骨肉瘤患者行大剂量甲氨蝶呤化疗后肝功能异常及与血药浓度的相关性分析

目的 分析骨肉瘤患者大剂量甲氨蝶呤化疗肝功能异常及其血浓度分布特点,探讨肝肝功能异常与甲氨蝶呤血浓度的相关性.方法 回顾性收集30例骨肉瘤患者大剂量甲氨蝶呤化疗肝功能指标及化疗后0、24、48和72 h的甲氨蝶呤血浓度,统计分析化疗后肝功能异常情况及其与甲氨蝶呤不同时间点血药浓度的相关性.结果 大剂量甲氨蝶呤化疗后肝功...     

A histochemical study of changes observed in the mouse diaphragm after organophosphate poisoning.

A sublethal dose of sarin (GB, isopropyl methylphosphonofluoridate) was administered to mice. The animals were killed up to 28 d after dosing and frozen sections were made of the excised diaphragms which were stained using haematoxylin and eosin and a modified Gomori trichrome method. Muscle fibre degeneration and mononuclear infiltration were seen, notably at 24 h and 3 d. A number of histochemical procedures were carried out, including the GBHA procedure for ionized calcium. Calcium accumulation, seen at 4 h, was the earliest abnormality observed. All changes were rapidly regressing by 5 d and histological appearances were normal by 14 d. It was concluded that sarin produced myopathic changes preceded by calcium accumulation.     

Lack of correlation between the acute haemodynamic response to intravenous captopril and plasma concentrations of angiotensin II in patients with chronic cardiac failure

Summary We have given a series of incremental intravenous injections of captopril to ten patients with chronic cardiac failure.Small doses of captopril produced significant changes in pulmonary artery end-diastolic pressure and right atrial pressure, up to a total cumulative dose of captopril of 2.5 mg, after which further injections had no significant effect. There were large changes in systemic vascular resistance and blood pressure up to a cumulative dose of captopril of 5.0 mg, after which the injection of larger doses caused no further significant changes.Small doses of intravenous captopril produced large increases in plasma renin activity and plasma angiotensin I concentrations up to a total cumulative dose of captopril of 1.25 mg, after which there were no significant further changes in either plasma renin activity or plasma angiotensin I concentration. However the plasma concentration of angiotensin II fell more slowly, no further change being recorded after a total cumulative dose of captopril of 10 mg.These results suggest that plasma renin activity is not the only determinant of plasma angiotensin II concentrations.     

人工麝香对急性寒凝血瘀模型大鼠凝血时间及血小板聚集率的影响

目的：观察人工麝香对急性寒凝血瘀证模型大鼠血小板聚集率及凝血时间的影响。方法：采用s.c.盐酸肾上腺素和冰水刺激复制大鼠急性寒凝血瘀证模型,以复方丹参片作为阳性对照研究人工麝香对急性寒凝血瘀证大鼠凝血时间及血小板聚集率的影响。结果：人工麝香高、中、低剂量组的血小板聚集率明显低于模型组（P〈0.05或P〈0.01）,人工麝香高剂量组的凝血酶时间（TT）、凝血酶原时间（PT）、凝血活酶时间（APTT）值明显高于模型组（P〈0.05）。结论：可以明显缓解急性寒凝血瘀证的血瘀症状,在活血化瘀方面有重要的应用价值。     

Thirteen-week intravenous repeated dose toxicity study of T-3762, a novel parenteral quinolone antimicrobial agent, and four-week recovery test in cynomolgus monkeys

A thirteen-week intravenous repeated dose toxicity study of T-3762, parenteral quinolone antimicrobial agent, and four-week recovery test was carried out in male and female cynomolgus monkeys at dosages of 26, 52 and 104 mg/kg. The following results were obtained. 1) There was no death of animals during administration period at any dose levels. In general signs, there was no abnormality at any dose levels. 2) In appetite, body weights and ophthalmological examination, there was no abnormality attributable to the treatment. 3) In urinalysis, hematological examination and biochemical examination, there was no abnormality attributable to the treatment. 4) In organ weights, macroscopic findings and histopathological findings, there was no abnormality attributable to the treatment. 5) From these results in this study, no-toxic dose level of T-3762 for cynomolgus monkeys is considered over 104 mg/kg.     

