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Background: Coronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed.Methods: We conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1-4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined.Findings: The trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a β2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration.Interpretation: UNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials.Funding: The study was funded by Innovationsfonden Denmark and UNION therapeutics.

BackgroundPeptide-based vaccination is a rational option for immunotherapy of prostate cancer. In this first-in-man phase I/II study, we assessed the safety, tolerability and immunological impact of a synthetic long peptide vaccine targeting Ras homolog gene family member C (RhoC) in patients with prostate cancer. RhoC is a small GTPase overexpressed in advanced solid cancers, metastases and cancer stem cells.MethodsTwenty-two patients who had previously undergone radical prostatectomy received subcutaneous injections of 0.1 mg of a single RhoC-derived 20mer peptide emulsified in Montanide ISA-51 every 2 weeks for the first six times, then five times every 4 weeks for a total treatment time of 30 weeks. The drug safety and vaccine-specific immune responses were assessed during treatment and thereafter within a 13-month follow-up period. Serum level of prostate-specific antigen was measured up to 26 months postvaccination.ResultsMost patients (18 of 21 evaluable) developed a strong CD4 T cell response against the vaccine, which lasted at least 10 months following the last vaccination. Three promiscuouslypresented HLA-class II epitopes were identified. Vaccine-specific CD4 T cells were polyfunctional and effector memory T cells that stably expressed PD-1 (CD279) and OX-40 (CD134), but not LAG-3 (CD223). One CD8 T cell response was detected in addition. The vaccine was well tolerated and no treatment-related adverse events of grade ≥3 were observed.ConclusionTargeting of RhoC induced a potent and long-lasting T cell immunity in the majority of the patients. The study demonstrates an excellent safety and tolerability profile. Vaccination against RhoC could potentially delay or prevent tumor recurrence and metastasis formation.Trial registration numberNCT03199872.

In some hospitals, clinical pharmacists review the medication to find drug-related problems (DRPs) in acutely admitted patients. We aimed to identify the nature of identified DRPs and investigate factors of potential importance for the clinical implementation of pharmacist suggestions. In 100 randomly selected medication review notes, we retrospectively evaluated the clinical implementation and classified 1) timing and communication of the review; 2) DRPs and related suggestions for the physician; and 3) DRPs’ potential clinical relevance to patients as ‘beneficial’, ‘somewhat beneficial’, ‘no relevance’ or ‘other relevance’. Of 327 DRPs (0-13 DRPs/patient), 48% were implemented. The clinical implementation was higher if the medication review note was made prior to (instead of after) the physician's admission, and even higher if the suggestions were communicated verbally (instead of only in writing) to the physicians (44 versus 79%, P

The Danish Society of Clinical Pharmacology was founded in 1976, and mainly thanks to the persistent efforts of the society, clinical pharmacology became an independent medical speciality in Denmark in 1996. Since then, clinical pharmacology has gone from strength to strength. In the Danish healthcare system, clinical pharmacology has established itself as an indispensible part of the efforts to promote the rational, safe and economic use of drugs. Clinical pharmacologists are active in drug committees both in hospitals and in the primary sector. All clinical pharmacology centres offer a local medicines information service. Some centres have established an adverse drug effect manager function. Only one centre offers a therapeutic drug monitoring service. Clinical pharmacologists are responsible for the toxicological advice at the Danish Poison Information Centre at Bispebjerg University Hospital in the Capital Region. The Department of Clinical Pharmacology at Aarhus University Hospital works closely together with forensic toxicologists and pathologists, covering issues regarding illicit substances, forensic pharmacology, post-mortem toxicology, expert testimony and research. Therapeutic geriatric and psychiatric teach-inns for specialist and junior doctors are among the newest initiatives organized by clinical pharmacologists. Clinical pharmacologists work also in the Danish Medicines Agency and in the Danish pharmaceutical industry, and the latter has in particular a great growth potential for creating new jobs and career opportunities for clinical pharmacologists. As of July 2016, the Danish Society of Clinical Pharmacology has 175 members, and 70 of these are specialists in clinical pharmacology corresponding to approximately 2.5 specialists per 1000 doctors (Denmark has in total 28,000 doctors) or approximately 12 specialists per one million inhabitants.

