[Agranulocytosis in a patient treated with metamizole and clopidogrel].
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Aged↗
Biomedical subjects
S Krähenbühl
Publications and source records attributed to S Krähenbühl.
[Minocycline-induced lupus erythematodes].
We report the case of an 18-year-old woman with arthralgia and swelling of distal joints at hands and feet, photosensitive reaction, butterfly rash, fatigue, tachypnea and unspecific cardiac pain three months after beginning a treatment with minocycline for acne. Recurrence of symptoms at a higher intensity occurred within hours of reexposition with minocycline. The antinuclear antibody test was positive. After withdrawal of minocycline, the symptoms improved and minocycline-induced lupus was diagnosed. In the Swissmedic and WHO adverse drug reaction databases 267 other cases of possible minocycline-induced lupus were identified. Typical clinical and laboratory features are arthralgia, arthritis, myalgia, increased transaminases and/or jaundice, unspecific symptoms like fatigue and fever, skin disorders and positive antinuclear antibodies.
Acne Vulgaris↗
[Prevalence of potential drug-drug interactions in ambulatory patients with statin therapy].
AIM: To asses the prevalence of potentially critical drug-drug interactions (DDIs) in outpatients treated with a statin. PATIENTS/METHODS: Data of patients (e.g. age, sex, comorbidities, individual statin, number of drugs, number of diagnoses) were collected from 242 Swiss practitioners. The medication was screened electronically for potentially critical DDIs. RESULTS: We included 2742 statin-treated patients (mean age 65.1 +/- 11.2 [SD] years, 3.2 +/- 1.6 diagnoses, 4.9 +/- 2.4 drugs prescribed) from the German (53.3%), French (36%) or Italian speaking (10.7%) part of Switzerland. Of those, 401 (14.6%) had a total of 591 potentially severe DDIs; 190 patients (6.9%) had potential statin DDIs, 288 (10.5%) potential non-statin DDIs, mainly due to pharmacodynamic mechanisms. The prevalence of potential DDIs was similar between regions, except for a trend for a higher prevalence of drug-statin interactions in the French-speaking part. The number of drugs per patient and a diagnosis of arrhythmia or heart failure were identified as risk factors for DDIs. CONCLUSIONS: Drug combinations with potentially severe DDIs are common in patients treated with statins due to pharmacotherapy of their co-morbidities. Special attention in this specific population should be drawn on patients with polypharmacy and those with drug treatments for arrhythmia or heart failure.
Adverse Drug Reaction Reporting Systems↗
[Recurrent acute pancreatitis during pravastatin-therapy].
Acute pancreatitis can rarely be caused also by drugs. Several substances from different drug classes have been associated with the occurrence of acute pancreatitis. Regarding the class of the hydroxymethylglutaryl-CoA-reductase-inhibitors (statins) case-reports have been published in the literature in association with each individual statin. We present a 60-years-old male who developed twice an acute pancreatitis while being treated with pravastatin. Because some case reports describe the reoccurrence of acute pancreatitis after exposure to a different statin, recommendations for further therapy remain complex. There are also case reports of pancreatitis associated with fibrates and information on rare adverse reactions associated with ezetimibe is sparse.
Acute Disease↗
Toxicity of statins on rat skeletal muscle mitochondria.
We investigated mitochondrial toxicity of four lipophilic stains (cerivastatin, fluvastatin, atorvastatin, simvastatin) and one hydrophilic statin (pravastatin). In L6 cells (rat skeletal muscle cell line), the four lipophilic statins (100 micromol/l) induced death in 27-49% of the cells. Pravastatin was not toxic up to 1 mmol/l. Cerivastatin, fluvastatin and atorvastatin (100 micromol/l) decreased the mitochondrial membrane potential by 49-65%, whereas simvastatin and pravastatin were less toxic. In isolated rat skeletal muscle mitochondria, all statins, except pravastatin, decreased glutamate-driven state 3 respiration and respiratory control ratio. Beta-oxidation was decreased by 88-96% in the presence of 100 micromol/l of the lipophilic statins, but only at higher concentrations by pravastatin. Mitochondrial swelling, cytochrome c release and DNA fragmentation was induced in L6 cells by the four lipophilic statins, but not by pravastatin. Lipophilic statins impair the function of skeletal muscle mitochondria, whereas the hydrophilic pravastatin is significantly less toxic.