The rate of 2,5-hexanedione intoxication, not total dose, determines the extent of testicular injury and altered microtubule assembly in the rat

Charles River CD rats (220 g) were intoxicated with 1.0, 0.5, or 0.25% 2,5-hexanedione (2,5-HD) in the drinking water for a total of 21, 35, or 69 days, respectively. All rats received a total dose of 131 +/- 2 mmol/kg 2,5-HD at dose rates ranging from 1.9 to 6.1 mmol/kg/day. Rats were sacrificed 4 weeks after ending intoxication to evaluate the extent of testicular injury. An exposure rate of 6.1 mmol 2,5-HD/kg/day produced uniformally low testis weights (49% of control) and severe germ cell depletion, while exposure at 1.9 mmol/kg/day gave normal testis weights and histology. Exposure at the intermediate dose rate of 3.8 mmol 2,5-HD/kg/day produced an intermediate degree of testicular injury. In a separate experiment, testis pyrrole content and microtubule assembly behavior were measured in rats exposed to 2,5-HD at the various dose rates for 3 weeks. The rate of intoxication determined the extent of biochemical abnormality. Rats exposed to 1.0, 0.5, or 0.25% 2,5-HD had microtubule nucleation times 55, 63, and 72% of control and pyrrole contents equivalent to 2.14, 1.40, and 1.18 nmol 2,5-dimethylpyrrole/mg testis protein. These data demonstrate that 2,5-HD-induced testicular injury, unlike the nervous system toxicity, is dependent upon the rate of intoxication independent of total dose.     

Detection of germ cell genotoxic potential of carbon disulphide using sperm head shape abnormality test

1. Adult male albino rats (CF Strain) were administered i.p. CS2 dissolved in cotton seed oil at doses of 25, 50, 100 and 200 mg/kg b. wt. for a period of 60 days. Effect of CS2 on epididymis, adrenal weight, sperm count and sperm head shape abnormality was studied. 2. Epididymal weight remained unaltered in 25, 50 and 100 mg/kg CS2 treated groups, whereas in highest dose of CS2 treated (200 mg/kg) group a non-significant reduction in epididymis weight was observed. A slight increase in adrenal weight was observed in lower doses groups (25 and 50 mg/kg) while a considerable decrease in adrenal weight was noted in highest dose (200 mg/kg) of CS2 treated group in the present study. 3. An increase in sperm head shape abnormality and decrease in sperm count was observed in all the CS2 treated groups. However, the changes were statistically significant only after higher dose of CS2 treatment as compared to control. 4. This study suggests that CS2 may have the potential to induce adverse effects on male reproductive system of rats. Sperm head shape abnormality assay used in this study also elicits germ cell genotoxic potential of carbon disulphide.     

The biological activity of a single dose of tamoxifen in the adult ovariectomized rat

1 The peripheral and central activities of tamoxifen were studied in the ovariectomized adult rat, up to 16 d after a single dose of 7.0 or 0.7 mg/kg. 2 Food consumption and body weight were decreased; only food consumption returned to control values after 16 d. 3 The weights of the uterus and of the uterine luminal fluid were increased for up to 8 d. 4 Serum follicle-stimulating hormone (FSH) concentrations decreased, but only significantly 1 and 8 d after 7.0 mg tamoxifen/kg. Serum luteinizing hormone (LH) and prolactin concentrations were elevated for up to 4 d. 5 Lordosis behaviour was absent throughout the period studied. 6 Within 3 d of administration, tamoxifen partially antagonized the oestrogen-induced changes in uterine luminal fluid, prolactin and LH secretion and lordosis behaviour. 7 Tamoxifen did not alter oestrogen-induced changes in uterine weight, food consumption and body weight. 8 The experiments demonstrate that tamoxifen is active for up to 16 d after a single intraperitoneal dose; oestrogen agonist, partial agonist and antagonist activities were demonstrated. The duration and type of activity depends upon the dose of tamoxifen and the target tissue response examined.     

