Effect of two superovulation treatments on subsequent fertility in the confined dairy cow

During a 13-month period, 64 lactating dairy cows of 2 genetic lines, Holstein and crossbred, housed indoors year-round were subjected to 2 superovulations and embryo collections within 112 days post partum. Half of the follicle stimulating hormone (FSH) treatments were given in a descending dosage regimen (Treatment A; 6.5 mg, 5.5 mg, 4.5 mg, and 3.5 mg, twice a day, total 40 mg) over 4 days; the remaining half of the treatments were administered in a constant dosage regimen (Treatment B) of 5 mg twice a day over 4 days. There were no significant differences due to treatment in the number of cows stimulated (more than 2 corpora lutea) nor in the number of ova/embryos collected. However, embryos were obtained from more cows (P<0.05) when treated with the descending dosage regimen. More cows (P<0.05) were stimulated by the superovulatory treatment during the first period than during the second period regardless of the regiment used, treatment A or B. More embryos (P<0.05) were obtained from the Holstein line than from the crossbred line. Fifty-two cows were inseminated at least once after the second embryo collection. Overall, 41 cows (79%) became pregnant after the second collection, requiring up to 4 services. These results suggest that the reproduction of dairy cattle housed indoors year-round is not adversely affected by 2 superovulation treatments and embryo collections within 112 days post partum. The question as to whether the administration of FSH is more efficacious in a descending dosage regimen or a constant dosage regimen was not resolved.     

环磷酰胺诱导小鼠血小板减少症模型的建立(英文）

比较由环磷酰胺两种不同给药方式诱导小鼠血小板减少症模型的效果,并对效果较稳定的一种给药方式进行最佳造模剂量摸索,以期确定一个造模效果较好,毒副作用较低,利于观察治疗药物疗效的血小板减少症模型。模型A组,第1天尾静脉注射环磷酰胺200 mg/kg,然后连续6 d,每天1次以维持剂量30 mg/kg腹腔注射环磷酰胺。模型B组,按150 mg/kg皮下注射环磷酰胺,每天1次,连续3 d。结果显示模型B组造模效果较好,故以模型B组给药方法进行剂量摸索实验。由第7天的血小板计数可知环磷酰胺低（100 mg/kg）、中（120 mg/kg）、高（140 mg/kg）剂量均可引起血小板减少症,而低剂量组与其他组比较有高效低毒的特点,更有利于观察治疗药物的作用,可用于具有升血小板作用药物的药效学研究     

Contribution of atenolol,bendrofluazide, and hydrallazine to management of severe hypertension.

The efficacy of various combinations of atenolol, bendrofluazide, and hydraliazine given twice daily was assessed in a double-blind trial on 39 patients with moderate to severe essential hypertension. Concurrent treatment with all three drugs proved most effective and produced a mean reduction in blood pressure of 43/31 mm Hg. In the dosage used, hydrallazine affected only the diastolic blood pressure, and when added to either bendrofluazide or bendrofluazide plus atenolol it produced a further mean reduction in pressure of 6 mm Hg. Once-daily treatment with atenolol and bendrofluazide was as effective in reducing blood pressure as the same combination given twice daily, and the hypotensive effect was still present at least 24 hours after the last dose of tablets. A combined tablet of atenolol and bendrofluazide taken once daily would be a simple regimen to follow and would provide almost as much hypotensive effect as a twice-daily regimen incorporating a modest dose of hydrallazine. The hypotensive effect of atenolol was equal to that of bendrofluazide on systolic pressure but significantly better than that of bendrofluazide on diastolic pressure. Atenolol reduced plasma renin and urate concentrations but increased plasma potassium levels. The biochemical effects of atenolol, therefore, may be an advantage over those of bendrofluazide when deciding on first-line treatment for essential hypertension.     

Comparison of high-dose intravenous methylprednisolone with low-dose oral prednisolone in acute renal allograft rejection in children.