Animals↗
The effect of interviewing techniques on young children's responses to questions.
BACKGROUND: Research into the effect of interviewing techniques has been predominantly within the paradigm of eyewitness testimony. This review focuses on the issues of questioning and examines whether children's responses are affected by questioning techniques, and whether these effects are generic to all interviewing contexts. METHODS: Systematic literature searches were used to identify areas of concern and current findings in research on interviewing young children (aged 4-12). RESULTS: The style and wording of questioning can affect children's responses and accuracy positively and negatively. These effects were especially apparent in interviews with the youngest children. CONCLUSIONS: The implications of these findings are relevant in all contexts where an adult questions a child. It has been demonstrated that interviewing techniques can affect responses from children and that it is therefore imperative that interviewers are aware of, understand and control their influence in order to elicit complete, accurate and reliable information from the child.
Adult↗
Hepatic carbohydrate metabolism in rats after laparotomy and laparoscopy.
BACKGROUND: Portal venous and mesenteric blood flow are reduced by 40-60% in humans and animals during laparoscopic surgery compared to laparotomy. Little is known about whether these intraabdominal micro- and macrocirculatory changes are associated with alterations in the hepatic energy metabolism. METHODS: We operated on male Sprague-Dawley rats, performing either laparoscopy (CO2, 6 mmHg; n = 27) or laparotomy (n = 28), and compared the results with two control groups: intraperitoneal (i.p.) endotoxin administration (n = 28, positive control) and anesthesia only (n = 28, negative control). We investigated the impact of the two different surgical techniques on daily food intake, body weight gain, glycogen content in the liver, levels of blood glucose, and liver function tests (LFTs) on postoperative days 1, 2, 4, and 8. Local (hepatic) and systemic inflammatory responses (interleukin-6 and tumor necrosis factor-alpha) during the postoperative time course were also determined. Data were analyzed using the Kruskal-Wallis test or univariate analysis of variance. RESULTS: Body weight gain, food intake, liver and spleen weights, as well as LFTs [except aspartate aminotransferase (AST)] did not differ among the four groups. The significant increase in the AST level following laparoscopy compared to the anesthesia-only group was found on postoperative days 1 and 2; however, a similar difference was not detected after laparotomy or i.p. endotoxin injection. Laparoscopy showed no alterations in the hepatic glycogen stores compared to anesthesia only, whereas laparotomy and endotoxinemia significantly reduced the hepatic glycogen stores on postoperative days 2 and 4. The systemic postoperative inflammatory response did not differ between laparotomy and laparoscopy, but it was higher in both groups than in anesthesia only. In rats treated with endotoxin, the systemic inflammatory response was even higher than in the two surgical groups. The hepatic inflammatory response did not differ between the four groups. CONCLUSION: This study shows a significant postoperative decrease in the hepatic glycogen content after laparotomy and i.p. endotoxin injection but not after laparoscopy. Food intake and inflammatory response cannot explain this difference between the two surgical groups, which suggests that alterations in the postsurgical hormonal stress response are the most likely explanation for these findings.
Animals↗
[Pharmacokinetics and pharmacodynamices in the elderly].
Pharmacokinetic and dynamic alterations, the appearance of multiple illnesses which are treated with polypharmacy and, possibly as a consequence of polypharmacy, impaired compliance with drug therapy are associated with a higher incidence of drug-drug interactions and adverse drug reactions in geriatric patients. The most important among these alterations are discussed and possible solutions are presented.