Induction of drug-metabolizing enzymes and toxicity of trans-stilbene oxide in rat liver and kidney

The effect of trans-stilbene oxide (TSO) on organ function and morphology and on drug-metabolizing enzymes was determined in male Sprague-Dawley rats. TSO (300 or 600 mg/kg) was administered i.p., once daily for 5 consecutive days. At a dose of 3400 mg/kg, TSO did no alter body weight, but increased liver weight. The higher dose (600 mg/kg) markedly decreased body weight. TSO treatment (300 mg/kg) induced several drug-metabolizing enzymes. Epoxide hydrolase activity was enhanced in the liver, kidney and lung. In contrast, arylhydrocarbon hydroxylase activity was not significantly altered. Glutathione S-transferase activity, with 1-chloro-2,4-dinitrobenzene as substrate, and uridine diphosphoglucuronyl transferase activity, with p-nitrophenol as substrate, were also increased in the liver and kidney after TSO treatment. It appears that TSO induces hepatic and renal enzyme activities in a similar manner. Treatment with the higher dose of TSO depressed accumulation of p-amino-hippurate by renal cortical slices and increased blood urea nitrogen concentration. Histological examination of kidney sections after treatment with TSO revealed no abnormality. The lower dose led to negligible alteration in liver and the higher dose resulted in mild to moderate hepatic cellular.     

The clinical usefulness and transference of cefcapene pivoxil (CFPN-PI) into the maternal cubital blood, umbilical blood and amniotic fluid in premature rupture of the membranes

We studied the transference of cefcapene pivoxil (CFPN-PI) into the maternal cubital blood, umbilical blood and amniotic fluid as well as its clinical usefulness. 58 pregnant women without complications who had a premature rupture of membranes after day 0 of the 36th week of pregnancy and delivered a child with a normal transvaginal labor were enrolled this study. As a result, we found that the maternal serum level of CFPN-PI reached a detectable level at 1 hr 15 min post dose, reached the maximum (Cmax) at 2 hr 30 min, and was maintained at 0.15-1.14 micrograms/ml until 4 hr 35 min. In the umbilical serum, the drug concentration reached a detectable level at 1 hr 45 min post dose, was maintained at Cmax of 0.40 microgram/ml from 3 hr 3 min until 4 hr 27 min, and showed a level as high as 0.14 microgram/ml at 7 hr 7 min. In the amniotic fluid, the drug concentration reached a detectable level of 0.09 microgram/ml at 2 hr 48 min post dose, reached Cmax at 3 hr 55 min, and was maintained at 0.15-0.61 microgram/ml until 13 hr 37 min. Concerning the prophylactic effects of CFPN-PI against infections, one case of puerperal intrauterine infection in the parent and two cases of neonatal infection were observed, showing an effectiveness of 95%. In terms of adverse events, neither abnormality in maternal laboratory test data suspected as due to CFPN-PI, nor abnormality in subjective and objective findings was observed. In the neonates, no abnormality suspected as due to CFPN-PI was detected, either, including growth retardation until the 3-month medical examination. We think that CFPN-PI can be a first choice drug for prophylaxis of infections in cases of premature rupture of membranes after the 36th week of pregnancy, because of convenience of oral administration, coupled with excellent safety and potent prophylactic effectiveness against infections resulting from a long term maintenance of high levels in the umbilical blood and amniotic fluid.     