Rationale and objectives To study the magnetic resonance imaging signal intensity of the liver and gall bladder before and after ingestion of a new oral manganese containing contrast medium at three different field strengths. Materials and methods Twelve healthy male volunteers (mean age, 24.9 years; range, 20–39 years) underwent abdominal magnetic resonance imaging (T2W COR, T1W COR, T1W TRA) at 0.23T, 0.6T, and 1.5 T before and after the contrast administration. The duration of fasting was identical before the two studies. Volunteers were randomized into two equal groups (n = 6) to ingest either half or full strength CMC-001 providing either 0.8 or 1.6.g MnCl2 plus absorption promoters. The CMC-001 dose was dissolved in 400 mL water and ingested 2 1 2 hours before imaging. The resulting images were evaluated with regard to visualization of the liver and the gall bladder by three radiologists. The signal intensity of the liver was also measured. Blood and urine samples were collected before and after ingestion of CMC-001. Results The intake of CMC-001 caused a significant increase in the signal intensity of the liver at all three field strengths and at both dosages (up to 90%) on the T1W images. The internal structure of the liver was significantly better delineated. The bile in gall bladder was bright after ingestion of the low dose, but dark after the full dose. On the T2W images, CMC-001 lowered the signal intensity of liver with up to 30%. CMC-001 had a slight metallic taste, but of no importance according to the volunteers. No systematic adverse reactions caused by the contrast medium were registered. No changes in the blood levels of various routine parameters were measured. Conclusion It is possible to increase the signal intensity of the liver significantly by oral intake of essential nutritional elements including manganese. The imaging window is more than 2 hours.

Aims In chronic renal failure, the clearance of most ACE inhibitors including enalapril is reduced. Hence, with conventional dosage, plasma enalaprilat may be markedly elevated. It is unclear whether this excess of drug exposure affords an improved control of blood pressure. The aim of the present study was to evaluate short-term blood pressure response to two different plasma levels of enalaprilat. Methods As part of an open, randomized, controlled trial of the effect of high and low dosage of enalapril on the progression of renal failure, short-term blood pressure response was evaluated. Data were analysed in all patients completing 3 months of follow-up. The patients were allocated to two trough plasma concentrations of enalaprilat, either above 50 ng ml−1 (high) (n = 17) or below 10 ng ml−1 (low) (n = 18), and the daily dose of enalapril titrated accordingly. Results Median (range) glomerular filtration rate (GFR) at baseline was 18 (7.9) in the high enalaprilat concentration group and 17 (7.3) ml min−1 1.73 m2 in the low concentration group (NS). Nine patients in each group were on treatment with enalapril at baseline with a median daily dose of 5 mg in both the high (5–10) and low (2.5–20) concentration group. At 3 months’ follow-up, the dose was 10 (2.5–30) and 1.9 (1.25–5) mg (P

Summary Background : Inter-individual response to azathioprine is partly due to inter-individual variation in the thiopurine methyltransferase (TPMT) activity. The TPMT genotype, which reflects the TPMT activity, has previously been studied in healthy Caucasians, with the most common variant allele being TPMT*3A. TPMT genotyping in adult patients with Crohn's disease has never been performed systematically. Aim : To determine the TPMT genotype distribution in adult patients with Crohn's disease. Methods : One hundred and twenty randomly selected Danish patients (64 females and 56 males) with azathioprine-dependent Crohn's disease were included, and a polymerase chain reaction assay was used for TPMT genotyping. The patients were genotyped for the low-level genotype G460A and A719G transitions. Results : One hundred and nine patients (90.3%; 95% confidence interval, 84.1–95.3) had a wild-type/ wild-type genotype, whereas 10 patients (8.3%; 95% confidence interval, 4.1–14.8) had one non-functional mutant allele and one patient (0.8%; 95% confidence interval, 0.02–4.6) had two non-functional mutant alleles. Only the TPMT*3A variant allele was found. Conclusions : The study showed a TPMT genotype distribution amongst adult Danish patients with Crohn's disease which was similar to the distribution of TPMT variant alleles normally found in healthy Caucasians.

