Higher chlorzoxazone clearance in obese children compared with nonobese peers.

AIMS: To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obese children vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS: Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS: Obese children had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-∞ value of CLZ was decreased by 46% in obese children compared to nonobese children. The F was was increased twofold in obese children compared to nonobese children, P < 0.0001. Diabetic biomarkers were significantly increased in obese children, while fasting blood glucose and Hba1c levels were nonsignificant between groups. Liver fat content was not associated with CLZ Cl. CONCLUSION: Oral clearance of CLZ was increased two-fold in obese children vs. nonobese children aged 11-18 years. This indicates an increased CYP2E1 activity of clinical importance, and dose adjustment should be considered for CLZ.

Treatment of 5413 hypertensive patients: a cross-sectional study.

BACKGROUND: Most hypertensive patients are managed in primary care in Denmark, but previous studies have shown that only 21-43% of hypertensive patients achieve optimal blood pressure (BP) control. Antihypertensive drug treatment, risk factors and cardiovascular disease (CVD) are some of the important factors to consider when optimizing the individual treatment strategy in hypertensive patients. OBJECTIVE: To examine treatment of BP according to Danish guidelines (BP < 140/90 mmHg generally and <130/80 mmHg for diabetics) in a population from general practice in relation to risk factors, CVD and diagnosis of diabetes. METHODS: A cross-sectional study comprising 184 practices and 5413 hypertensive patients was carried out in Denmark. The general practitioners filled in information on each patient's risk factors, CVD and antihypertensive drug treatment. Patients filled in a questionnaire on risk factors. The outcome measures were optimal BP control according to Danish guidelines and antihypertensive drug treatment. RESULTS: Mean patient age was 65.9 years [95% confidence interval (CI): 65.6-66.1]. Optimal BP control was achieved in 29.1% (95% CI: 27.9-30.3) of the study population. Among 842 diabetics with or without CVD, optimal BP control was achieved in 10.9% (95% CI: 8.8-10.3), while 38.7% (35.5-41.9) of patients with CVD achieved optimal BP control. The majority of all patients were treated with 1 (32.5%, 95% CI: 32.5 (31.3-33.8)) or two antihypertensive drugs (39.0%, 95% CI: 38.2-40.8). In hypertensive diabetics, 17.7% were not treated with an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker. CONCLUSION: In general practice, the proportion of hypertensive patients achieving optimal BP control is inadequate. The majority of hypertensive patients are treated with only one or two antihypertensive drugs.

Dose-response study of probiotic bacteria Bifidobacterium animalis subsp lactis BB-12 and Lactobacillus paracasei subsp paracasei CRL-341 in healthy young adults.

OBJECTIVE: This study was performed to investigate the dose-response effects of supplementation with Bifidobacterium animalis subsp lactis (BB-12) and Lactobacillus paracasei subsp paracasei (CRL-431) on blood lipids, recovery from feces and bowel habits. Changes of the fecal microflora was analyzed in the 10(10) CFU/day probiotic and placebo group. DESIGN: The study was designed as a randomized, placebo-controlled, double-blinded, parallel dose-response study. SUBJECTS: Healthy young adults (18-40 years) were recruited by advertising in local newspapers. Of the 75 persons enrolled, 71 (46 women, 25 men, mean age 25.6 years (range 18-40 years)) completed the study. INTERVENTION: The volunteers were randomly assigned into five groups receiving either placebo or a mixture of the two probiotics in the concentration of 10(8), 10(9), 10(10) or 10(11) CFU/day in 2 weeks run-in period, 3 weeks intervention and 2 weeks wash-out. Diary reporting bowel habits and well being (abdominal bloating, flatulence and headache) was kept for all 7 weeks and blood lipids, fecal recovery of BB-12 and CRL-431, as well as fecal microflora was tested before, immediately and 2 weeks after intervention. RESULTS: The fecal recovery of BB-12 increased significantly (P < 0.001) with increasing dose. In the group receiving 10(11) CFU/day BB-12 was recovered from 13 out of 15 volunteers. CRL-431 was not recovered in any of the fecal samples. Supplementation with probiotics did not change the fecal bacterial composition. A significant linear increase in fecal consistency (looser stool) with increasing probiotic dose (P = 0.018) was observed. No overall dose-response effect was found on the blood lipids. High doses of probiotics were well tolerated. CONCLUSION: A dose-related recovery of BB-12 from feces was observed.

