Scale-up effects on dissolution and bioavailability of propranolol hydrochloride and metoprolol tartrate tablet formulations

This study evaluated the effects of batch size on the in vitro dissolution and the in vivo bioavailability of immediate release formulations of propranolol hydrochloride and metoprolol tartrate. The formulations were manufactured as small and large batches (6 kg and 60 kg for propranolol; 14 kg and 66 kg for metoprolol), and dissolution was performed using USP Apparatus I at 100 rpm and pH 1.2. Two panels of 14 subjects each were randomly assigned to receive the small and large batches of either propranolol or metoprolol in an open randomized single-dose study. Blood samples were collected over a 24-hour (propranolol) or 18-hour (metoprolol) period and analyzed by validated methods. As determined by thef ₂ metric (similarity factor), the dissolution of the small and large batches of propranolol and metoprolol was similar. The mean C_max and AUC_inf for the small batch of propranolol were 79.0 μ g/L and 536 μ g/L/hr and for the large batch they were 83.5 μ g/L and 575 μ g/L/hr. C_max and AUC_inf for the small batch of metoprolol were found to be 95.5 μ g/L and 507 μ g/L/hr and for the large batch, 95.1 μ g/L and 495 μ g/L/hr. The 90% confidence intervals for the small and large batches were within the 80% to 120% range for InC_max, and InAUC_inf for both the propranolol and metoprolol formulations. These results suggest that the scale-up process does not significantly affect the bioavailability of highly soluble, highly permeable drugs and in vitro dissolution tests may be useful in predicting in vivo behavior.     

The effects of buprenorphine, nalbuphine and butorphanol alone or following halothane anaesthesia on food and water consumption and locomotor movement in rats.

Locomotor activity and food and water consumption are potentially indices of post-operative pain in laboratory rodents, but it is important to establish whether these variables are directly affected by opioid analgesics or by halothane anaesthesia in normal rats. The effects of three opioids, buprenorphine, nalbuphine and butorphanol administered alone or following halothane anaesthesia, were studied in groups of normal non-operated adult Wistar rats. All 3 analgesics affected food intake and activity levels, but had little or no effect on water intake. Buprenorphine caused a significant elevation of activity levels and a reduction in food intake at clinical doses (0.01 and 0.05 mg/kg s/c). Nalbuphine (0.5, 1 and 2 mg/kg s/c) caused a reduction in food intake but had a smaller stimulatory effect on locomotion. Butorphanol (0.4 mg/kg s/c) caused a reduction in food intake and elevation in activity. These results suggest that water consumption is likely to be a more reliable variable to use when assessing post-operative pain and the efficacy of analgesics in rats.     

High-performance liquid chromatography of nalbuphine, butorphanol and morphine in blood and brain microdialysate samples: application to pharmacokinetic/pharmacodynamic studies in rats

A rapid and sensitive assay for quantification of nalbuphine, butorphanol and morphine in blood (50 microL) and brain microdialysate ( approximately 40 microL) samples was developed. Blood samples were extracted with ethyl acetate. Analysis was performed with high-performance liquid chromatography (HPLC) coupled to an electrochemical detector. The mobile phase was a mixture of 0.1 M sodium phosphate buffer, methanol and octane-sulfonic acid with ratio and pH depending on compound and matrix. The limits of quantification in blood samples were 25, 50 and 25 ng/mL for nalbuphine, butorphanol and morphine, respectively and 0.5 ng/mL for morphine in microdialysate samples. Based on sample volume, sensitivity and reproducibility, these assays are particularly suitable for pharmacokinetic/pharmacodynamic studies in rodents.     

Conversion of tartrate to malate and monoethyl tartrate in grape leaves

¹⁴CO₂ evolution from l(+)-tartrate-[U-¹⁴C] in grape leaves was observed confirming the dissimilation of tartrate. 30 sec after the administration of l(+)-tartrate-[U-¹⁴C], 3 compounds were found to contain ¹⁴C. Two of them were identified as monethyl tartrate and malate by chromatographic and MS studies. It is suggested that the ¹⁴CO₂ evolved is derived from malate-[U-¹⁴C] which is metabolically formed from l(+)-tartrate-[U-¹⁴C], and that monoethyl tartrate is not an intermediate for the conversion to malate.     