Effects of N,N′-methylene-bis-acrylamide (MBA) on mouse germ cells — sperm count and morphology,and testicular pathology

The sperm count and morphology, and testicular histopathology were studied in mice over a period of 75 days following a single oral administration of 50, 100, and 200 mg/kg N.N-methylene-bis-acrylamide (MBA). With a 50 and 100 mg/kg dose, the sperm abnormality reached a maximum at 30 days, whereas the sperm count reached a minimum at 35 days. The abnormality and decrease in sperm count were both dose dependent. Following the administration of 200 mg/kg MBA, the appearance of abnormal sperm showed a diphase pattern, i.e., first at 7–15 days without any reduction of the sperm count and second at 30 days after treatment. Testicular histopathological changes showed that resting spermatocytes, succeeding leptotene and zygotene spermatocytes were either absent or reduced 1–3 days after treatment with 200 mg/kg MBA. These early histopathological changes seemed to precede both the increase in abnormal sperm and the decrease in sperm count observed 30–35 days post-treatment, and also suggested that resting spermatocytes were most sensitive to MBA exposure among various spermatogenic cells.     

Prazosin in hypertension. Part II. Effects of the initial dose.

The events after the first dose of prazosin have been studied. Twenty-four patients with hypertension were given a single 1 mg tablet. Supine and erect blood pressures were recorded at 15-minute intervals for up to 270 minutes. Six had no previous therapy, 18 were uncontrolled on other drugs, chiefly thiazides or beta-adrenergic blockers or a combination of both. In 10 patients in whom no symptoms of postural hypotension occurred, there was a mean maximum erect diastolic blood pressure fall of 21/14mmHg at an average of 110 minutes after the dose. The remaining 14 had symptoms of postural hypotension of which four were milk, seven moderate and three severe. The mean maximum erect diastolic blood pressure reduction in this group was 67/52mmHg at a mean of 90 minutes after the dose. Subsequent therapeutic response was better in those with an abrupt initial blood pressure fall. Twenty-two further patients were studied in the same manner with a single dose 0.5mg (tablet), 11 of them in a double-blind within-patient crossover study with placebo. Postural symptoms or significant tachycardia did not occur with this dose. Most patients experience some postural hypotension after the first dose of prazosin. Symptoms occur only when this fall is marked, and the extent of the fall is dose related.     

Does tachyphylaxis occur to the non-pulmonary effects of salmeterol?

1. The potential for tachyphylaxis to the non-pulmonary effects of salmeterol, a long-acting selective beta 2-adrenoceptor agonist was investigated in 12 healthy male subjects in a double-blind two period crossover study design. 2. Subjects received cumulative doses of up to 400 micrograms (50 + 50 + 100 + 100 + 100 micrograms at 45 min intervals) inhaled salmeterol prior to a 13 day dosing schedule of twice-daily inhaled salmeterol 100 micrograms or placebo. Twelve hours after the last dose of salmeterol or placebo, subjects again received cumulative doses of up to 400 micrograms inhaled salmeterol. 3. Pulse rate, blood pressure, 12-lead ECG, physiological tremor and peak expiratory flow rate (PEFR) were measured before administration of cumulative doses of salmeterol, at 10, 20, 30 and 40 min after each incremental dose of salmeterol and at 4, 6 and 8 h after the first dose. Blood samples were taken for plasma potassium, magnesium, non-esterified fatty acids (NEFA) and blood glucose concentrations at 20 and 40 min after each dose and at 4, 6 and 8 h after the first dose. 4. Eleven subjects completed the study. One subject withdrew due to beta 2-adrenoceptor related adverse events. All other adverse events reported were mild in nature. 5. Dose-related changes to the effects of salmeterol on pulse rate, QTc interval, tremor, PEFR, blood glucose and plasma potassium were seen, but there was no dose-related effect of salmeterol on blood pressure, plasma magnesium and NEFA. 6. Tachyphylaxis occurred to the effects of salmeterol on tremor, QTc and blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genotoxic potential of an organophosphate insecticide, phosphamidon (dimecron): an in vivo study in mice

