The pharmacokinetics of Casodex in laboratory animals

1. The pharmacokinetics of Casodex, a novel, non-steroidal antiandrogen, have been investigated following single oral and i.v. doses and during daily oral dosing to male and female rats and male dogs.

2. The binding of ¹⁴C-Casodex to rat, dog and human plasma proteins, determined by equilibrium dialysis, was high with values >95%; in dog there was evidence for decreased binding at concentrations >12 μg/ml.

3. Casodex was slowly absorbed over prolonged periods and its bioavailability decreased with increase in dose from 72% and 88% in male and female rats respectively at 1?mg/kg to 10% and 12% at 250?mg/kg; in dog bioavailability decreased from 100% at 0.1?mg/kg to 31% at 100?mg/kg.

4. Elimination of Casodex from plasma was slow with terminal elimination half-lives of about 1 day in rat and about 6 days in dog. On daily administration to rats Casodex accumulates slightly in plasma at 10?mg/kg but not at 250?mg/kg; in dog appreciable accumulation (9–12-fold), calculated from the ratio of trough plasma concentrations at steady state to those after a single dose, was observed at 2.5 and 10?mg/kg, but at 100?mg/kg the accumulation ratio was much lower (4-fold).     

The pharmacokinetics of propofol in laboratory animals

1. The pharmacokinetics of propofol in an emulsion formulation (‘Diprivan’) have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT.

2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood.

3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open ‘mammillary’ model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (V_ss=2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80ml/kg per min in rats, dogs and pigs to about 340ml/kg per min in rabbits.     

The influence of glucosamine on the antiexudative effect of nonsteroidal anti-inflammatory agents

The study of the antiexudative activities of voltaren, indomethacin and piroxicam in combination with glucosamine on the model of carrageenan inflammation showed that the combination makes it possible to decrease the effective doses of nonsteroidal anti-inflammatory drugs by 2-2.7 times with the preservation of the pronounced antiexudative activity. A diverse influence of aminosugar on the anti-inflammatory effect of nonsteroidal anti-inflammatory drugs depending on the sequence and routes of administration is connected with their membrane mechanisms and metabolic features of amino sugar.     

Comparative evaluation of the neuroprotective activity of phenotropil and piracetam in laboratory animals with experimental cerebral ischemia

The neuroprotective properties of phenotropil and piracetam were studied in Wistar rats with low and high sensitivity with respect to cerebral ischemia caused by bilateral irreversible simultaneous occlusion of carotid arteries and gravitational overload in craniocaudal vector. In addition, the effects of both drugs on microcirculation in the brain cortex under ischemic injury conditions were studied. Phenotropil and (to a lower extent) piracetam reduced the extent of neuralgic deficiency manifestations, retained the locomotor, research, and memory functions in animals with gravitational cerebral ischemia, increased the survival of experimental animals, and favored the restoration of local cerebral flow upon the occlusion of carotid arteries.     

柱前衍生化法测定盐酸氨基葡萄糖软膏的含量

目的建立柱前衍生化RP-HPLC法测定盐酸氨基葡萄糖软膏的含量。方法采用NH2色谱柱(250 mm×4.6 mm,5μm),流动相为乙腈-水(体积比90∶10),流速为1.0 mL.min-1,衍生化试剂为异硫氰酸苯酯,检测波长254 nm。结果在本色谱条件下,盐酸氨基葡萄糖质量浓度在12.75~38.25 mg.L-1内呈良好的线性关系,回收率为100.4%。结论该方法准确、可靠,适用于盐酸氨基葡萄糖软膏的含量测定。     

The pharmacokinetics of propofol in laboratory animals.

1. The pharmacokinetics of propofol in an emulsion formulation ('Diprivan') have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT. 2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood. 3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open 'mammillary' model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (Vss = 2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80 ml/kg per min in rats, dogs and pigs to about 340 ml/kg per min in rabbits.     

The pharmacokinetics of Casodex in laboratory animals.

