[Treatment of community-acquired pneumonia--treatment]. / Samfundserhvervet pneumoni--behandling.

Penicillin is the drug of choice for treatment of community-acquired pneumonia (CAP) in Denmark. The primary determinant for therapeutic activity of penicillin is ''penicillin time'' (T>MIC), i.e. time with penicillin concentration above minimum inhibitory concentration. Eradication of S. pneumoniae requires T>MIC above 40-50%. The second determinant for therapeutic activity is the ratio between maximum penicillin concentration in serum and MIC (Cmax/MIC). Considering penicillin pharmacokinetics, intravenous penicillin 2 million units four times a day is recommended as empirical treatment of CAP.

Pharmacokinetic characterization of a pig model of ciclosporin A nephrotoxicity following intravenous administration.

BACKGROUND: Recently, we investigated pharmacokinetics and acute nephrotoxicity of oral ciclosporin A (CsA) in pigs. We found that pigs require higher oral CsA doses to obtain comparable area under the concentration versus time curve (AUC) levels to renal transplant patients. The purpose of this study was to examine pharmacokinetics and possible acute renal effects of intravenous CsA in order to further characterize the pig as a model of CsA nephrotoxicity. METHODS: Twenty-eight pigs were randomized into four groups: control and three groups subjected to a single CsA infusion at 3, 6, or 9 mg kg(-1). Blood samples for determination of whole blood CsA concentrations were collected over 7 h under general anaesthesia. At 0, 2, and 5 h, we measured blood pressure, serum creatinine, and haemoglobin, as well as renal blood flow (RBF), relative glomerular filtration rate (rGFR), and kidney volume using magnetic resonance imaging. RESULTS: CsA distribution exhibited two-compartmental behaviour. Compared to renal transplant patients, pigs had approximately the same total clearance of CsA (mean 0.31-0.34lh(-1)kg(-1)), which yields comparable AUC after equivalent dosage in both species. However, the volume of distribution at steady state (mean 1.9-3.0lkg(-1)) was lower in pigs. RBF remained stable in all groups, whereas rGFR decreased in all groups reaching statistical significance in the controls. CONCLUSIONS: Pigs require approximately the same intravenous CsA doses to obtain comparable total AUC to renal transplant patients. Single CsA infusion up to 9 mg kg(-1) for 1h has no deteriorating effect on renal haemodynamics and function.

Constant intravenous ghrelin infusion in healthy young men: clinical pharmacokinetics and metabolic effects.

Ghrelin levels fluctuate rapidly and dynamically with surges before meal times and postprandial troughs, and ghrelin increases appetite and food intake. Circulating ghrelin correlates negatively with body mass index (BMI), but obese individuals have a reduced postprandial decrease in ghrelin levels. Whether this reflects changes in secretion or clearance of ghrelin is uncertain. We therefore studied the pharmacokinetics of ghrelin in relation to anthropometric and biochemical measures. We also studied the effects of ghrelin on hormones and metabolites. In fasting humans, we used a constant infusion rate of ghrelin lasting 180 min at 5 pmol.kg body wt(-1).min(-1) in a randomized, double-blind, placebo-controlled crossover study. Serum ghrelin (s-ghrelin; total levels) was distributed and eliminated according to a two-compartment model. s-Ghrelin initial half-life was 24 +/- 2 min and terminal half-life 146 +/- 36 min, respectively. Mean residence time (MRT) of ghrelin was 93 +/- 16 min. MRT correlated positively with both BMI (r = 0.51, P < 0.001) and high-density cholesterol (HDL) levels (r = 0.75, P < 0.001). Serum insulin levels remained constant during ghrelin infusion, whereas plasma glucose increased 0.3 +/- 0.1 mmol/l (P < 0.01) and free fatty acid levels more than doubled (to 1.03 +/- 0.08 mmol/l, P < 0.001), translating into a significant reduction of insulin sensitivity (P < 0.001). In conclusion, 1) we describe novel pharmacokinetics of ghrelin that are useful when tailoring ghrelin infusion rates in clinical experiments, 2) BMI and HDL correlate positively with MRT of infused ghrelin, and 3) supraphysiological ghrelin levels impair insulin sensitivity.

Blunted non-nitric oxide vasodilatory neurotransmission in penile arteries from renal hypertensive rats.

The present study was designed to explore whether there are any effects on neurogenic responses in penile small arteries during the development of hypertension in a one-kidney, one-clip (1K1C) model, a non-renin-dependent model of renovascular hypertension. Five weeks after surgery, male Sprague-Dawley rats were given vehicle, bendroflumethiazide (7.5 mg/kg/day), or L-arginine (2 g/kg/day) in their drinking water for five weeks. Experiments were performed on penile small artery rings (150-200 microm) mounted on microvascular myographs for electrical field stimulation (EFS), and erectile tissue was processed for immunohistochemistry. Maximal neurogenic contractions were unmodified in penile preparations. Relaxations induced by EFS were reduced in the presence of ADMA. In 1K1C rats, neurogenic vasorelaxation mediated by nitric oxide (NO) was unaltered, while relaxation resistant to NO synthase inhibition was blunted. L-arginine and bendroflumethiazide lowered blood pressure in 1K1C rats, but vasodilation was still blunted in the penile arteries. Immunoreactivity for factor VIII and neuronal NO synthase was unaltered in penile arteries from 1K1C animals. Endothelium-dependent vasorelaxation evoked by acetylcholine was also blunted in preparations from 1K1C rats, while exogenous NO relaxation was unaffected. Plasma concentrations and urinary excretion of ADMA did not differ among the experimental animals. Our findings indicate that the reduced release of a non-NO vasodilatory neurotransmitter accounts for the impaired neurogenic vasodilation of the penile arteries. Although ADMA inhibits penile vasorelaxation, it is unlikely to affect erectile function in 1K1C rats.