Adult↗
Myocardial function and energy metabolism in carnitine-deficient rats.
Carnitine is essential for mitochondrial metabolism of long-chain fatty acids and thus for myocardial energy production. Accordingly, carnitine deficiency can be associated with cardiomyopathy. To better understand this disease, we determined myocardial function and energy metabolism in a rat model of carnitine deficiency. Carnitine deficiency was induced by a 3- or 6-week diet containing N-trimethyl-hydrazine-3-propionate, reducing cardiac and plasma carnitine by 70-85%. Myocardial function was investigated in isolated isovolumic heart preparations. Carnitine-deficient hearts showed left ventricular systolic dysfunction, reduced contractile reserve, and a blunted frequency-force relationship independently of the substrate used (glucose or palmitate). After glycogen depletion, palmitate could not sustain myocardial function. Histology and activities of carnitine palmitoyl transferase, citrate synthase, and cytochrome c oxidase were unaltered. Thus, as little as 3-6 weeks of systemic carnitine deficiency can lead to abnormalities in myocardial function. These abnormalities are masked by endogenous glycogen and are not accompanied by structural alterations of the myocardium or by altered activities of important mitochondrial enzymes.
Adenosine Triphosphate↗
[Abuse of benzodiazepines and similar substances].
Benzodiazepines and benzodiazepine-like substances belong to the drugs prescribed and consumed most frequently. While acute toxicity is low in comparison to other hypnotics, physical and psychological dependence can develop during continuous ingestion of these drugs over months. Withdrawal symptoms can therefore develop, if the ingestion of these drugs is stopped abruptly. If a withdrawal of benzodiazepines is considered, this should be discussed in detail with the patient and be performed gradually over months. Faster withdrawals or withdrawal in polytoxicomanic patients should be performed in a specialized unit. After a successful withdrawal, patients should have psychological support in order to prevent relapses.
Benzodiazepines↗
Identification and tissue distribution of two differentially spliced variants of the rat carnitine transporter OCTN2.
In this paper we show that the only known Na(+) dependent transporter of carnitine in mammals, organic cation transporter number 2 (OCTN2), is subject to differential splicing. Cloning of OCTN2 in different rat tissues identified two splicing variants. We have developed a real time quantitative polymerase chain reaction method for quantification of these splice variants. Both splice variants could be detected in all tissues examined with a relative abundance of 0.1-1% of the full length transcript. We also draw attention to the previously described mutations in clinical examples of primary carnitine deficiency in humans where the described mutations appear to be those of a splicing or mis-splicing event.
Alternative Splicing↗
Mitochondria: important target for drug toxicity?
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Animals↗
Toxicity of amiodarone and amiodarone analogues on isolated rat liver mitochondria.
BACKGROUND: Amiodarone is a well-known mitochondrial toxin consisting of a benzofuran ring (ring A) coupled to a p-OH-benzene structure substituted with 2 iodines and a diethyl-ethanolamine side chain (ring B). AIM: To find out which part of amiodarone is responsible for mitochondrial toxicity. METHODS: Amiodarone, ring A and B without the ethanolamine side-chain and iodines (B0), ring A and B with iodines but no ethanolamine (B2), ring B with 1 iodine and no ethanolamine (C1) and ring B with ethanolamine and 2 iodines (D2) were studied. RESULTS: In freshly isolated rat liver mitochondria, amiodarone inhibited state 3 glutamate and palmitoyl-CoA oxidation and decreased the respiratory control ratios. B0 and B2 were more potent inhibitors than amiodarone and B2 more potent than B0. C1 and D2 showed no significant mitochondrial toxicity. After disruption, mitochondrial oxidases and complexes of the electron transport chain were inhibited by amiodarone, B0 and B2, whereas C1 and D2 revealed no inhibition. Beta-oxidation showed a strong inhibition by amiodarone, B0 and B2 but not by C1 or D2. Ketogenesis was almost unaffected. CONCLUSIONS: Amiodarone, B0 and B2 are uncouplers of oxidative phosphorylation, and inhibit complexes I, II and III, and beta-oxidation. The benzofuran structure is responsible for mitochondrial toxicity of amiodarone and the presence of iodine is not essential.
