlled crossover study assessing the antitremor effect of a single dose of 3,4-DAP in 19 patients with ET. They did not find any significant change in tremor severity as measured by clinical ratings or accelerometry.

Antimicrobial drug use in hospitalised paediatric patients: a cross-national comparison between Germany and Croatia.

PURPOSE: To compare the utilisation of systemic antimicrobials at the paediatric units of the university hospitals in Marburg (Germany) and Rijeka (Croatia). METHODS: A prospective, observational analysis of hospital records from 300 incident users of antimicrobials in each study centre that were younger than 19 years. Antimicrobial utilisation was analysed in six gender-specific age groups with respect to drug choice, duration of treatment and hospital stay, indication and route of administration. The extent of antimicrobial drug use was assessed by the number of treatment courses. RESULTS: In each hospital, more than 1/3 of the patients were younger than 1 year. The duration of hospital stay was about two-fold longer in Rijeka (18.5 +/- 5.8 days) than in Marburg (8.6 +/- 3.8 days). Pneumonia and other respiratory tract infections were the most common indications in Marburg (38.6%) and Rijeka (58.7%). The cumulative percentage of patients treated with an equal number of different antimicrobials was lower in Rijeka than in Marburg. The most commonly used antimicrobials were ampicillin (40.3%) and cefuroxim (35.9%) in Marburg, but ceftriaxone (43.3%) and cefotaxim (14.0%) in Rijeka. CONCLUSIONS: A shorter treatment duration, less variation in the prescribing pattern and a greater adherence to the use of recommended antimicrobials argue for a more rational antimicrobial drug use in Marburg than in Rijeka. However, a further identification of drug choice determinants is warranted.

[Hospital "full"--must the emergency physician go farther?]. / Krankenhaus "belegt"--Muss der Notarzt weiterfahren?

All beds in the surgical department of a hospital are occupied. The dispatch center is announcing a rescue unit transporting a heavy injured casualty. The surgeon is running to the emergency room. What to do under the view of the german legal system?

[Limitations of preclinical emergency medicine from the legal viewpoint]. / Grenzen der präklinischen Notfallmedizin aus juristischer Sicht.

Revised and Annotated Version of the Author's Lecture held at the 13th Annual Meeting on Emergency Care Medicine on 14 March 1998 at Baden-baden, Germany. This article highlights the limitations of preclinical emergency care medicine from a legal viewpoint. Among other problems, focus is also on the problem whether a particular emergency care measure can be expected from the emergency physician. Much attention is devoted to a discussion on treating a patient against his will, this constituting a differentiated borderline case in emergency medicine. Another equally differentiated problem concerns the economic aspects--for example, whether an emergency treatment pays returns in terms of economy. This is no limitation in individual cases where emergency treatment is medically indicated, but it does exercise an influence on pre-planning the security level of emergency care services. There are no limitations for emergency services from a legal point of view imposed by the patient's age or his or her domicile in a home for the aged or infirm.

[Legal issues in unconscious emergency patients]. / Das rechtliche Problem mit dem bewusstlosen Notfallpatienten.

Basic legal questions of medical treatment in unconscious emergency patients are discussed. Legal issues in the German judiciary are presented.

Voluntary consumption of amphetamine, cocaine, ethanol and morphine by rats as influenced by a preceding period of forced drug intake and clozapine.

Forced nicotine intake was previously found to decrease a subsequent free choice selection, whereas clozapine (CL) caused a marked increase in its consumption. Here these findings are extended to ethanol, cocaine, morphine and amphetamine. Forced intake of ethanol, cocaine, morphine and amphetamine had no major effect on a subsequent voluntary intake. CL, a dopamine D4 antagonist, increased the voluntary consumption of amphetamine and morphine with no effects on ethanol or cocaine intake. Only for cocaine was it found that low-consuming rats increased but high-consuming rats decreased their voluntary cocaine intake by CL. Thus, forced drug exposure per se does not lead to subsequent enhancement of voluntary intake; CL exerts differential effects on intake of these drugs, and a specific dopaminergic set point may govern the voluntary intake of cocaine by individual rats.

Genetic polymorphisms of cytochrome P450 2C9 causing reduced phenprocoumon (S)-7-hydroxylation in vitro and in vivo.

The effect of cytochrome P450 (CYP) 2C9 polymorphisms on the stereoselective biotransformation of the oral anticoagulant phenprocoumon (PPC) to inactive, monohydroxylated metabolites was studied in vitro and in vivo. In human liver microsomes, the (S)-7-hydroxylation--being the major metabolic pathway--was significantly compromised in a gene-dose-dependent manner in samples expressing the CYP2C9*2 or CYP2C9*3 allele. The CYP2C9*3/*3 genotype corresponded to an almost fourfold lower (S)-7-hydroxylation rate than CYP2C9*1/*1 (wild-type). The intrinsic clearance of human recombinant CYP2C9*2 and CYP2C9*3 for the (S)-7-hydroxylation was 28.9 and 50.9% lower than of CYP2C9*1, respectively. The area under the plasma concentration-time curve (AUC) of PPC metabolites after oral intake of 12 mg racemic PPC was significantly lower in volunteers expressing the CYP2C9*2 or CYP2C9*3 allele. Increasing plasma AUC metabolic ratios (parent compound/metabolite) in CYP2C9*2 and CYP2C9*3 variant allele carriers were found for each hydroxylation reaction and the CYP2C9*3/*3 genotype corresponded to an about 10-fold higher metabolic ratio of PPC (S)-7-hydroxylation relative to CYP2C9*1/*1. CYP2C9 polymorphisms cause a markedly compromised PPC (S)-7-hydroxylation. However, PPC metabolism appears overall less influenced by CYP2C9 genotype compared with other oral anticoagulants and it may thus be a valuable alternative for therapeutic anticoagulation of patients expressing CYP2C9 variant alleles.

Amantadine, a N-methyl-D-aspartate receptor antagonist, does not enhance postoperative analgesia in women undergoing abdominal hysterectomy.

UNLABELLED: N-methyl-D-aspartate (NMDA) antagonists administered before surgery will improve postoperative analgesia, presumably by inhibiting spinal sensitization processes. However, current clinical formulations of NMDA antagonists either enable only an oral application (i.e., dextromethorphan) or are associated with psychotropic side effects, as with the IV delivery of ketamine. Because of its noncompetitive NMDA receptor antagonist characteristics, amantadine may improve postoperative analgesia when administered before surgically induced trauma. In this prospective, randomized clinical study, we examined whether female patients undergoing elective abdominal hysterectomy experienced less postoperative pain when IV amantadine was applied in comparison with placebo before the start of surgery. Thirty patients were randomly assigned to receive 500 mL saline IV before the induction of standardized general anesthesia in Group 1 (Control group) or, in a double-blinded manner, 200 mg amantadine IV in 500 mL saline in Group 2 (Treatment group). Postoperative pain control was provided via IV patient-controlled analgesia with piritramide. During the first 48 h after tracheal extubation, pain perception was assessed by visual analog scales, and all analgesic requirements were documented. There were no significant differences between the two groups with respect to pain scores, postoperative analgesic requirements, and the incidence of side effects. Because of no differences in postoperative pain or opioid consumption, we conclude that a preoperative dose of 200 mg amantadine IV fails to enhance postoperative analgesia in patients undergoing elective abdominal hysterectomy. IMPLICATIONS: Because of no differences in postoperative pain or opioid consumption, we conclude that a preoperative dose of 200 mg amantadine IV fails to enhance postoperative analgesia in patients undergoing elective abdominal hysterectomy.