Background: Our aim was to study the pharmacokinetics and pain scores following administration of single oral doses of either diclofenac or high-dose acetaminophen (paracetamol). Methods: In the morning, the day after tonsillectomy, children 5-15 years of age were randomized in a double-blind manner to receive either diclofenac 1-2 mg.kg -1 (n = 11) or acetaminophen 22.5 mg.kg -1 (n = 10). Postoperative pain was assessed by self-report and blood samples were drawn every 30 min for 4 h after medication. Results: Large interindividual differences in maximum plasma diclofenac concentrations (C max ) were found. Mean C max was 2.4±1.3 μg.ml -1 and mean t max was 2±0.5 h. No significant reduction in pain score with diclofenac was seen at any of the assessments during the study period. Eight of 10 children achieved C max of acetaminophen within the 10-20 μg.ml -1 antipyretic range. Mean tabs was 0.7±0.3 h and mean C max and t max were 12.7±3.8 μg ml -1 and 1.4±0.5 h, respectively. No significant reduction in pain score with acetaminophen was seen at any of the assessments during the study period. Conclusions: The achieved concentrations of diclofenac and acetaminophen were not able to significantly reduce the children's pain score during the 5 h postingestion study period. Analgesic plasma acetaminophen concentrations may be higher than those required for antipyresis.

Background/Aims: Consecutive patients originally diagnosed with acute non-A, non-B hepatitis were followed up to assess the long-term morbidity and mortality and to re-evaluate the etiology in surviving patients. Methods: Follow-up was performed in 178 patients with acute non-A, non-B hepatitis enrolled in the Copenhagen Hepatitis Acuta Programme in the period 1969–1987. Mortality and morbidity were assessed using: i) death certificates and ii) diagnoses at discharge following all somatic admissions. All patients who were alive were offered a re-examination encompassing clinical, biochemical and virological evaluation. Results: After a median of 23 years, 71 (40%) had died and seven (4%) were untraceable. Overall mortality and mortality due to cirrhosis and accidents, mainly intoxication with drugs, were significantly higher compared to those of an age- and sex-matched Danish population. Chronic hepatitis had been diagnosed in 19 (11%) and cirrhosis in 16 (9%). Of 100 patients who were alive, 57 accepted a re-examination. Anti-HCV was detected in 24 (42%) and 19 (33%) were HCV-RNA positive. Of the viremic patients, 11 (58%) had elevated P-ALT, but only three (16%) had already been diagnosed with HCV infection. A history of intravenous drug use was tantamount to anti-HCV positivity. Conclusions: Danish patients with community-acquired acute non-A, non-B hepatitis had an increased mortality due to liver cirrhosis during the first years after the acute infection. Alcohol was the etiological agent in several cases, but HCV infection may also have been present. However, the long-term HCV-related morbidity and mortality were low.

The effects of a pure ginseng preparation on a variety of cognitive functions was compared with those of placebo in a double-masked, randomized, test-retest design. The subjects were healthy volunteers older than 40 years of age who were given the ginseng preparation or placebo for 8 to 9 weeks. Of the 112 subjects who completed the study, 55 received ginseng and 57 received placebo. The ginseng group showed a tendency to faster simple reactions and significantly better abstract thinking than the controls. However, there was no significant difference between the two groups in concentration, memory, or subjective experience.

Drug-induced liver injury has been associated with more than 800 different drugs, leading to hospital admission in 1 of 600 to 3500 admissions. This amounts to 2 to 3% of all hospitalisations due to adverse drug reactions, or about 3% of all jaundiced patients. The prognosis of clinically overt drug hepatotoxicity is relatively serious. The clinical picture is essentially nonspecific, with a highly variable latency period from days to years. Drug hepatotoxicity can mimic almost any kind of liver disease. A thorough drug history, a low threshold of suspicion and the exclusion of other causes of liver disease are important for the detection of drug-induced liver disorders. Treatment consists of discontinuation of suspected drug(s), acetylcysteine in the course of paracetamol (acetaminophen) toxicity, and liver transplantation in selected cases of fulminant liver failure. Guidelines regarding the use of selected drugs such as methotrexate and halothane should be followed. Potentially hepatotoxic drugs should be used cautiously in alcoholic patients with or without liver involvement. Patients with uncompensated liver disease should receive a reduced dose of drugs adjusted to the degree of liver function impairment. The general public should be warned against abuse of hepatotoxic drugs such as paracetamol and anabolic steroids.