Amiodarone↗
Cholangiopathy after short-term administration of piperacillin and imipenem/cilastatin.
We describe a patient who suffered from intestinal perforation after abdominal trauma. Perioperatively, he was treated with a single dose of piperacillin and 9 doses of imipenem/cilastatin over 3 days. The patient was discharged 5 days after surgery in good clinical condition and with normal liver values except for a marginal elevation of alanine aminotransferase. Two weeks after discharge, he developed fatigue, fever and pruritus, necessitating rehospitalization. He was jaundiced and had elevated alkaline phosphatase and transaminases. After exclusion of an intra-abdominal fluid collection, a vascular problem, and infectious or autoimmune liver disease, a liver biopsy was performed. The biopsy revealed centrizonal bilirubinostasis, a portal infiltrate rich in eosinophils and cholangitis. Lymphocyte transformation tests for piperacillin and imipenem/cilastatin were positive, suggesting an immunological mechanism for the observed hepatopathy. Cholestasis gradually decreased but was detectable for several weeks. The patient had a full clinical and biochemical recovery after 3 months. We conclude that short-term therapy with piperacillin, imipenem/cilastatin or the combination of these drugs can lead to the same type of hepatopathy as described for amoxycillin/clavulanic acid or antistaphylococcal penicillins. Liver biopsy and positive lymphocyte transformation are compatible with an immunological mechanism.
Adult↗
Alcohol-induced myopathy: what is the role of mitochondria?
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Ethanol↗
Veno-occlusive disease, nodular regenerative hyperplasia and hepatocellular carcinoma after azathioprine treatment in a patient with ulcerative colitis.
We report the case of a 66-year-old male with ulcerative colitis diagnosed in 1987, who had been treated with azathioprine (AZA) for the past two years (average dose about 1.6 mg/kg/day). In May 1999 he presented with painless jaundice, fatigue and recent weight loss. Cholestatic enzymes were elevated, alpha-fetoprotein was normal and hepatitis B/C serology negative. After diagnosis of veno-occlusive disease (VOD) and hepatocellular carcinoma (HCC) via biopsy, tumour resection was performed. The histology was typical for a well-differentiated HCC with trabecular and pseudoglandular structures. Neighbouring liver tissue was atrophic, with nodular regenerative hyperplasia (NRH), peliosis-like sinusoidal ectasias and intra-sinusoidal accumulation of blood, associated with peri-sinusoidal fibrosis. Although none of the well-established risk factors for HCC such as cirrhosis, hepatitis B/C, metabolic liver disease or toxins were present, this patient developed HCC. This and previous reports suggest that NRH and/or VOD associated with AZA represent a risk factor for HCC. AZA should therefore not only be stopped in patients with NRH/VOD but patients should also be screened for HCC.
Aged↗
Impaired hepatic fatty acid oxidation in rats with short-term cholestasis: characterization and mechanism.
