硝苯地平双层渗透泵片的制备及家兔体内药动学研究

目的:以硝苯地平为模型药物制备渗透泵制剂,并进行家兔体内药动学研究.方法:与Adalat@GITS硝苯地平控释片比较,采用相似因子法对处方进行考察优化;将制备的硝苯地平渗透泵片和自制的普通片,分别对家兔单剂量口服给药,采用HPLC法对给药后家兔血浆中药物浓度进行测定.结果:通过处方优化,制备了难溶性药物硝苯地平24 h的控释制剂;渗透泵控释片和普通片的达峰时间分别为(12.05±0.28)h和(5.98±0.47)h,峰浓度分别为(0.299±0.035)mg·L<'-1>和(0.452±0.038)mg·L<'-1>,相对生物利用度为119.5%±7.2%.结论:通过制备双层渗透泵片,能够实现硝苯地平体外溶出实验下24 h零级释药,能显著延长硝苯地平家兔体内达峰时间,降低峰浓度,并且提高了药物的生物利用度.     

非诺贝特固体分散片的试制

以PEG4000和十二烷基硫酸钠为载体，采用溶剂—熔融法制备了非诺贝特固体分散体，再与适当辅料混合压片制得非诺贝特固体分散片。用正交设计表L9(3^4)筛选处方。溶出度实验表明自制片较市售两种制剂溶出快。     

甲壳胺-硝苯地平速释片的制备及生物利用度

报道了用硝苯地平（ＮＦ）和甲壳胺（ＣＴＳ）共同研磨后制备ＮＦ速释片的工艺．ＮＦ速释片与市售片剂的溶出度试验表明，其体外累积溶出百分率经０．５ｈ分别为８０％和不足２０％，人口服两片剂的对照试验表明，ＮＦ速释片组体内达峰明显缩短，生物利用度也有显著提高．     

尼群地平缓释片剂的研究

研究了尼群地平缓释片剂的处方、制备工艺和溶出速率,用GC-MS法测定了12名健康受试者口服自制缓释片(C)、市售国产片剂(A)和进口某公司片剂(B)后的体内血药浓度,体内数据按零级溶出、一级吸收口服单室模型,经计算求得药动学参数。结果表明,A、C两制剂相对于B制剂的生物利用度为31.8％及64.8％。与普通片剂相比,缓释片血浓度曲线较为平坦且下降缓慢。     

葡萄糖酸锌兔体内药物动力学及生物利用度研究

本文介绍了用原子吸收分光光度法测定葡萄糖酸锌(Zinc Gluconate,ZG)兔体内血清锌浓度,用一室模型分析了ZG在家兔体内的药动学参数以及硫酸锌片剂,ZG水剂相对于ZG片剂对锌的生物利用度,硫酸锌片剂,ZG水剂相对于ZG片剂对锌的生物利用度分别为24.9％和62.1％。实验结果表明:ZG具有口服吸收快,维持时间长,峰浓度高的特点,是一优于硫酸锌的良好补锌剂。     

尼群地平片剂生物利用度的研究

为提高国产尼群地平片剂的生物利用度,采用球磨混合粉碎法工艺进行处方设计,试制出新处方片剂,与西德Bayer公司片剂进行了体外溶出、体内生物利用度的比较。体内血浆药浓用GC-MS法测定,体内数据按零级溶出、一级吸收口服单室模型,经计算机用Gauss-Newton-Damping法处理求得药动学参数。本文研制的尼群地平新处方片剂生物利用度已超过西德Bayer公司片剂。     

非诺贝特胶囊剂及家犬体内生物利用度

目的采用纳米分散技术制备非诺贝特胶囊剂,以提高其溶出度及生物利用度。方法用反溶剂沉淀法和高压匀质法制备非诺贝特纳米混悬剂,并通过喷雾干燥将其固化以制备胶囊剂,用差示扫描量热法(differential scanning calorimetry,DSC)和X-射线粉末衍射分析表征药物在胶囊剂中的存在状态,并测定药物的溶出度及家犬体内的生物利用度。结果非诺贝特以纳米晶体状态分散于胶囊剂中,自制胶囊溶出度为国产胶囊的3倍,相对生物利用度为国产胶囊的(274.5±15.6)%。结论自制非诺贝特胶囊剂可以通过增加非诺贝特的分散度来提高药物的溶出度与生物利用度。     