1. The pharmacokinetics of Casodex, a novel, non-steroidal antiandrogen, have been investigated following single oral and i.v. doses and during daily oral dosing to male and female rats and male dogs. 2. The binding of 14C-Casodex to rat, dog and human plasma proteins, determined by equilibrium dialysis, was high with values greater than 95%; in dog there was evidence for decreased binding at concentrations greater than 12 micrograms/ml. 3. Casodex was slowly absorbed over prolonged periods and its bioavailability decreased with increase in dose from 72% and 88% in male and female rats respectively at 1 mg/kg to 10% and 12% at 250 mg/kg; in dog bioavailability decreased from 100% at 0.1 mg/kg to 31% at 100 mg/kg. 4. Elimination of Casodex from plasma was slow with terminal elimination half-lives of about 1 day in rat and about 6 days in dog. On daily administration to rats Casodex accumulates slightly in plasma at 10 mg/kg but not at 250 mg/kg; in dog appreciable accumulation (9-12-fold), calculated from the ratio of trough plasma concentrations at steady state to those after a single dose, was observed at 2.5 and 10 mg/kg, but at 100 mg/kg the accumulation ratio was much lower (4-fold).     

Studies of antidote therapy for nisoldipine intoxication in experimental animals

In anesthetized rats under artificial respiration, intravenous infusion of nisoldipine (0.1 mg/kg x min) caused significant decreases in blood pressure, heart rate, cardiac output and peripheral resistance. The animals died 54.7 +/- 11.1 min after initiation of the infusion. The electrocardiogram showed sinus bradycardia, increasing AV blockade and displacement of the pacemaker into the AV node or the bundle of His. Survival time under nisoldipine infusion increased more than two-fold with simultaneous infusion of calcium gluconate, isoprenaline (isoproterenol) or dopamine. Norepinephrine (noradrenaline) had no significant effect on survival time; the latter decreased to 19.4 +/- 1.6 min by plasma volume expansion with polygeline. All antidotes prolonging survival time also normalized the cardiac output diminished after nisoldipine. Electrocardiographic changes were antagonized only by isoprenaline. Suitable antidotes for intoxication or over-dosage of nisoldipine are calcium salts as well as beta-sympathomimetic drugs; sheer volume substitution and peripheral vascular constriction should not be resorted to.     

放射治疗与加温疗法对荷VX_2瘤动物细胞因子的影响

目的:探讨放疗、热疗对细胞因子的影响。方法:选择健康雄性大白兔60只,将实验动物随机分为放疗组20只、热疗组20只、对照组20只。移植VX2瘤株12 d后,对实验组动物进行放疗、热疗照射,对照组不治疗,监测白细胞介素-2(IL-2)、白细胞介素-6(IL-6)、肿瘤坏死因子(TNF)、胰岛素样生长因子(IGF)的变化。结果:实验动物生存期较对照组延长15 d左右。IL-2在血清中的含量逐渐降低,降低幅度与病死率相关;IL-6、IGF的含量逐渐增高,增高幅度越大则病死率越高,对照组变化最大;TNF逐渐增高,放疗组和热疗组变化幅度大,生存期提高。结论:放疗对VX2瘤效果好,对细胞因子有一定的影响;热疗是治疗肿瘤重要的辅助疗法,有提高免疫功能的作用。     

The influence of cytaphate on the status of oxidative metabolism in rats with diabetic nephropathy

The antioxidant effect of cytaphate (0,0-dimethyl-N-cytisinyl phosphate) has been studied in outbred white rats with alloxan-induced insulin-dependent diabetes mellitus. The content of malonic dialdehyde, diene conjugates, ketodienes, middle-weight molecules, primary and secondary products of lipid peroxidation (LPO), and Schiff bases and the activity of catalase, glutathione peroxidase, and adenosine deaminase in erytrocytes have been evaluated. The state of oxidative protein modification, the content of malonic dialdehyde and diene conjugates, and the superoxide-anion production in the blood plasma have been determined. In the blood of animals with model diabetes, the LPO and oxidative protein modification processes were intensified and the level of superoxide anion production was increased. The administration of cytaphate led to a decrease of the LPO intensity and oxidative protein modification and to normalization of the level of superoxide anion production and the activity of enzymes involved in the antioxidant protection system.     