Udgivelsesdato: 2009 PURPOSE: To evaluate the effect of a combined or a single educational intervention on the prescribing behaviour of general practitioners (GPs). The primary endpoint was effect on inappropriate prescribing according to the Medication Appropriateness Index (MAI). METHODS: General practitioners were randomised to either (1) a combined intervention consisting of an interactive educational meeting plus feedback on participating patients' medication, (2) a single intervention with an interactive educational meeting or (3) a control group (no intervention). Elderly (>65 years) patients exposed to polypharmacy (>/=5 medications) were identified and approached for inclusion. Data on medications prescribed over a 3-month period were collected, and the GPs provided detailed information on their patients before and after the intervention. A pre- and post-MAI were scored for all medications. RESULTS: Of the 277 GPs invited to participate; 41 (14.8%) volunteered. Data were obtained from 166 patients before and after the intervention. Medication appropriateness improved in the combined intervention group but not in the single intervention group. The mean change in MAI and number of medications was -5 [95% confidence interval (CI) -7.3 to -2.6] and -1.03 (95% CI -1.7 to -0.30) in the combined intervention group compared with the group with the educational meeting only and the no intervention group. CONCLUSIONS: A combined intervention consisting of an interactive educational meeting plus recommendations given by clinical pharmacologists/pharmacists concerning specific patients can improve the appropriateness of prescribing among elderly patients exposed to polypharmacy. This study adds to the limited number of well-controlled, randomised studies on overall medication appropriateness among elderly patients in primary care. Important limitations to the study include variability in data provided by participating GPs and a low number of GPs volunteering for the study.

24 consecutive patients (14 females; median age 36, range 18–77) with liver biopsy proven acute non-A, non-B hepatitis (NANBH) were assayed for antibodies to hepatitis C virus (HCV). 14 (58%) were positive initially or during follow-up. Three patients were positive within 4 weeks following onset of symptoms and 7 patients in a serum sample obtained 4–8 weeks after clinical onset. Seroconversion was documented in 7/8 patients in paired sera from the acute phase of the disease. Anti-HCV was detected in 6% and 13% of control patients with acute hepatitis A and toxic hepatitis. NANBH in 6/14 patients (43%) with anti-HCV progressed to chronic liver disease (CLD). In contrast none of the anti-HCV negative patients developed CLD (p=0.02). In addition, 2 anti-HCV positive patients developed fulminant and fatal hepatitis. The predominant route of HCV transmission was intravenous drug abuse. It is concluded that hepatitis may be ascribed to HCV infection in more than half of patients with community aquired NANBH, t...

Udgivelsesdato: June OBJECTIVE: To describe the prevalence of inappropriate prescribing in primary care in Copenhagen County, according to the Medication Appropriateness Index (MAI) and to identify the therapeutic areas most commonly involved. SETTING: A cross-sectional study was conducted among 212 elderly ( >65 years) polypharmacy patients (five or more different medications) listed to 41 general practitioners (GPs) in the County of Copenhagen. METHOD: Patients exposed to polypharmacy were identified via the database recording the drug subsidy system of Danish pharmacies. For each patient, data were collected on subsidised medications prescribed over 3 months by the patients' own GPs. The GPs were asked to provide baseline information regarding the patients' medical history and detailed information regarding the subsidised and non-subsidised medications prescribed to the patients. A MAI was scored for medication prescribed to the patients. Topical, dermatological medications and medications not used regularly were excluded. RESULTS: 212 patients were prescribed 1621 medications by their GPs at baseline. In all, 640 (39.5%) of the medications had one or more inappropriate ratings in the 10 criteria making up the MAI. The main part of the patients (94.3%) had one or more inappropriate ratings among their medications. A total of 12.3% of the medications were rated as 'not indicated', 6% were rated as 'ineffective', 6.7% were given in an incorrect dose, 0.7% were prescribed with incorrect directions, 1.3% had impractical directions, 0.7% of the drugs had clinically significant drug-drug interactions, 8.6% had clinically significant drug-disease/condition interactions, 3.1% were unnecessary duplications, 16.5% were given in an unacceptable duration and 27.1% of the medications were not the least expensive alternative. The therapeutic groups most commonly involved in inappropriate prescribing were medications for treatment of peptic ulcer, cardiovascular medications, anti-inflammatory medications, antidepressants, hypnotics and anti-asthmatics. CONCLUSION: The overall prescribing quality in primary care in Copenhagen County, Denmark is good. However, the majority of patients used one or more medications with inappropriate ratings. The inappropriate prescribing relates to specific therapeutic groups and criteria, which should be targeted in future interventions.