微囊化吲哚美辛片剂的研讨

以明胶-CAP 为囊材,经复凝聚法制备吲哚美辛微囊,再按所筛选的最佳处方制备微囊化片剂。该片与市售片相比,体外 T_(50)延长约5.6倍,家兔体内达峰时间滞后,能明显减轻对大鼠胃的刺激性。     

葡萄糖酸锌兔体内药物动力学及生物利用度研究

本文介绍用原子吸收分光(?)度法测定葡萄糖酸锌(Zinc Gluconate,ZG)兔体内血清锌浓度,用一室模型分析了ZG 在家兔体内的药动学参数及硫酸锌片剂、ZG 水剂相时于ZG片剂对锌的生物利用度分别为24.9%和62.1%.实验结果表明:ZG 具有口服吸收快,维持时间长,峰浓度高的特点,是一优于硫酸锌的良好补锌剂.     

西罗莫司固体分散体在Beagle犬体内的药动学研究

目的研究自制西罗莫司固体分散片在Beagle犬体内的药动学。方法6只Beagle犬分别按单剂量给药方案和多剂量给药方案口服西罗莫司受试制剂和参比制剂;采用UPLC-MS/MS法测定Beagle犬给药后不同时间的全血血样浓度。结果西罗莫司线性范围为0.50~20.00ng·mL^-1。Beagle犬单次口服西罗莫司受试制剂和参比制剂后的C max市售片>C max自制片,T max市售片C SSmax自制片,T max市售片相似文献   

Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro

[6,7-³H] Estrone (E) and [6,7-³H]estradiol-17 (E₂) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E₂ were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 g/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (mol chemical bound per mol DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E₂, respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E₂, respectively. The values for male hamster kidney were < 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3,000 times higher than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate.Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 10³–10⁴ have been found for potent, 10² for moderate, and 1–10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured limit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action. Similar considerations can be made for the liver where any true covalent DNA binding must be below a level of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding.Paper presented at the Satellite Symposium of the European Society of Toxicology, Rome, March 29, 1983     

Metabolic interaction between imipramine and carbamazepine in vivo and in vitro in rats

Summary The pharmacokinetic consequences of the combination of carbamazepine with imipramine in male Wistar rats have been investigated. It was found that a 2-week treatment with the combination resulted in the increase of the concentrations of the parent compounds and a simultaneous decrease in their metabolites in blood plasma i.e. carbamazepine inhibited imipramine demethylation in the side chain while imipramine inhibited carbamazepine 10,11-epoxidation. The velocity of imipramine 2-hydroxylation and 10,11-epoxy-carbamazepine hydration did not seem to be changed by the combination. On the basis of studies in vitro it is concluded that the observed metabolic interaction between carbamazepine and imipramine is due to the competition of the drugs for the active centre of cytochrome P 450 and to a certain qualitative alteration of the enzyme by imipramine as can be deducted from the decrease of carbamazepine binding to the cytochrome. Send offprint requests to K. J. Netter     

Buprenorphine and naloxone alone and in combination in opioid-dependent humans

Subjective, physiological and behavioral effects of subcutaneously administered hydromorphone (6 mg), naloxone (0.2 mg), buprenorphine (0.2 and 0.3 mg), and two buprenorphine-naloxone combinations (buprenorphine 0.2 mg plus naloxone 0.2 mg and buprenorphine 0.3 mg plus naloxone 0.2 mg) were assessed under double-blind conditions in six opioid-dependent volunteers. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 120 min after drug administration. Hydromorphone decreased pupil diameter and respiration, increased blood pressure and increased scores on subjective measures indicating opioid-like effects. Buprenorphine given alone had no significant effect on any variable measured. Naloxone given alone produced opioid abstinence-like effects which were measurable on subject- and observer-rated behavioral measures and physiological measures. Buprenorphine in combination with naloxone somewhat attenuated the naloxone-precipitated withdrawal response. Overall, the naloxone-buprenorphine combinations produced effects which were qualitatively similar to the effects of naloxone alone, suggesting a low potential for abuse of the combination product by opioid-dependent individuals.Supported by a grant from Reckitt and Colman Pharmaceutical Division and USPHS Grants DA-00050 and DA-04089 from the National Institute on Drug Abuse     