Two corticosteroid regimens were compared in a randomised, prospective study of 48 consecutive acute rejection episodes occurring at least one month after transplantation in 22 children who had received renal allografts. The higher dose schedule (intravenous methylprednisolone 600 mg/m2 daily for three days) was no more effective than the lower (oral prednisolone 3 mg/kg daily for three days) in reversing rejection, being successful in 70% as opposed to 72% of episodes. Few major side effects were seen with either treatment, but unpleasant sensations were reported much more frequently in the group given intravenous methylprednisolone; this regimen was much more disruptive of the patient''s life. Oral prednisolone in the dosage described is as effective as about 10 times that dose of intravenous methylprednisolone; it is much cheaper and is viewed as less unpleasant by patients.     

Synergy between tetrandrine and FK 506 in prevention of diabetes in BB rats

Delayed administration of tetrandrine, a novel broad-spectrum anti-inflammatory agent, to BB rats at a dosage schedule of 20 mg kg ⁻¹ day ⁻¹ from 79 days of age reduced the cumulative incidence of diabetes from 73.1 to 41.7% (p<0.01). Brief treatment with the potent immunosuppressive agent FK506 at a dosage schedule of 0.5 mg kg⁻¹ day ⁻¹ from 79 days of age for 5 days had no significant effect on the cumulative incidence of diabetes (66.7%, p > 0.1). However, the combination of tetrandrine and FK506 in the afore-mentioned dosage schedules reduced the incidence of diabetes to only 3.6% (p <0.001). These results suggest that the strong synergy between tetrandrine and FK506 may offer a safe and effective therapeutic strategy for the treatment of patients with recent onset or imminent IDDM.     

Adverse Reactions to Daily and Intermittent Rifampicin Regimens for Pulmonary Tuberculosis in Hong Kong

This paper reports the nature, incidence, and severity of adverse reactions to regimens of rifampicin and ethambutol given once weekly, twice weekly, or daily and to a standard reserve regimen in a total of 330 Chinese failure patients who completed at least six months'' chemotherapy in a therapeutic comparison in Hong Kong.The adverse reactions which occurred on the regimens of intermittent rifampicin were termed cutaneous, abdominal, “flu”, and respiratory; in addition, purpura and abnormal liver function tests were encountered. There was an association of adverse reactions with the interval between doses and with the dose size of rifampicin, the highest incidence occurring with once-weekly rifampicin in high dosage. A procedure was developed for managing adverse reactions to intermittent rifampicin. Of 202 patients treated with intermittent rifampicin 60 developed adverse reactions, but in only 7 (3%) was it necessary to terminate the drug, though a further 10 (5%) were changed to daily rifampicin. On daily rifampicin, generalized hypersensitivity, cutaneous reactions, (one with purpura), and impaired liver function were encountered. Adverse reactions on the standard ethionamide, pyrazinamide, and cycloserine regimen were frequent and some were serious.     

Adapting test timing to the sleep-wake schedule: effects on diurnal neurobehavioral performance changes in young evening and older morning chronotypes

The synchrony effect refers to the beneficial impact of temporal matching between the timing of cognitive task administration and preferred time-of-day for diurnal activity. Aging is often associated with an advance in sleep-wake timing and concomitant optimal performance levels in the morning. In contrast, young adults often perform better in the evening hours. So far, the synchrony effect has been tested at fixed clock times, neglecting the individual's sleep-wake schedule and thus introducing confounds, such as differences in accumulated sleep pressure or circadian phase, which may exacerbate synchrony effects. To probe this hypothesis, the authors tested older morning and young evening chronotypes with a psychomotor vigilance and a Stroop paradigm once at fixed morning and evening hours and once adapting testing time to their preferred sleep-wake schedule in a within-subject design. The authors observe a persistence of synchrony effects for overall median reaction times during a psychomotor vigilance task, even when testing time is adapted to the specific individual's sleep-wake schedule. However, data analysis also indicates that time-of-day modulations are weakened under those conditions for incongruent trials on Stroop performance and the slowest reaction times on the psychomotor vigilance task. The latter result suggests that the classically observed synchrony effect may be partially mediated by a series of parameters, such as differences in socio-professional timing constraints, the amount of accumulated sleep need, or circadian phase, all leading to differential arousal levels at testing.     