Pain intensity and bioavailability of intramuscular asparaginase and a local anesthetic: a double-blinded study.

BACKGROUND: To evaluate if dissolution of asparaginase in lidocaine can relieve pain of an intramuscular injection in children without changes in bioavailability. PROCEDURE: The study was designed as a double-blinded study, randomizing 12 children with acute lymphoblastic leukemia (ALL) to four different combinations of injections, including two injections where asparaginase was dissolved in a lidocaine solution and two in sterile water. Seventeen treatment courses of asparaginase, each consisting of four injections, were evaluated. Pain intensity (Pain Visual Analog Scale, VAS-score) and pharmacokinetics of the drug was evaluated. RESULTS: The pain scores showed a significant difference between the two solutions of asparaginase (+/-lidocaine) (P value < 0.0001). Lidocaine did not influence the pharmacokinetics of the drug. CONCLUSIONS: Asparaginase with addition of lidocaine significantly decreases the pain as measured by the visual analog scale without changing the bioavailability or the absorption rate of the enzyme.

Glibenclamide blunts coronary flow reserve induced by adenosine and dipyridamole.

OBJECTIVE: A reduced coronary flow reserve is considered indicative of significant coronary stenosis. As experimental data suggest that adenosine and dipyridamole induce vasodilatation by opening of ATP-sensitive potassium channels, we sought to determine the effect of glibenclamide, an antidiabetic blocker of ATP-sensitive potassium channels, on adenosine- and dipyridamole-induced coronary flow reserve. DESIGN: Coronary flow velocities were measured in 15 pigs using a Doppler flow wire. The effect of increasing glibenclamide concentrations (0.1-10 microM) on adenosine-induced coronary flow reserve was examined in five animals. Ten pigs served as time controls. The time controls were subsequently treated by 3 microM glibenclamide (n = 5) or corresponding vehicle (n = 5) and the flow response to 0.56 mg/kg dipyridamole determined. RESULTS: Glibenclamide elicited a concentration-dependent inhibition of adenosine-induced coronary flow reserve, reaching significance at glibenclamide concentrations of 3 and 10 microM. The coronary flow reserve stimulated by dipyridamole was reduced significantly by 3 microM glibenclamide. CONCLUSION: Glibenclamide blunts coronary flow reserve stimulated by adenosine and dipyridamole. This interaction may have clinical implications in diabetics undergoing adenosine- or dipyridamole-dependent diagnostic procedures.

Anti-Erwinia asparaginase antibodies during treatment of childhood acute lymphoblastic leukemia and their relationship to outcome: a case-control study.

PURPOSE: A case-control study was performed to determine whether patients who had been treated with Erwinia asparaginase as part of their treatment for childhood acute lymphoblastic leukemia (ALL) and who showed relapsed of their disease more often developed anti-asparaginase antibodies than patients who remained in remission. METHODS: A group of 13 patients who showed relapsed of their disease (median follow-up 35 months) were randomly matched with control patients of the same risk group (two control patients to each case), who had received therapy of the same intensity during the same period (median follow-up 70 months). Anti- Erwinia asparaginase antibodies were measured (ELISA method) during maintenance therapy after asparaginase treatment (30,000 IU/m(2) daily for 10 days in all patients plus twice weekly for 2 weeks in intermediate-risk and high-risk ALL patients). RESULTS: The overall incidence of anti- Erwinia asparaginase antibodies was 8% (3 of 39 patients). There was no statistically significant difference in the incidence of antibody formation between patients who had suffered relapse (1 of 13) and those who had not (2 of 26). In two of the three patients who developed antibodies, the antibodies disappeared after some time, whereas one patient had measurable antibody levels for more than a year after asparaginase therapy. CONCLUSIONS: In this study, the development of anti-Erwinia asparaginase antibodies was rare and was unrelated to the risk of relapse.

Antibody formation during intravenous and intramuscular therapy with Erwinia asparaginase.

BACKGROUND: Determination of the frequency of antibody formation during first and second exposure to Erwinia asparaginase after i.v. and i.m. administration. PROCEDURE: Thirty-nine children with newly diagnosed acute lymphoblastic leukemia (ALL) were included in this prospective study. Antibodies were determined (ELISA method) in plasma from these patients on specific days during and after therapy with 30,000 IU/m(2) i.v. or i.m. every day for ten days during the induction phase (first exposure). For 19 children, antibodies were measured in plasma during and after the re-induction phase (second exposure) following treatment with 30,000 IU/m(2) i.v. or i.m. twice a week for two weeks (Mondays and Thursdays). On the same days of therapy, enzyme activity (spectrophotometric method) and the concentration of asparagine (HPLC) was determined. RESULTS: During the first exposure, none of the patients developed anti-Erwinia asparaginase antibodies. During the second exposure, one patient (1 of 8 patients) treated intravenously developed antibodies, which were associated with disappearance of enzyme activity and reappearance of asparagine. Three of eleven patients developed antibodies of pharmacokinetic importance after i.m. therapy. None of the children had any clinical symptoms of hypersensitivity. CONCLUSIONS: The formation of antibodies and subsequently altered pharmacokinetics of Erwinia asparaginase seemed to be of importance only during a second period of asparaginase therapy.