Consistency in catecholamine and cortisol excretion in males and females

Data from a series of experiments performed on 24 female and 24 male subjects were used to evaluate the consistency in urinary catecholamine and cortisol excretion. Data were available from 8 laboratory situations of varying activity level and content, spaced at intervals of maximum 3 months. Correlational analyses showed that for cortisol, interindividual consistency was higher for measures obtained on the same day than for measures obtained on different days. Interindividual consistency was generally high in catecholamine and cortisol excretion during non-stressful situations in both sexes. During experimental stress, however, consistency was as high as during nonstress for males, while it was lower for females. Analysis of variance components confirmed these results and showed that in males variation due to interindividual differences was high during both baseline and experimental-stress situations, while in females it was high during baseline situations only. During experimental stress, variation for females was due primarily to interaction. It is suggested that the males showed a more generalized stress response over situations than the females.     

Nicotine metabolism and urinary elimination in mouse: in vitro and in vivo

This study aimed at elucidating the in vivo metabolism of nicotine both with and without inhibitors of nicotine metabolism. Second, the role of mouse CYP2A5 in nicotine oxidation in vitro was studied as such information is needed to assess whether the mouse is a suitable model for studying chemical inhibitors of the human CYP2A6. The oxidation of nicotine to cotinine was measured and the ability of various inhibitors to modify this reaction was determined. Nicotine and various inhibitors were co-administered to CD2F1 mice, and nicotine and urinary levels of nicotine and four metabolites were determined. In mouse liver microsomes anti-CYP2A5 antibody and known chemical inhibitors of the CYP2A5 enzyme blocked cotinine formation by 85–100%, depending on the pre-treatment of the mice. The amount of trans-3-hydroxycotine was five times higher than cotinine N-oxide, and ten times higher than nicotine N-1-oxide and cotinine. Methoxsalen, an irreversible inhibitor of CYP2A5, significantly reduced the metabolic elimination of nicotine in vivo, but the reversible inhibitors had no effect. It is concluded that the metabolism of nicotine in mouse is very similar to that in man and, therefore, that the mouse is a suitable model for testing novel chemical inhibitors of human CYP2A6.     

Strain-dependency in motor activity and in concentration and turnover of catecholamines in synchronized rats

Circadian rhythm in motor activity was studied with an Animex motimeter in six strains of rats (ACI, BH, BS, DA, LEW, TNO) synchronized by a 12 hr light: 12 hr dark cycle. ANOVA revealed significant interstrain differences in motor activity as well as in the concentration and turnover of central noradrenaline and dopamine. Strain-dependent differences were also found with regard to tyrosine hydroxylase inhibition on motor activity. However, no significant interstrain correlations were found between endogenous concentration and/or turnover rates of the catecholamines and motor activity in normal and drug-treated rats.     

Pharmacokinetics and tolerability of artesunate and amodiaquine alone and in combination in healthy volunteers

Objectives  The WHO recommends artemisinin-based combination therapies for treatment of uncomplicated falciparum malaria. At least 15 African countries have adopted artesunate plus amodiaquine as treatment policy. As no pharmacokinetic data on this combination have been published to date, we investigated its pharmacokinetic interactions and tolerability in healthy volunteers in Africa. Methods  In a randomized, three-phase, cross-over study, amodiaquine (10 mg/kg) and artesunate (4 mg/kg) were given as single oral doses to 15 healthy volunteers. Artesunate was given to all volunteers on day 0. On day 7 they received either amodiaquine or amodiaquine plus artesunate and the alternative regimen on day 28. The pharmacokinetics of artesunate and amodiaquine and their main active metabolites dihydroartemisinin and desethylamodiaquine were compared following monotherapy and combination therapy using analysis of variance. Results  Thirteen volunteers completed the study, and pharmacokinetic parameters could be determined for twelve volunteers. When given in combination, the mean AUC was lower for dihydroartemisinin [ratio 67% (95% CI 51–88%); P = 0.008] and desethylamodiaquine [ratio 65% (95% CI 46–90%); P = 0.015] when compared with monotherapy. Adverse events of concern occurred in four volunteers (27%): grade 3 transaminitis (n = 1), neutropaenia (n = 2), and hypersensitivity (n = 1). Conclusion  The total drug exposure to both drugs was reduced significantly when they were given in combination. The clinical significance of these interactions is unclear and must be studied in malaria patients. The frequency and nature of adverse events among the healthy volunteers were of concern, and suggest laboratory monitoring would be needed in malaria patients treated with artesunate plus amodiaquine.     