To evaluate the inter-group and intra-group reliability of a modified Medication Appropriateness Index (MAI) for use in primary care. Elderly (>65 years) polypharmacy (≥5 drugs) patients in Copenhagen County participated in the study. Information concerning their medical history and information regarding each drug taken by them was provided by their own general practitioners. A MAI was scored by two groups of evaluators for every drug. To evaluate inter-group agreement, 211 drugs taken by 30 patients were rated according to the ten criteria making up the MAI. Both evaluator groups provided summaries of comments on the medication of each patient. Intra-group agreement was determined from MAI ratings performed twice at two different times on 86 drugs taken by ten patients. Agreement and chance-adjusted agreement were determined, the latter through kappa statistics. The proportion of positive (ppos) and negative (pneg) agreement was also determined. The overall chance-adjusted inter-group agreement (kappa) was moderate. The agreement was good on the criteria practical directions and drug–disease interaction, moderate on the criteria dosage and duration, fair on the criteria indication, effectiveness, duplication and expense, and poor on the criterion drug–drug interaction. The overall chance-adjusted intra-group agreement was good for all criteria and very good for the criteria indication and practical directions. The MAI is used to quantify appropriate and inappropriate prescribing and changes in prescribing quality in intervention studies. However, caution should be used when comparing results across different settings and evaluators. Our study suggests that the index should only be used in intervention studies if the same group rates the appropriateness pre- and post-intervention.

BackgroundMost angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure.MethodsFifty nine out-patients with plasma creatinine >150 µmol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design.ResultsMedian glomerular filtration rate (GFR) was 23 (range 6—60) ml/minute/1.73 m2. The daily dose of enalapril was 10 (2.5—20) mg and the trough serum concentration of enalaprilat was 31.8 (2. The median clearance of enalaprilat was 28 (16—68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%.ConclusionPatients with chronic renal failure given small or moderately high doses of enalapril may thus have markedly elevated levels of serum enalaprilat. Whether this affords extra renoprotection, or on the contrary may inappropriately impair renal function, is not known, and should be investigated in prospective, controlled studies.

Objective Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes. Methods Twelve healthy subjects who lived at sea level were exposed to altitude-induced hypoxia for 7 days at 4559 m above sea level. Hepatic CYP enzyme activity was measured before departure, at 24 and 96 hours after arrival to high-altitude location, and at 1 month after return to sea level. CYP enzyme activities were measured by means of the metabolic ratios of sparteine (CYP2D6), endogenous cortisol metabolism (CYP3A4), and caffeine (CYP1A2), as well as by the S/R ratio of mephenytoin (CYP2C19) and antipyrine clearance. Results The metabolic ratio of sparteine increased after 24 hours at high altitude (median difference, 0.15; 95% confidence interval, 0.05 to 0.28) and remained increased after 96 hours. The ratio decreased after return to sea level (median difference, −0.15; 95% confidence interval, −0.29 to −0.03; P = .016, Friedman test). The metabolic ratio of cortisol decreased after 24 hours (median difference, −2.0; 95% confidence interval, −3.5 to −0.5) but returned to sea level values after 96 hours at high altitude (median difference, 1.6; 95% confidence interval, 1.0 to 4.2; P = .047, Friedman test). These changes indicate a small decrease in the activity of CYP2D6 and CYP3A4. There were no significant changes regarding the metabolic ratio of caffeine, the S/R ratio of mephenytoin, or antipyrine clearance. Conclusion The small changes observed suggest that acute hypoxia has no clinically significant effects on CYP enzymes in humans. Clinical Pharmacology & Therapeutics (2002) 71, 214–220; doi: 10.1067/mcp.2002.121789