Encephalopathy in toxicity tests on laboratory animals

Clinical signs of encephalopathy followed administration of lethal doses of a wide range of drugs, foods, pesticides and other agents in 92 reviewed studies on laboratory animals. Common signs of depression of the brain were anorexia, hypokinesia, hypothermia, prostration, ataxia, pallor, and hyporeflexia and of stimulation were convulsions, hyperreflexia, tremors, muscular spasms, and fever. Less common signs included catalepsy, exophthalmos, phonation, piloerection, bradypnea, tachypnea, automatism, flaccidity, a Straub reaction, erection of the penis, nystagmus, spacial disorientation, and hunch back. Aggressiveness took the form of fighting when animals were aggregated and occasionally automutilation when segregated. Certain signs such as vomiting and panting occurred only in cats and dogs. In chronic studies at sublethal daily doses, there were relatively few signs of encephalopathy. At autopsy, the brain was found relatively resistant to changes in weight, to hydration and to dehydration. Histologically there was no evidence of tissue encephalopathy in a third to a half of the studies. In the remaining studies, the brain was found to have participated in the general inflammatory reaction (capillary or capillary-venous congestion) to toxic doses of the agent under study. Less common histopathological reactions included thrombosis, edema, granulocytic infiltrative meningitis and cerebral abscesses.     

Immune response to experimental infection with bovine leukemia virus (BLV) in domestic and laboratory animals

The immune response to cell-associated and cell-free BLV inoculation was studied in calves, lambs, rabbits and specific pathogen-free chickens. Inoculation of cell-associated or cell-free BLV failed to induce infection in rabbits and chickens (strain PDRC), but resulted in the infection of Holstein-Frize calves and of lambs, which exhibited a specific immune response over the entire observation period. Specific antibodies to glycoprotein and p24 fractions of BLV were detected in the infected animals. BLV could be recovered from serologically positive animals.     

The influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats

The effect of thymoquinone (TQ), the main constituent of the volatile oil of Nigella sativa seeds, on the nephropathy and oxidative stress induced by doxorubicin (DOX) in rats was investigated. A single intravenous injection of DOX (6 mg/kg) induced a severe nephrotic syndrome (after 5 weeks) associated with hypoalbuminemia, hypoproteinemia, elevated serum urea, hyperlipidemia, and a high urinary excretion of protein, albumin and N-acetyl-beta-D-glucosaminidase (NAG). In the kidney, DOX induced a significant increase in total triglycerides (TG), total cholesterol (TC), and lipid peroxides and a significant decrease in non-protein sulfhydryl (NPSH) content and catalase (CAT) activity. Treatment of rats with TQ (10 mg/kg per day) supplemented with the drinking water for 5 days before DOX, and daily thereafter, significantly lowered serum urea, TG, and TC. Similarly, TG, TC and lipid peroxides in the kidneys of TQ-treated rats were decreased significantly compared with DOX alone. Moreover, NPSH content and CAT activity in the kidneys of TQ-treated DOX group were significantly elevated compared with DOX alone. Treatment with TQ significantly suppressed DOX-induced proteinuria, albuminuria, and urinary excretion of NAG. The results confirm the involvement of free radicals in the pathogenesis of nephropathy induced by DOX. Likewise, the study demonstrates the high antioxidant potential of TQ and its marked effect on the suppression of DOX-induced nephropathy. The data suggest that TQ might be applicable as a protective agent for proteinuria and hyperlipidemia associated with nephrotic syndrome.     

The efficacy of glucosamine in treating complicated hyperreactive experimental myocardial infarct]

The effect of glucosamine hydrochloride on the course of complicated hyperreactive myocardial infarction in dogs was studied. Glucosamine contributed to the restoration of reactivity in the animals. The reactivity became corresponding for normoreactive myocardial infarction. Glucosamine normalized carbohydrate and protein metabolism in the necrosis zone, cAMP and cGMP and also their ratio that led to healing by postinfarction scar, and in none of the cases the heart aneurysm developed. The optimizing healing of hyperreactive myocardial infarction under the influence of glucosamine is mediated through the mechanisms of reactivity and the regulation of metabolic processes.