The genotoxic effect of phosphamidon in mice in an in vivo test system was investigated by 3 different assays: chromosomal aberration, micronucleus and sperm-shape abnormality. The chemical was administered to groups of mice via 3 routes (i.p., p.o. and s.c.), acutely in 3 dose regimens (5, 4 and 3 mg/kg) and subacutely or chronically (5 X 1 mg/kg). The animals were sacrificed at different times: after 6, 24, 48 and 120 h for chromosomal aberration, 30 h for micronucleus and 35 days for sperm-shape abnormality. Significant effects were observed in all assays. Chronic exposure to fractionated doses induced less effect than the equivalent acute dose. The results were dose- as well as time-responsive and indicated the genetic peril of phosphamidon in the present, in vivo system.     

Effect of phenyl-tert-butylnitrone, mexidol and nooglutil on the ischemic lesion zone and memory in rats following middle cerebral artery occlusion

An ischemic cerebral affection zone amounting to 22.51 +/- 3.0% of the ipsilateral hemisphere volume was found on the frontal brain sections in the frontoparietal cortex of rats 72 h after occlusion of the distal branch of the medial cerebral artery. The new nootropic drug nooglutyl [N-(5-hydroxynicotinoyl)-L-glutamic acid] in a dose of 10 mg/kg, as well as mexidol or phenyl-tert-butylnitrone (PBN) in a dose of 100 mg/kg, introduced into the vein at the moment of occlusion and intraperitoneally for two days after operation, effectively restricted the affected zone: nooglutyl, up to 7.6 +/- 2.28%; mexidol, up to 9.55 +/- 1.9%; and PBN, up to 12.8 +/- 1.7% of the ipsilateral hemisphere volume. On the third day after operation, animals preliminarily learnt to the passive avoidance conditioned reflex exhibited violated memory retrieval. The retrieval was significantly improved in the test animals treated with mexidol and especially nooglutyl.     

Toxicological studies on pipemidic acid. V. Effect on diarthrodial joints of experimental animals.

Pipemidic acid (PPA) orally given in a dose of 100 mg/kg/day or more was found to cause lame gait in immature beagle dogs of about 3 months old. Their diarthrodial joints were abnormal with increased synovial fluid and blister formation under the outer layer of the articular cartilage. However, such an abnormality was not found in dogs younger than 2 weeks or older than 12 months. The blisters were formed at the joint areas bearing the body weight at a time when PPA was considered to be present there. Nalidixic and piromidic acids, structural analogues of PPA, also caused abnormality similar to PPA. The severity of the arthropathy was slight with piromidic acid as compared with PPA and nalidixic acid. The gait abnormality was almost disappeared spontaneously even if medication was continued. The incidence of the arthropathy was not or rarely observed in any young rats, rabbits and monkeys.     

Comparison of the efficacy of naproxen sodium and dihydrocodeine tartrate in the treatment of post-operative pain

A single-blind, parallel study was carried out in 54 patients with post-operative pain after minor orthopaedic procedures to compare the efficacy and tolerance of naproxen sodium and dihydrocodeine tartrate. Patients were allocated at random to receive oral treatment as soon as analgesia became necessary with an initial dose of either 550 mg naproxen sodium or 30 mg dihydrocodeine tartrate, then doses of 275 mg and 30 mg, respectively, when required up to a maximum of 5 doses per day for 3 days. Assessments were made of pain severity and pain relief 2 and 4 hours after the first dose and at the end of each day. The results indicated that naproxen sodium gave statistically significantly greater pain relief than dihydrocodeine tartrate after the first dose. Both treatments were well tolerated and few side-effects were reported. Three patients in each group were withdrawn due to lack of efficacy (combined with adverse effects in 1 naproxen sodium patient), and 1 patient in each group was withdrawn because of side-effects.     

Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats.