Hepatic drug metabolism was examined in patients with chronic pancreatitis and healthy controls by using a cocktail design with three different model compounds: antipyrine to express phase-I oxidation, oxazepam to express phase-II conjugation, and indocyanine green (ICG), a high-clearance compound.Eight patients with chronic pancreatitis and seven healthy controls participated. Patients were diagnosed by the presence of typical morphologic changes of the pancreas on imaging and had a moderately but significantly reduced exocrine function and no or only slight impairment of the glucose tolerance. No one had a history or clinical signs of liver disease. Clearance of the three model compounds was estimated after the administration of 1 g antipyrine and 15 mg oxazepam orally and a bolus of indocyanine green, 0.5 mg/kg body weight, intravenously.The antipyrine clearance and ICG clearance were significantly decreased in the patients compared with the controls (mean, 27.2 ml/min; 95% confidence interval (CI), 19.4-35; versus 46.2 ml/min; 34.7-58.7, and 501 ml/min; 4014601, versus 771 mU/min; 677-865 (P0.05), respectively). The oxazepam clearance did not differ significantly between the two groups (181 ml/min (145-217) versus 178 ml/min (152-204)). The model drug clearance ratios between the patient and control clearances showed decreased values for antipyrine and ICG compared with the oxazepam data (0.59 and 0.65 versus 1.02, respectively). Patients and controls were characterized by a body weight of 58.2 kg (53.1-63.3) and 83.4 kg (72.7-94.1), respectively, and a body mass index (BMI) of 19.6 kg/m2 (17.9-21.3) versus 25.9 kg/m2 (23.4-28.4) (P0.05 for both).Patients with chronic pancreatitis characterized by a moderately reduced exocrine function and absence of diabetes mellitus and overt liver disease had a decreased antipyrine oxidation and ICG clearance, whereas no difference was seen in oxazepam conjugation when compared with healthy volunteers. In chronic pancreatitis the hepatic phase-I oxidation is reduced compared with the phase-II conjugation, as shown by the model drug clearance ratios. The clearance of ICG was also affected, pointing at a reduced hepatic plasma flow, provided that the hepatic extraction fraction is normal for these patients.

The effect of zinc supplementation on antipyrine clearance was evaluated in 14 outpatients with stable alcoholic liver disease, of whom nine had biopsy proven alcoholic cirrhosis.There was no change in antipyrine clearance after 14 days of zinc supplementation (median 12.5 vs 12.9 ml.min-1). However, a significant increase in P-prothrombin-proconvertin was found. There was a positive correlation between S-zinc and antipyrine clearance at inclusion (rs = 0.76) as well as after zinc supplementation (rs = 0.72).No effect of zinc supplementation on antipyrine clearance was found. The positive correlation between S-zinc and antipyrine clearance could be due to the confounding effect of alcoholic liver disease.

The disposition of oral oxazepam was investigated in seven patients with decompensated cirrhosis and encephalopathy and in nine healthy individuals to further examine the hypothesis of preservation of glucuronidation in liver disease. The patients showed a severe reduction in the quantitative liver function as assessed by estimation of the clearance of antipyrine; the median value was 9 ml.min-1 and the range was 6 to 12 ml.min-1. Apparent clearance of oxazepam in cirrhotic patients was 0.55 ml.min-1.kg-1, with a range of 0.46 to 1.24 ml.min-1.kg-1, compared with 1.19 ml.min-1.kg-1 and a range of 0.80 to 1.66 ml.min-1.kg-1 in the controls (p less than 0.05). The unbound clearance of oxazepam in patients was 4.1 ml.min-1.kg-1, with a range of 3.4 to 5.5 ml.min-1.kg-1, compared with 25.4 ml.min-1.kg-1, and a range of 16.7 to 43.7 ml.min-1.kg-1, p less than 0.001, in the controls. In patients with liver disease, the unbound clearance of oxazepam correlated significantly with antipyrine clearance (r = 0.88; p less than 0.05). The results suggest a reduced capacity for glucuronidation in patients with decompensated liver disease and severe hepatic failure that corresponds to the general reduction in the quantitative liver function.