Unchanged acetylation of isoniazid by alcohol intake.

SETTING: In 10 healthy subjects, the influence of acute alcohol intake on the pharmacokinetics of isoniazid (INH) was studied. OBJECTIVE: To test the hypothesis that alcohol increases the conversion of INH by acetylation into its metabolite acetylisoniazid. DESIGN: In a crossover design, an oral dose of 300 mg INH was administered on 2 separate days, 14 days apart, with or without alcohol to a serum alcohol of about 21 mmol/l (1 g/l) maintained for 12 h. RESULTS: Neither the metabolism of INH nor that of acetylisoniazid was changed by acute alcohol intake. CONCLUSION: Acute alcohol intake has no impact on the conversion of INH to its metabolite acetylisoniazid, which is catalysed by the enzyme N-acetyltranferase. Accordingly, a metabolic effect of acute alcohol intake on INH metabolism probably contributes little to the therapeutic failure of anti-tuberculosis treatment among alcoholics.

Blood pressure in acute stroke. The Copenhagen Stroke Study.

This study examines blood pressure (BP) and independent factors related to BP in the acute phase of stroke. The study is part of the community-based Copenhagen Stroke Study. In a multivariate regression model we analyzed the impact of clinical and medical factors on admission BP. BP declined with increasing time from stroke onset with a total of 8/4 mm Hg. Independent factors related to diastolic BP were ischemic heart disease (-3.9 mm Hg), male gender (2.2 mm Hg), known hypertension prior to stroke (8.6 mm Hg), and primary hemorrhage (9.7 mm Hg). Independent factors related to systolic BP were age (3.6 mm Hg/10-year increase), atrial fibrillation (-7.2 mm Hg), ischemic heart disease (-6.0 mm Hg), intracerebral hemorrhage (13.3 mm Hg), and known hypertension prior to stroke (16.3 mm Hg). No independent relations were seen between BP and diabetes, claudication, previous stroke, smoking, daily alcohol consumption, initial stroke severity and lesion size. The increase in BP in the acute phase of stroke is a uniform response to the ischemic event per se. BP is not related to stroke severity. Several factors are independently related to the BP level in acute stroke. The clinical significance of this is yet to be tested, but these factors may contribute to the seemingly complex relation between BP and outcome.

Modulation of Na,K-ATPase by associated small transmembrane regulatory proteins and by lipids.

The effects of phospholipid acyl chain length (n(c)) and cholesterol on Na,K-ATPase reconstituted into liposomes of defined lipid composition are described. The optimal hydrophobic thickness of the lipid bilayer decreases from n(c) = 22 to 18 in the presence of 40 mol% cholesterol. Hydrophobic matching as well as specific interactions of cholesterol with the phosphorylation/dephosphorylation reactions is found to be important. A novel regulatory protein has been identified in Na,K-ATPase membrane preparations from the shark (phospholemmanlike protein from shark, PLMS) with significant homology to phospholemman (PLM), the major protein kinase substrate in myocardium. Both are members of the FXYD gene family. Another member of this family is the Na,K-ATPase gamma subunit indicating that these proteins may be specific regulators of the Na,K-ATPase. A regulatory mechanism is described in which association/dissociation of PLMS with the Na,K-ATPase is governed by its phosphorylation by protein kinases.

[Fatal intracerebral hemorrhage after amphetamine intake]. / Letal intracerebral blødning efter indtagelse af amphetamin.

