Pharmacodynamic relationship between PCSK9, alirocumab,and LDL-C lowering in the ODYSSEY CHOICE I trial

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Non-linearities in the pharmacokinetics of di-(2-ethylhexyl) phthalate and metabolites in male rats

The disposition of the plasticizer di-(2-ethylhexyl) phthalate (DEHP) and four of its major metabolites was studied in male rats given single infusions of a DEHP emulsion in doses of 5, 50 or 500 mg DEHP/kg body weight. Plasma concentrations of DEHP and metabolites were followed for 24 h after the start of the infusion. The kinetics of the primary metabolite mono-(2-ethylhexyl) phthalate (MEHP) was studied separately.The concentrations of DEHP in plasma were at all times considerably higher than those of MEHP, and the concentrations of MEHP were much higher than those of the other investigated metabolites. In animals given 500 mg DEHP/kg, the areas under the plasma concentration-time curves (AUCs) of the other investigated metabolites were at most 15% of that of MEHP. Parallel decreases in the plasma concentrations of DEHP, MEHP and the and (-1) oxidized metabolites indicated that the elimination of DEHP was the rate-limiting step in the disposition of the metabolites. This was partly supported by the observation that the clearance of MEHP was higher than that of DEHP. Nonlinear increases in the AUCs of DEHP and MEHP indicated saturation in the formation as well as the elimination of the potentially toxic metabolite MEHP.     

Endobronchiale Applikation von Adrenalin in der kardiopulmonalen Reanimation Pharmakokinetische und -dynamische Untersuchungen beim Hund

Zusammenfassung Das Ziel der vorliegenden Untersuchungen bestand darin, das pharmakokinetische Profil von Adrenalin bei endobronchialer (e.b.) und intravenöser (i.v.) Applikation zu erarbeiten und die gemessenen Adrenalin-Plasmaspiegel mit hämodynamischen Messungen zu korrelieren. Die e.b. Applikation von 100 g/kg Adrenalin erwies sich als ebenso effektiv, wie die i.v.-Gabe von 10 g/kg. Dabei war der Wirkungseintritt der e.b.-Gabe von Adrenalin nur geringfügig um einige Sekunden verzögert. Die Bioverfügbarkeit für e.b. verabreichtes Adrenalin lag zwischen 80 und 85%. Der therapeutische Effekt blieb nach e.b.-Applikation von 100 g/kg Adrenalin wesentlich länger erhalten (ca. 30 min) als nach i.v.-Gabe von 10 g/kg (ca. 3–5 min). Aus den Ergebnissen wird geschlossen, daß die tiefe endobronchiale Instillation von 2–3 mg Adrenalin (verdünnt in 5–10 ml Kochsalzlösung) als alternative Dosierungstechnik bei klinischen Reanimationen betrachtet werden kann.

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Pharmacokinetics and -dynamics of epinephrine administered endobronchially

Summary The present animal study was designed to investigate the pharmacokinetic behavior of epinephrine after endobronchial (e.b.) and intravenous (i.v.) administration and its correlation to pharmacodynamic measurements. We found the effectiveness of e.b.-epinephrine (100 g/kg BW) to be in the same magnitude as i.v.-epinephrine (100 g/kg BW) with only a slight delay in the pharmacodynamic onset of a few seconds. The bioavailability of e.b.-administration of epinephrine was in the range of 80–85%. The therapeutic effect of e.b.-epinephrine (100 pg/kg BW) lasted much longer (30 min) when compared to i.v.-epinephrine (10 g/kg BW) where the pharmacodynamic effect was terminated after 3 to 5 min. For the clinical situation of cardiopulmonary resuscitation a dose of 2–3 mg epinephrine in 5–10 ml of physiological saline instilled deeply into the bronchial system should be considered as alternative administration technique with fast onset and good effectiveness.

Herrn Prof. Dr. Dr. h.c. F. Stelzner zum 65. Geburtstag gewidmet     

Pharmacokinetics of cefradine, sulfamethoxazole and trimethoprim and their metabolites in a patient with peritonitis undergoing continuous ambulatory peritoneal dialysis

Cefradine and co-trimoxazole pharmacokinetics were studied in a patient with peritonitis that complicated continuous ambulatory peritoneal dialysis (CAPD). Concentrations in the plasma reached after oral administration of 500 mg cefradine four times daily and 400/80 mg co-trimoxazole four times daily were for cefradine 100g/ml, for trimethoprim 15g/ml, and for sulfamethoxazole 100/ml, respectively. In the dialysate concentrations were reached of 35–70/ml cefradine, 2–5/ml trimethoprim and 8–17g/ml sulfamethoxazole. The values for sulfamethoxazole are regarded too low to be clinically effective. Half-lives protein binding values and CAPD clearances are presented. Low CAPD clearances were obtained during the night and high values during the day. The dosage yielded too high plasma trimethoprim concentrations, while sulfamethoxazole dialysate concentrations were too low. It seems questionable therefore whether co-trimoxazole can be used orally for the treatment of CAPD peritonitis.     