1 The disposition of metronidazole and its major metabolites was compared in 11 subjects aged 86 ± 6 years and 8 aged 30 ± 6 years. 2 The plasma clearance of metronidazole was 1.20 ± 0.53 and 1.25 ± 0.22 ml min-1 kg -1, the volume of distribution 0.77 ± 0.27 and 0.77 ± 0.09 1 kg -1 and the half-life 7.8 ± 1.9 and 7.2 ± 0.9 h in elderly and young subjects, respectively (P > 0.05). 3 The area under the plasma concentration-time curve of the hydroxy metabolite was 32 ± 14 and 21 ± 3 mM min-1 (P < 0.05) whereas its half-life was 21 ± 14 and 12 ± 2 h (P < 0.05) in the elderly and young subjects, respectively. 4 The recovery in the urine of metronidazole and its metabolites was 42 ± 21% and 87 ± 6% of dose in elderly and young subjects, respectively (P < 0.05). With this reservation the only elimination pathways of metronidazole affected by old age were the renal excretion of unchanged compound and the hydroxy metabolite. 5 It is concluded that the ability to eliminate metronidazole is preserved in old age and that age-related dose adjustments are not necessary.

The influence of a diet deficient in energy or protein on hepatic oxidation (Phase I reactions) and glucuronidation (Phase II reactions) in man has been examined. Nine healthy volunteers were fed an energy deficient diet (daily energy intake 4.3 MJ; daily protein intake 0.94 g/kg) and a protein deficient diet (daily energy intake 11.4 MJ; daily protein intake 0.31 g/kg) in random order. The control energy and protein intakes were 12.0 MJ and 1.52 g/kg, respectively. Each test diet period lasted 12 days. On Day 10, antipyrine 1000 mg and metronidazole 500 mg were given and elimination in saliva was determined. The metabolism of neither drugs was changed during the two dietary interventions, nor was their clearance to metabolites. On Day 12, the metabolism of oxazepam 15 mg was studied. The energy deficient and the protein deficient diet reduced the clearance rate of oxazepam by 20.3%, and 14.1% respectively. The elimination half-life was prolonged by 17.4% after the former and by 11.4% after the latter diet. Thus, both a low energy and a low protein intake decreased the glucuronidation of oxazepam, whereas no effect was observed on the rate of oxidation, expressed as the metabolism of antipyrine and metronidazole.

After 96 administrations of metronidazole to 36 subjects, it was found that the clearance could be determined from one plasma sample, the dose, and a volume of distribution estimated from sex, age, body weight, and height, without loss of precision and accuracy compared with conventional clearance determinations (r greater than 0.97). In 230 sample pairs the plasma and saliva concentrations of metronidazole were identical (r = 0.99). In 119 subjects the one-sample clearance of metronidazole was unimodally distributed. Body weight (r = 0.28) and the alcohol consumption (r = 0.23) correlated with the metronidazole clearance. In the same subjects the consumption of tobacco (r = 0.28), alcohol (r = -0.19), coffee/tea (r = 0.27), age (r = -0.24), and sex (r = 0.28) correlated with the antipyrine clearance. The clearances of metronidazole and antipyrine were correlated (r = 0.34). The differential influence of the environmental factors on the elimination rates supports differential metabolism of metronidazole and antipyrine.