A fatal case of massive intracerebral hemorrhage in a 20-year-old woman after first-time amphetamine abuse is described along with a review of the literature.

Development of a polyclonal antibody-based sensitive enzyme-linked immunosorbent assay for fumonisin B(4).

Polyclonal antibodies (PAb) against fumonisin B(4) (FmB(4)), which have good cross-reactivity with four major fumonisins, were produced by immunizing a rabbit with FmB(4)-keyhole limpet hemocyanin conjugate. A sensitive competitive direct enzyme-linked immunosorbent assay (CD-ELISA) for fumonisins was developed. Because of the limited supply of FmB(4), both FmB(1)-horseradish peroxidase conjugate (HRP) and FmB(3)-HRP were tested as the toxin-enzyme markers in the CD-ELISA. In the FmB(1)-HRP-based CD-ELISA, the concentrations of FmB(1), FmB(2), FmB(3), and FmB(4) causing 50% inhibition of binding of enzyme marker (IC(50)) were 9.0, 2.1, 9.0, and 6.5 ng/mL (or the relative cross-reactivities toward FmB(1), FmB(2), FmB(3), and FmB(4) were 58.5, 309.5, 58.5, and 100%), respectively. In the FmB(3)-HRP-based CD-ELISA, the IC(50) values for FmB(1), FmB(2), FmB(3), and FmB(4) were 7.1, 1.9, 7.6, and 5.3 ng/mL (or the relative cross-reactivities toward FmB(1), FmB(2), FmB(3), and FmB(4) were 74, 280, 70, and 100%), respectively. The FmB(3)-HRP-based CD-ELISA was then used in a series of analytical recovery experiments using Fusarium moniliforme corn culture material spiked with FmB(1) and with clean corn spiked with a FmB(3)/FmB(4)-containing extract. The overall recovery of FmB(1) from culture material in the range of 10-100 ppm was 65%. The detection limit for FmB(1) with clean corn as matrix was between 100 and 500 ppb. F. moniliforme cultures were analyzed with the developed CD-ELISA and a well-established FmB(1) antibody-based ELISA, which is not sensitive to FmB(4). Differences in the fumonisin levels found by the two assays were used as an indication of the presence of FmB(4) in the culture material and, therefore, as a method to identify FmB(4)-producing strains. Using ELISA in combination with HPLC individual B-series fumonisins were quantified. The ELISA developed in the present study would be a useful supplement to FmB(1) antibody-based ELISA for screening of Fusarium strains for the production of major fumonisins.

Bioavailability and pharmacokinetics of isradipine after oral and intravenous administration: half-life shorter than expected?

Isradipine is a calcium channel-blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half-life of 8-9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half-life was observed, and the present trial was therefore conducted in order to estimate the half-life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross-over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for 10-12 hr after administration and half-life and bioavailability were estimated. Mean terminal half-life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be 0.28. None of the 10 subjects suffered from side effects. In the present intravenous study the half-life of isradipine seems to be of much shorter than demonstrated in previous oral studies.

[Clinical pharmacological drug information. Well over one year's experience]. / Klinisk farmakologisk laegemiddelrådgivning. Godt et års erfaring.

Clinical pharmacology was established quite recently in Denmark as a medical specialty. It comprises--among other items--clinical pharmacological drug information service, the primary aim of which is to provide service to health personnel with clinical responsibility involving drugs and specific patient-related questions. Questions forwarded to the clinical pharmacological drug information service at two Copenhagen hospitals have been summarized. The questions were categorized according to the profession and the affiliation to the health care system of the inquirer as well as the nature of the question. At the two hospitals, 118 and 77 questions were answered from January 1st 1997 to June 1st 1998, respectively. Physicians employed at hospitals were responsible for the majority of the questions. Most questions concerned adverse drug reactions, choice of therapy/drug, and therapy during pregnancy or breast feeding.

