The synthetic prostaglandin E1 analogue rioprostil reduces the nephrotoxic potential of cyclosporine A

Acute CyA nephrotoxicity involves alteration in the proximal tubule and leads to glomerular lesions. Administration of a vasodilatator agent such as the prostaglandin E1 analogue Rioprostil (Bayer AG, BAY 06893) might prevent preglomerular vasoconstriction and hence reduce cyclosporin nephrotoxicity. As an increased excretion of urinary enzymes as a consequence of CyA-nephrotoxicity is well known we investigated in 40 male Wistar rats the excretion of three urinary enzymes: the brush border enzyme gamma-glutamyltransferase (GGT), the leucine aminopeptidase (LAP), and the lysosomal enzyme N-acetyl-beta-glucosaminidase (NAG). Additionally we determined s-creatinine and CyA plasma level. The kidneys were studied histologically at the end of the study. Wistar rats receiving 20 or 50 mg CyA/kg/d showed a marked deterioration in renal function and an increase of all urinary enzymes determined. In the rats receiving 20 mg CyA/kg/d and Rioprostil (150 micrograms/d) renal function and the enzymes determined remained in the normal range. There was no change in the enzyme excretion and only a minor improvement of renal function in rats receiving 50 mg CyA/kg/d and Rioprostil. Histological findings showed prevention of CyA nephrotoxicity in the 20 mg/kg/d group and diminished renal damage in the 50 mg/kg/d group.     

Single- vs Multiple-Dose Pharmacokinetics of Clozapine in Psychiatric Patients

Clozapine plasma levels were monitored in 16 patients during a series of three consecutive treatments (single dose-multiple dose-single dose). Each patient received a single 75-mg dose (3 x 25 mg) with clozapine tablets, and serial plasma samples were collected over 48 hr after the dose. At 48 hr, a multiple-dose regimen was started, consisting of an initial dose escalation period followed by dosing at a constant regimen for at least 6 days. After the last dose, serial plasma samples were again obtained over 72 hr. Drug was then withheld for at least 7 days, a final single 75-mg dose was given, and plasma sampling was repeated. A subset of the patient population (N = 7) was used to test for a food effect during the single-dose treatments. The pharmacokinetic parameters between the initial and the final single dose periods were not significantly different. Similarly, there were no differences within patients when given the dose after fasting (fed 1 hr after dose) or with a meal. In contrast, the terminal elimination rate differed between the single-dose and the multiple-dose treatments (t1/2 m3 = 7.9 hr single dose and 14.2 hr multiple dose) (P less than 0.05) and the dose-normalized area under the plasma concentration/time curves increased 27% with multiple dosing. Since a previous study in patients (Choc et al., Pharm. Res. 4:402-405, 1987) showed dose proportionality of clozapine plasma concentrations during multiple-dose regimens, the present results cannot be described by Michaelis-Menten kinetics.     

Tissue distribution, disposition, and metabolism of cyclosporine in rats

Tissue distribution, disposition, and metabolism of 3H-cyclosporine were studied in rats after single and repeated oral doses of 10 and 30 mg/kg and after an iv dose of 3 mg/kg. The oral doses of 10 and 30 mg/kg were dissolved in polyethylene glycol 200/ethanol or in olive oil/Labrafil/ethanol. Absorption from both formulations was slow and incomplete, with peak 3H blood levels at 3-4 hr. Approximately 30% of the radioactive dose was absorbed, which is consistent with oral bioavailability data for cyclosporine. More than 70% of the radioactivity was excreted in feces and up to 15% in urine. Elimination via the bile accounted for 10 and 60% of the oral and iv doses, respectively. Since unchanged cyclosporine predominated in both blood and tissues at early time points, the half-lives of the distribution phases (t 1/2 alpha) of parent drug and of total radioactivity were similar. In blood, kidney, liver, and lymph nodes, t 1/2 alpha of cyclosporine ranged from 6-10 hr. Elimination of radioactivity from the systemic circulation was multiphasic, with a terminal half-life of 20-30 hr. 3H-Cyclosporine was extensively distributed throughout the body, with highest concentrations in liver, kidney, endocrine glands, and adipose tissue. The concentrations of both total radioactivity and parent drug were greater in tissues than in blood, which is consistent with the high lipid solubility of cyclosporine and some of its metabolites. Skin and adipose tissue were the main storage sites for unchanged cyclosporine. Elimination half-lives were slower for most tissues than for blood and increased with multiple dosing. The amount of unchanged drug was negligible in urine and bile.(ABSTRACT TRUNCATED AT 250 WORDS)     

Einsatz von Bone-morphogenetic Protein-7 (BMP-7) in der Behandlung von Pseudarthrosen der oberen und unteren Extremität