Formation of cyanide after i. v. administration of the oxime HI 6 to dogs

HI6(pyridinium, 1-[[[4-(aminocarbonyl)pyridinio] methoxy]methyl]-2-[(hydroxyimino)methyl]-dichloride belongs to a series of bisquaternary pyridinium oximes that are effective against poisoning with extremely toxic organophosphates. Since HI6 has been shown to be unstable at pH 7.4 and to release significant amounts of cyanide, a study was undertaken to determine the degree of cyanide formation from HI 6 in vivo. When HI 6 (100 mol/kg) was administered i. v. to dogs, the animals showed no signs of cyanide toxicity but exhibited some cholinomimetic symptoms, including retching, hypersalivation and enhanced intestinal motility. Cyanide content in whole blood was monitored after production of methemoglobinemia (30%) by 4-dimethylaminophenol in order to sequester cyanide within red cells. Maximal cyanide contents of 20 mol/l were found in blood after 90 min. Calculation of the area under the concentration versus time curve for blood cyanide indicates that about 4% of HI 6 produced cyanide. Determination of the pharmacokinetic parameters of HI 6 (V_D=0.31 l/kg; k_el=0.76 h^–1) and of cyanide (V_D=0.086 l/kg; k_el=0.52 h^–1) together with the apparent first order rate constant of cyanide formation from HI 6 in vitro (0.174 h^–1, pH 7.4, 37°) allowed the simulation of a cyanide concentration curve that fitted with the experimental data points, indicating that cyanide formation in vivo was not bio-catalyzed. It is concluded that cyanide formation from HI 6 may not be regarded as a potential hazard, since cyanide elimination exceeded markedly its formation. Whether this conclusion also holds true for man has to be established.     

Growth,regression and cell death in rat liver as related to tissue levels of the hepatomitogen cyproterone acetate

Previous studies have shown that xenobiotic compounds such as the environmental pollutant -hexa-chlorocyclohexane (-HCH) and the synthetic sex steroid cyproterone acetate (CPA) induce growth of rat liver by hypertrophy and hyperplasia. After withdrawal of the growth stimuli, liver hypertrophy was usually found to be readily reversible. Conflicting observations were made concerning the fate of liver hyperplasia: hepatic hyperplasia persisted when induced by -HCH but was found to be partially reversible when induced by CPA. The present study confirms the reversibility of hepatic hyperplasia induced by CPA in rats: about 30% of liver DNA present at maximal liver enlargement disappeared within 6 days after cessation of CPA treatment. Simultaneously, a dramatic increase in the rate of cell elimination by apoptosis was found. Glutamate-pyruvate transaminase and alkaline phosphatase in serum did not show major increases, suggesting that cell death was not due to lytic membrane damage. Furthermore, if treatment with CPA was continued or resumed, the enhanced DNA content persisted and the number of apoptotic bodies was greatly reduced. These observations suggest that the occurrence of cell death is due to withdrawal of the growth stimulus CPA. It may reflect a regulatory phenomenon serving to maintain homeostasis of cell number.Further studies showed that CPA is rapidly eliminated from rat liver and serum: t 1/2 in the liver is about 11 h. In contrast, -HCH was previously found to be eliminated more slowly: t 1/2 approximately 144 h. The present study revealed that -HCH, CPA and nafenopin lower the number of apoptotic bodies. This suggests that inducers of liver growth can inhibit hepatocellular death by apoptosis. It is concluded that the regression of hyperplasia after CPA withdrawal may be due to its rapid elimination. On the other hand the relatively long persistence of -HCH may result in inhibition of cell death and thereby stabilize hepatic hyperplasia.Abbreviations CPA cyproterone acetate - -HCH -hexachlorocyclohexane - PB phenobarbital - NAF nafenopin - AB apoptotic body - b.w. body weight - p. admin. post-administration - GPT glutamate-pyruvate transaminase - ALP alkaline phosphatase Dedicated to Professor W. Koransky on the occasion of his 65th birthday     

Boric acid single dose pharmacokinetics after intravenous administration to man

Eighth young adult male volunteers with a basic (alimentary) plasma boric acid concentration of <0.10–0.46 mg/l were given a single dose of boric acid (562–611 mg) by 20 min IV infusion. The plasma concentration curves, followed for 3 days, best fitted a three-compartment open model, although two subjects had to be left out due to inconstant basal plasma concentration values or failure to fit to the three-compartment model. The 120 h urinary excretion was 98.7±9.1% of dose, Cl_tot 54.6±8.0 ml/min/1.73 m², t_1/2 21.0±4.9 h and distribution volumes V₁, V₂, and V₃: 0.251±0.099, 0.456±0.067 and 0.340±0.128 l/kg.     

Behandlung mit Mexiletin

Summary Pharmacokinetics of the antiarrhythmic agent mexiletine were found to be highly variable. Ineffective or toxic doses can be avoided by monitoring mexiletine concentrations in patients plasma. However, the success of antiarrhythmic therapy is mainly determined by the severety of the underlying disease. Therefore, the efficacy of treatment with mexiletine should be controlled by Holter monitoring.

Herrn Prof. Dr. G. Schütterle zum 60. Geburtstag gewidmet     

巴氨西林的人体药代动力学研究

目的建立正常人血浆中巴氨西林浓度的HPLC测定方法,研究巴氨西林在正常人体内的药代动力学行为.方法采用反相高效液相色谱-紫外检测的方法,测定巴氨西林在人体中的主要代谢产物氨苄西林的血药浓度.流动相11mmol/LKH\-2PO\-4(含0.1ml/L冰醋酸)-甲醇(78∶22,v/v).色谱柱为HypersilODS2,5μm,150mm×4.6mmID,紫外检测波长231nm.测定20名男性健康志愿受试者单剂量口服800mg巴氨西林片后血药浓度-时间过程.结果方法的专属性较好,血浆中杂质不干扰样品的测定.方法的回收率大于90%,日间日内变异系数低浓度小于20%,高浓度小于10%,线性范围0.316～20.220μg/ml(r=0.9998,n=5),最低检测浓度0.316μg/ml,符合生物样品分析要求.受试者口服巴氨西林片800mg后,以巴氨西林体内的主要活性代谢产物氨苄西林估算的末端相半衰期(T1/2)1.13±0.31h,峰时间(Tmax)0.81±0.30h,峰浓度(Cmax)10.75±2.53μg/ml,MRT2.01±0.40h,21.25±4.20μg·