Cardiopulmonary, hemocytologic and biochemical effects of xylazine in goats

Intramuscular administration of xylazine at the rate of 0.22 mg/kg body weight caused a significant reduction in respiratory rates. Mean arterial blood pressure and rectal temperature were not altered. Preadministration of atropine did not affect the depth and pattern of respiration; however, the heart rate increased. A significant reduction in pH and arterial oxygen tension and an increase in carbon dioxide tension was observed after xylazine and xylazine following atropine treatment. Hemocytologic changes included a decrease in total erythrocytes, leukocytes, hematocrit and hemoglobin concentration and a rise in neutrophils with relative decrease in lymphocytes. Biochemical changes included a slight rise in potassium and a decrease in sodium concentration. Glucose level was significantly increased at maximum depth of sedation. The changes in hemocytologic and biochemical parameters returned to near preadministration level in 24-72 hours. No alteration was observed in the electrocardiogram. Xylazine was well tolerated, and the sedation was rapid in onset and lasted for about 30 minutes. The recovery was uneventful.     

Yohimbine hydrochloride reversal of ketamine hydrochloride and xylazine hydrochloride immobilization of Bengal tigers and effects on hematology and serum chemistries

Six bengal tigers (Panthera tigris tigris) were immobilized five times at 2-wk intervals with ketamine hydrochloride (ketamine) and xylazine hydrochloride (xylazine) mixtures at different dose levels. Hematology and serum chemistry analyses on blood samples collected at each immobilization remained normal during the study. There were acute changes in hematocrit, chloride, potassium, glucose, and bilirubin as a function of xylazine dose level. The effect of yohimbine hydrochloride (yohimbine) on the depth and duration of immobilization was evaluated in a crossover design with every animal serving as its own control at each dose. Administration of yohimbine resulted in recovery of the animals within 4-8 min in contrast to greater than 60 min with no yohimbine treatment. There were no adverse effects noted with the yohimbine treatment and the tigers did not exhibit a relapse over the next 24 hr. Yohimbine at a dose of 5-15 mg per adult tiger provided effective reversal of 50-150 mg of xylazine per tiger.     

Cardiorespiratory effects of nifedipine in pregnant sheep

Four concentrations of nifedipine (AdalatR, Bayer) were infused into 25 pregnant sheep of 123-140 days of gestation (term, 147 days) and the effects on the ewe and the foetus have been studied. At all doses of nifedipine infused, maternal diastolic pressure fell by about 15% and maternal heart rate increased by 33%. There was no change in blood gases or pH. Uterine activity, as measured by uterine electromyographic recordings, was reduced due to an increase in the interval between periods of activity. The duration of a burst of activity remained unaffected. The effects of nifedipine on the foetus, were similar. Mean foetal arterial pressure fell by 4-5 mmHg and heart rate rose by 15 to 50%, both changes being maintained for the duration of the infusion and the increased heart rate for longer. The electrocorticogram of the foetal sheep was unaffected by nifedipine. The effects on foetal breathing movements were small. At the concentration of 5 micrograms/kg/min for either 2 or 4 hours the breathing pattern changed so that the episodes of breathing were shorter and more frequent. The total amount of breathing per hour was unaffected. Control infusion of ethanol had little effect on the ewe except for a significant increase in lactate production. In the foetus breathing was reduced at the highest concentration used.     

纳布啡在围手术期镇痛的研究进展

纳布啡是一种新型的菲族镇痛药,属于混合型阿片类受体激动/拮抗剂,可在脊髓水平激动κ受体发挥强效的镇痛效果,其镇痛作用起效迅速、药效持久、疗效确切;同时由于纳布啡独特的部分μ受体拮抗特性,使其与吗啡相比,在发挥镇痛作用的同时呼吸抑制轻、血流动力学平稳以及恶心呕吐、皮肤瘙痒、成瘾性等不良反应发生率更低,因此,纳布啡在围手术期镇痛和临床麻醉等多个领域有着广阔的应用前景。现结合纳布啡独特的药代动力学、药理学特点及作用机制,对纳布啡在围手术期镇痛的研究进展作一综述,以期为临床上合理、有效镇痛提供理论参考和实践依据。     

Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep

Adrenomedullin (AM) is a vasodilatory peptide hormone, playing a key role in the regulation of cardiovascular homeostasis. In view of the circulatory failure in sepsis, it is still debated as to whether the occurrence of vascular hyporeactivity against AM plays a causative or protective role. This study was designed as a prospective, controlled trial to elucidate the hemodynamic response following a titrating infusion of human AM in healthy and endotoxemic sheep. ANOVA demonstrated that AM infusion produced hypotension and tachycardia, and increased cardiac index in a dose-dependent manner, both in healthy and endotoxemic sheep. In addition, AM application reduced pulmonary vascular resistance index in ovine endotoxemia (P=0.02). These findings confirm that AM produces a hyperdynamic circulation, in the presence and absence of systemic inflammation. Further, exogenous AM could possibly be a useful adjunct in the common setting of sepsis-associated pulmonary hypertension.