Bone morphogenetic proteins (BMPs) are bone growth factors, which regulate bone formation during fetal development and bone repair after injury in postfetal life. Since 1992 BMP-7 has been produced by recombinant technique (rhBMP-7). Numerous animal models and clinical trials have shown that rhBMP-7 can induce de novo bone formation in segmental defects of bones and in cases of nonunion. Since 2001 rhBMP-7 has been approved for treatment of tibial nonunion in Europe. The effect of rhBMP-7 is comparable to the clinical and radiological results achieved with bone autografts. The problem of donor site morbidity (which occurs in up to 20% of all cases) is eliminated by the use of BMP-7. Long-term results and experience in clinical practice are not yet available.     

EMPACT syndrome

Background: Seizure prophylaxis with phenytoin is a common measure in oncologic patients with brain metastases. In these patients, generalized severe adverse drug reactions such as erythema multiforme (EEM) may occur. However, in a subgroup of patients with brain radiation therapy, EEM‐like lesions develop particularly in the radiation field. Most recently, the acronym EMPACT ( E rythema M ultiforme associated with P henytoin A nd C ranial radiation T herapy) was proposed to specifically describe this syndrome. Patient/Method: Here, we report on EMPACT syndrome in a 46‐year‐old woman. Therapeutic measures included seizure prophylaxis with phenytoin and total brain radiation therapy of brain metastases from bronchial carcinoma. Three weeks after introduction of phenytoin, the patient presented with EEM‐like skin lesions restricted to the original radiation field and facial mucocutaneous involvement. After a few days, the rash spread to the upper part of the body. She was also in poor general condition. Results: The immediate cessation of phenytoin therapy, combined with administration of systemic corticosteroids and high dose immunoglobulins along with intensive local treatment and pain medications, resulted in complete resolution of the skin eruption. Patch testing to phenytoin was positive after 72 hours. Conclusion: EMPACT should be classified as an specific entity among the EEM‐like drug reactions as it only appears after radiotherapy and seizure prophylaxis with the anticonvulsant phenytoin. We propose including specific type IV‐sensitization to phenytoin into the definition of EMPACT.     

Beta-blockers and primary prevention of coronary heart disease in patients with high blood pressure

We conducted a population-based, case-control study to determine whether beta-blockers, used for the treatment of hypertension, prevent first events of coronary heart disease. Cases were patients who had high blood pressure treated with medicines and who presented in 1982 to 1984 with angina or fatal or nonfatal myocardial infarction. Controls were a probability sample of health maintenance organization patients with pharmacologically treated hypertension and free of coronary heart disease. Blinded to case-control status, we reviewed the medical records of the 248 cases and 737 controls. The health maintenance organization's computerized pharmacy database was used to ascertain the use of beta-blockers. Fewer cases than controls were taking beta-blockers. This difference was confined to those with nonfatal infarctions. After adjustment for confounding, the estimated relative risk was 0.62 (95% confidence interval, 0.39 to 0.99). Higher doses of beta-blockers conferred greater protection. We conclude that beta-blockers may prevent first events of nonfatal myocardial infarction in patients with high blood pressure.     

Beitrag zur Kenntnis der Flöhe von Brit.-Kolumbien

Ohne Zusammenfassung     

Marknagelung bei der Humerusschaftfraktur

Zusammenfassung Die Humerusschaftfraktur ist in 10–18% der Fälle durch primäre Radialisparese kompliziert. Sekundäre Radialisläsionen treten iatrogen bei intramedullären Verfahren in 3%, bei Plattenosteosynthesen in 15,5% auf. In der überwiegenden Mehrzahl der Fälle (80%) ist der Radialisschaden rückläufig. Eine Verletzung der A. radialis ist eher selten; sie erfordert ein offenes Vorgehen mit lokaler Revision des Gefäßes und Frakturversorgung mittels Plattenosteosynthese. Die Marknagelosteosynthese ist bei einfachen, komplexen oder pathologischen Schaftfrakturen primär oder als Verfahrenswechsel nach primärer Fixateuranlage indiziert. Während auch ausgewählte Frakturen im Collum chirurgicum mit einem Nagel versorgt werden können, sind Frakturen im distalen Viertel des Humerus ausgeschlossen. Frakturen bei kleinen Kopffragmenten weisen ein erhöhtes Komplikationsrisiko auf. Zur Vermeidung von Läsionen der Rotatorenmanschette stehen wir der anterograden Nagelung noch zurückhaltend gegenüber. Bei differenzierter Indikationsstellung und Nachbehandlung erwies sich die retrograde Marknagelung als ein schonendes Verfahren mit hohem Patientenkomfort und gutem funktionellem Ergebnis.