Evaluation of pharmacokinetic interactions between bicyclol and co-administered drugs in rat and human liver microsomes in vitro and in rats in vivo

1. Bicyclol is a new synthetic anti-hepatitic drug and primarily metabolized by CYP3A. The aim of this study was to evaluate the pharmacokinetic interactions between bicyclol and co-administered drugs including metformin, pioglitazone, atorvastatin, fenofibrate, Cyclosporin A (CsA), and tacrolimus in rat and human liver microsomes (RLMs/HLMs) in vitro and in rats in vivo.

2. The depletion rate of bicyclol in RLMs was significantly inhibited by 44.8% and 35.5% after preincubation with pioglitazone and fenofibrate while the metabolite formation rate of bicyclol in HLMs was inhibited by 26.1% and 23.9% after preincubation and coincubation with tacrolimus, and by 20.2% after preincubation with CsA. Conversely, preincubation and coincubation with bicyclol significantly inhibited the depletion rate of pioglitazone in RLMs by 34.1% and 27.1%, respectively, and the formation rate of para- and ortho-hydroxy atorvastatin in RLMs and HLMs by 20.6–36.2%. There were no significant pharmacokinetic interactions between bicyclol and pioglitazone in rats after a single or multiple oral treatment.

3. As the selected inhibitory drug concentrations in vitro were significantly higher than those in clinical settings and the maximum inhibition rate did not exceed 50%, the clinically significant interaction between bicyclol and these co-administered drugs in humans is predicted less likely to happen.

     

Fluvastatin efficacy and tolerability in comparison and in combination with cholestyramine

The aim of this study was to investigate the new synthetic HMG-CoA reductase inhibitor, fluvastatin, for efficacy, safety and tolerability in comparison to cholestyramine. One hundred fifty one primary hypercholesterolaemic patients participated in this double-blind, parallel-group, randomized study. During the first 12 weeks of the study, fluvastatin (20 mg and 40 mg daily) was compared with cholestyramine (16 g per day). In the subsequent, 6-week part of the study, the comparative efficacy, safety and tolerability of 20 mg fluvastatin, combined with cholestyramine (4 g, 8 g, or 16 g) were assessed.Fluvastatin (40 mg) reduced LDL cholesterol by 28.0%, triglycerides by 10.5% and increased HDL cholesterol by 3.7%. Cholestyramine (16 g) reduced LDL cholesterol by 35.0%, but raised triglycerides and HDL cholesterol by 12.3% (p<0.01) and 3.7% respectively.The combination of fluvastatin 20 mg and cholesty-ramine (4 g, 8 g and 16 g) induced the following reductions in LDL cholesterol: 30.4%, 35.6% and 46.6% respectively. There was no significant change in triglycerides in either group although HDL cholesterol was raised by 4.9%, 8.3% and 7.2% respectively. One patient treated with fluvastatin and two treated with cholesty-ramine were withdrawn from the study due to elevation of liver transaminases. The most frequent subjective adverse effects in both treatment groups were mild, transient gastrointestinal complaints.Thus, fluvastatin was effective as a lipid-lowering agent; the effect was further enhanced when fluvastatin was combined with cholestyramine.     

Nicotine-induced hypophagia and hypodipsia in deprived and in hypothalamically stimulated rats

Nicotine, in doses of 0.15 and 0.45 mg/kg, induced hypophagia and hypodipsia in 20 hrs-deprived rats and elevated the threshold currents for hypothalamically induced feeding and drinking in satiated rats. These effects were blocked by pretreatment with 0.5 mg/kg mecamylamine, but not by pretreatment with 3.0 or 9.0 mg/kg hexamethonium. These results indicate a centrally-located mechanism for the hypophagic and hypodipsic effect of single injections of nicotine.