The influence of prednisolone on the elimination of antipyrine has been investigated. The one-sample antipyrine clearance was estimated in 23 outpatients with obstructive lung disease before and after treatment with prednisolone 30 or 50 mg/day for 7 days. During prednisolone administration antipyrine clearance decreased from 54.9 +/- 14.8 to 51.7 +/- 14.6 ml/min (mean +/- SD; p less than 0.05). The results indicate that prednisolone decreases the rate of antipyrine elimination, but not to an extent suggesting a clinically important change in hepatic drug metabolism.

Antipyrine clearance was estimated by a one-sample technique in 14 patients with acute fever and clinical pneumonia. Antipyrine clearance during the acute illness was 31.4 ± 7.6 ml/min (X ± SD). Fourteen and 28 days later during convalescence, clearance values were higher (47.8 ± 18.9 and 49.2 ± 15.0 ml/ min, respectively). We conclude that microsomal hepatic drug metabolism in adults is impaired during pneumonia. Clinical Pharmacology and Therapeutics (1985) 37, 701–704; doi:10.1038/clpt.1985.117

OBJECTIVES: To present an update on drug-induced pancreatitis reported to the Danish Committee on Adverse Drug Reactions.DESIGN: Retrospective study of spontaneous case reports to the Danish reporting system on adverse drug reactions.METHODS: All cases of suspected drug-induced pancreatitis reported to the Danish Committee on Adverse Drug Reactions from 1968 to 1999 were analysed. Three cases were excluded leaving 47 cases for analysis.RESULTS: Drug-induced pancreatitis made up 0. 1% of all the reports to the committee from 1968 to 1999. The proportion seemed to increase and was 0.3% during the last 8 years. The 47 cases corresponded to 0.1% of the number of patients discharged due to pancreatic disease (without cancers) per year in Denmark. Serious courses were frequent as indicated by death and hospitalisation being reported in 4 (9%) and 32 (68%) cases, respectively. Death occurred after valproate (two cases), clomipramine (one case) and azathioprine (one case). Definite relationship was stated for mesalazine (three cases), azathioprine (two cases) and simvastatin (one case) on the basis of re-challenge. A possible or probable causality was considered for a further 30 drugs including 5-acetylsalicylic acid agents, angiotensin-converting enzyme inhibitors, estrogen preparations, didanosine, valproate, codeine, antiviral agents used in acquired immunodeficiency syndrome therapy, various lipid-reducing agents, interferon, paracetamol, griseofulvin, ticlopine, allopurinol, lithium and the MMR (measles" mumps/rubella) vaccination.CONCLUSION: Drug-induced pancreatitis is rarely reported. The incidence may be increasing and the course is often serious. This is the first report on definite simvastatin-induced pancreatitis. Further studies on the pancreotoxic potential of drugs are warranted.

The aim of the study was to examine liver volume, portal vein flow, and indocyanine green (ICG) and antipyrine clearance in hyperthyroidism before and after antithyroid drug treatment.Liver volume and blood flow in the portal vein were investigated in nine fasting patients with hyperthyroidism by means of computed tomography scan and Doppler ultrasound, respectively. ICG clearance was estimated by bolus injection of ICG (0.5 mg/kg body weight) and antipyrine clearance with a one-sample technique. All patients were investigated before and after 3 months of antithyroid treatment, when euthyroidism had been achieved. The Wilcoxon matched-pairs test was used for statistical analysis.The median liver volume increased by 238 (155-289) ml (median, 95% confidence interval), corresponding to 19%, and the weight by 5.0 (0.0-8.0) kg (8%), and the antipyrine clearance decreased by 8 (3.1-34.4) ml/min (16%). These changes were all significant (P0.05). The relation between liver volume and body weight increased from 19.9 (16.5-23.7) ml/kg to 21.4 (17.1-21.9) ml/kg (P = 0.11). The liver blood flow as estimated by ICG clearance and Doppler ultrasound was not altered significantly after the treatment period (P = 0.07 and 0.77, respectively).The liver volume increased by 19% in nine hyperthyroid patients during treatment with antithyroids. Antipyrine clearance was reduced by 16%, whereas liver blood flow, as estimated by ICG clearance and Doppler ultrasound examination of portal vein flow, was not significantly altered. A differential regulation of liver volume and oxidative metabolic capacity in hyperthyroidism was seen.