[Gamma-hydroxybutyrate--an endogenous substance and a new central nervous system stimulant. Clinical aspects of acute poisoning]. / Gammahydroxybutyrat--en endogen substans og et nyt rusmiddel. Kliniske aspekter hos den akut forgiftede patient.

During the last six months, the Poison Control Centre at Bispebjerg Hospital, Copenhagen, Denmark, has observed an increasing number of patients intoxicated with GHB, a drug of abuse. The patients are often admitted to the emergency ward shortly after having taken the drug, unconscious or comatose. If younger patients present with these symptoms, intoxication with GHB should be seriously considered. The effects are seen within 15 to 30 minutes after oral ingestion of the drug. Spontaneous recovery usually occurs within three to five hours. The most common effects are mild euphoria, sedation, vomiting, somnolence, bradycardia, aggressive behaviour, apnoea, respiratory depression, and coma. Normally the patient breathes adequately, but insufficient respiration may occur and deaths have been described. The drug is often consumed together with alcohol and other drugs of abuse, which strengthens the effect of GHB. Treatment is symptomatic. A review of the literature with special emphasis on clinical effects included toxicology and treatment is given.

[Amphetamine, ecstasy and cocaine. Clinical aspects of acute poisoning]. / Amphetamin, ecstasy og cocain. Kliniske aspekter hos den akut forgiftede patient.

Consumption of the illicit drugs amphetamine, ecstasy and cocaine is increasing in Denmark and Europe leading to an increasing number of intoxications with these drugs. Abroad, several deaths after ingestion of a few doses of the drugs have been reported. Amphetamine, ecstasy and cocaine increase the amount of dopamine, norephedrine and serotonine in the nervous system, resulting in CNS stimulation and a general sympathomimetic stimulation. Symptoms to be treated originate mainly from the CNS and the cardiovascular system, and present as tachycardia, hypertension and seizures, later hypotension and coma. Hyperpyrexia, rhabdomyolysis and affections of the kidneys, lung and liver function are also often seen. Hyperpyrexia is an important marker of poor prognosis, and must be handled aggressively. A review of the literature concerning the optimal treatment based on pharmacological and diagnostic considerations is given in the article.

Enantioselective determination of isradipine in human serum using chiral stationary phase liquid chromatography and gas chromatography with nitrogen selective detection.

rac-Isradipine is a dihydropyridine type calcium antagonist. Its calcium entry blocking effect is due primarily to the (+)-(S)-enantiomer. This study describes a sensitive enantioselective method for the determination of isradipine in human serum. Following alkaline extraction into hexane, the enantiomers of isradipine are separated quantitatively by high-performance liquid chromatography on a Chiralcel OJ column at 39 degrees C. The collected fractions were evaporated and assayed using capillary gas chromatography on a HP 50+ column with nitrogen selective detection. Using 2.0 ml of serum, 0.7 nmol/1 (0.26 ng/ml) of each enantiomer could be determined with acceptable precision. The method has successfully been used to measure (+)-(S)- and (-)-(R)-isradipine concentrations in samples from volunteers after intravenous and oral administration of isradipine.

[Discrepancies between medical records and dispensing records in two large hospital departments in Copenhagen]. / Uoverensstemmelse mellem journal og medicinkardex på to store afdelinger i København.

This study was performed to investigate the possible differences between prescribed medicine, as entered in the hospital record, and the medicine dispensed to the patients according to the nurse's dispensing records (NDR's) in two clinical departments at a Copenhagen University Hospital. Discrepancies were defined as either dosage differences or drugs only present in one file, and were divided into major and minor discrepancies, according to clinical significance. In the first department, discrepancies were found in 61.4% of the records, and major discrepancies were found in 35.1%. In the second department, discrepancies were found in 70.5% of the cases, and major discrepancies in 42.5%. No correlation was found between the number of drugs per patient and the number of discrepancies. A significant difference exists between what is prescribed, and what is dispensed. This can have clinical as well as legal consequences.