Individuals who consume cocaine illegally have long since adopted or explored the nasal route of administration. This study was designed to determine in an animal model whether nasally applied cocaine could be transported directly from the nasal cavity to the central nervous system. Male Sprague-Dawley rats were used in the study. The nasal cavity was isolated to prevent drainage of nasally applied dosing solution to nonnasal regions. Cocaine was then administered, either by intranasal (in) administration or by intravenous (iv) injection. At different times post dose, blood and tissues from different regions of the brain were collected. Cocaine concentrations in plasma and tissue samples were analyzed by HPLC. After iv administration, similar cocaine contents in different brain regions were observed. Following in administration, cocaine content in samples collected within 60 min post dose were found to differ considerably in different brain regions. The highest content was observed in the olfactory bulb, followed by the olfactory tract and then the remaining part of the brain. To allow comparison of brain cocaine content after iv and in administration, brain cocaine contents were normalized by plasma cocaine concentrations. The ratios of the area under the cocaine concentration-time curve (AUC) between the olfactory bulb and plasma at early times following in administration were significantly higher than those obtained after the iv dose (13.4 +/- 5.56 vs 6.16 +/- 0.94, p < 0.05, for AUC ratio up to 2 min post dose; 9.39 +/- 1.47 vs 7.34 +/- 0.59, p < 0.05, for AUC ratio up to 4 min post dose). At 1 min post dose, the olfactory bulb-to-plasma cocaine concentration ratios following in administration was three times those obtained after iv administration. After 1 min, the olfactory bulb-to-plasma concentration ratios following in administration were found to be similar to or smaller than those obtained after iv administration. The tissue-to-plasma concentration ratios in other brain regions following in administration were found to be smaller than those obtained following iv dosing. We conclude that nasally administered cocaine was transported directly from the nasal cavity to the brain but that only a very small fraction of the dose was transported via the direct pathway.     

Codeine disposition in human hair after single and multiple doses

Objective: We studied the dose-proportion and time-course relationships for the incorporation of codeine into human hair after the administration of three different doses. Subjects: Male volunteers, with dark hair, were given oral codeine either as a single dose of 60 mg (n = 7) or 120 mg (n = 12), or as multiple doses of 30 mg 3 times daily for 5 days (n = 7) (450 mg total dose). Methods: Blood and urine were collected for various times for up to 72 h after dosing. Scalp hair was collected initially by plucking (up to 4 weeks) and later by cutting for up to 10 weeks. Plasma, urine, proximal 1 cm of hair and distal hair were each analyzed for codeine and its metabolites by positive-ion chemical ionization ion trap gas chromatography/mass spectrometry. Results: Codeine was detected in the proximal 1 cm of hair within 30 min of an oral 120-mg dose. Codeine was not detected in the distal hair segment until 3 weeks after receiving a dose of codeine. Codeine was detected in distal hair segments for at least 10 weeks at 30 pg mg^?1 hair following a single 120 mg codeine dose and at 90 pg mg^?1 hair following 30 mg codeine 3 times a day for 5 days. Morphine or the glucuronides of codeine or morphine were not detected in the hair specimens of these subjects. Conclusion: Codeine is rapidly distributed into the germanitive elements of hair in a dose-proportional manner. A portion of the codeine remains bound as the hair grows and can be detected in distal hair for up to 10 weeks after a single dose.     

耶氏肺孢子虫肺炎患者复方磺胺甲噁唑剂量调整分析

近年来,随着免疫抑制药、肿瘤化疗药物的应用,耶氏肺孢子虫肺炎的发病率呈明显上升趋势,而复方磺胺甲噁唑是治疗耶氏肺孢子虫肺炎的一线药物.本文为1例免疫球蛋白A(IgA)肾病患者口服免疫抑制药发生肺孢子虫肺炎,给予复方磺胺甲噁唑口服治疗后,出现恶心、呕吐等消化道药物不良反应,临床药师分析考虑其可能存在剂量较大、代谢异常等因...