Rats with long-term cholestasis have reduced ketosis during starvation. Because it is unclear whether this is also the case in short-term cholestasis, we investigated hepatic fatty acid metabolism in rats with bile duct ligation for 5 days (BDL5, n = 11) or 10 days (BDL10, n = 11) and compared the findings with those made with pair-fed control rats (CON5 and CON10, n = 11). The plasma beta-hydroxybutyrate concentration was reduced in BDL rats (0.54 +/- 0.10 vs. 0.83 +/- 0.30 mM at 5 days and 0.59 +/- 0.24 vs. 0.88 +/- 0.09 mM at 10 days in BDL and control rats, respectively). In isolated liver mitochondria, state 3 oxidation rates for various substrates were not different between BDL and control rats. Production of ketone bodies from [(14)C]palmitate was reduced by 40% in mitochondria from BDL rats at both time points, whereas production of (14)CO(2) was maintained. These findings indicated intact function of the respiratory chain, Krebs cycle, and beta-oxidation and suggested impaired ketogenesis (HMG-CoA pathway). Accordingly, the formation of acetoacetate from acetyl-CoA by disrupted mitochondria was reduced in BDL rats at 5 days (2.1 +/- 1.0 vs. 4.8 +/- 1.9 nmol/min per mg protein) and at 10 days (1.7 +/- 1.0 vs. 6.2 +/- 1.9 nmol/min per mg protein). The principal defect could be localized at the rate-limiting enzyme of the HMG-CoA pathway, HMG-CoA synthase, which revealed decreased activity, and reduced hepatic mRNA and protein levels. We conclude that short-term cholestasis in rats leads to impaired hepatic fatty acid metabolism due to impaired ketogenesis. Ketogenesis is impaired because of decreased mRNA levels of HMG-CoA synthase, leading to reduced hepatic protein levels and to decreased activity of this key enzyme of ketogenesis. - Lang, C., M. Schäfer, D. Serra, F. G. Hegardt, L. Krähenbühl, and S. Krähenbühl. Impaired hepatic fatty acid oxidation in rats with short-term cholestasis: characterization and mechanism. J. Lipid Res. 2001. 42: 22;-30.
Animals↗
Development and characterization of an animal model of carnitine deficiency.
Mammals cover their carnitine needs by diet and biosynthesis. The last step of carnitine biosynthesis is the conversion of butyrobetaine to carnitine by butyrobetaine hydroxylase. We investigated the effect of N-trimethyl-hydrazine-3-propionate (THP), a butyrobetaine analogue, on butyrobetaine hydroxylase kinetics, and carnitine biosynthesis and body homeostasis in rats fed a casein-based or a vegetarian diet. The K(m )of butyrobetaine hydroxylase purified from rat liver was 41 +/- 9 micromol x L(-1) for butyrobetaine and 37 +/- 5 micromol x L(-1) for THP, and THP was a competitive inhibitor of butyrobetaine hydroxylase (K(i) 16 +/- 2 micromol x L(-1)). In rats fed a vegetarian diet, renal excretion of total carnitine was increased by THP (20 mg.100 g(-1) x day(-1) for three weeks), averaging 96 +/- 36 and 5.3 +/- 1.2 micromol x day(-1) in THP-treated and control rats, respectively. After three weeks of treatment, the total carnitine plasma concentration (8.8 +/- 2.1 versus 52.8 +/- 11.4 micromol x L(-1)) and tissue levels were decreased in THP-treated rats (liver 0.19 +/- 0.03 versus 0.59 +/- 0.08 and muscle 0.24 +/- 0.04 versus 1.07 +/- 0.13 micromol x g(-1)). Carnitine biosynthesis was blocked in THP-treated rats (-0.22 +/- 0.13 versus 0.57 +/- 0.21 micromol x 100 g(-1) x day(-1)). Similar results were obtained in rats treated with the casein-based diet. THP inhibited carnitine transport by rat renal brush-border membrane vesicles competitively (K(i) 41 +/- 3 micromol x L(-1)). Palmitate metabolism in vivo was impaired in THP-treated rats and the livers showed mixed steatosis. Steady-state mRNA levels of the carnitine transporter rat OCTN2 were increased in THP-treated rats in skeletal muscle and small intestine. In conclusion, THP inhibits butyrobetaine hydroxylase competitively, blocks carnitine biosynthesis in vivo and interacts competitively with renal carnitine reabsorption. THP-treated rats develop systemic carnitine deficiency over three weeks and can therefore serve as an animal model for human carnitine deficiency.
Animals↗