Influence of buprenorphine analgesia on post-operative recovery in two strains of rats.

The objective of this study was to establish an effective post-operative analgesic regimen for Sprague-Dawley (SD) and Dark Agouti (DA) rats. Buprenorphine (0.01 or 0.05 mg/kg), a partial mu opioid agonist, was administered subcutaneously immediately on completion of a standardized surgical procedure, involving anaesthesia, laparotomy and visceral manipulation. Two of the four treatment groups and the saline control group received a second injection 9 h later. Behavioural observations by three independent observers provided no information in assessing pain in this model. All rats lost weight, consumed less food and water after surgery. On the first day, both SD and DA rats receiving buprenorphine lost less weight than untreated control groups. Using weight loss as an efficacy criterion, low-dose buprenorphine, given once or twice, provided effective analgesia in SD rats. A higher single dose provided no additional benefit and a second dose was detrimental, reducing body weight and food intake. In DA rats, the high dose, given twice, appeared to be more effective than the lower dose. All DA cage cohorts consumed < 10% pre-operative food despite buprenorphine treatment, suggesting a higher dosage may be necessary. However, all SD and 80% DA rats who received no buprenorphine gained body weight on the second day, whereas most of the buprenorphine-treated rats continued to lose weight for another 2 days, despite increased food consumption by both strains. Buprenorphine may adversely affect intestinal function over a number of days due to its enterohepatic circulation; this effect may be more severe in DA rats. Adverse metabolic effects of buprenorphine and other opioids may preclude their use in the future if it can be shown that non-steroidal anti-inflammatory drugs (NSAIDs) provide equally effective analgesia.     

Relief of pain by infusion of morphine after operation: does tolerance develop?

To see whether continuous intravenous infusion of opiates provides more effective postoperative relief of pain than conventional intramuscular injection these regimens were compared in a prospective double blind trial. Thirty patients undergoing elective cholecystectomy were allocated randomly to receive an infusion of morphine or an infusion of placebo (control group) for 24 hours. Both groups were allowed supplementary morphine boluses as requested. During the first 48 hours after operation the degree of pain was almost identical between the groups. Surprisingly, the group that was given the infusion of morphine received as much supplementary morphine as the control group during the first 24 hours and appreciably more during the 24 hours after the infusion had been withdrawn. Nausea and vomiting were more prevalent among the patients given the infusion of morphine. These results suggest that continuous infusion of morphine may be an inferior regimen to intermittent bolus administration in the relief of postoperative pain. This may be explained by the development of tolerance in patients who received the infusion of morphine.     

Levamisole in postoperative adjuvant immunochemotherapy for gastric cancer

Summary The usefulness of LMS in postoperative immunochemotherapy of gastric cancer was investigated. In compliance with the protocol, MMC was given at a dose of 20 mg on the day of gastrectomy, and an additional 10 mg on the next day IV. The patients receiving 600 mg Tegafur daily were then divided into two groups according to whether LMS was also given or not. LMS was administered for 3 days before the operation in a daily dose of 150 mg and for 1 year or more after operation according to a schedule of 3 days' administration followed by an 11-day interval. The 2-year follow-up demonstrated that in stage III patients, the LMS (+) regimen was superior to the LMS (–) regimen, since the former prolonged the relapse-free interval significantly. The survival rate for stage III disease was also significantly higher in the LMS (+) than in the LMS (–) group. There was no significant difference in the incidence of subjective or objective side-effects between two groups. The incidence of agranulocytosis was comparable in the two groups.Gastrointestinal Cancer Research Group, Japan Levamisole Research AssociationChairmen of the Gastrointestinal Cancer Research Group, Japan LMS Research AssociationController of the Gastrointestinal Cancer Research Group, Japan LMS Research AssociationMembers of the Data Collection and Analysis SubcommitteeThis study was carried out by the Gastrointestinal Cancer Research Group, Japan LMS Research Association (directed by Prof. Kiyoshi Inokuchi, Dept. of Surgery, Kyushu University and Prof. Eiro Tsubura, Dept. of Internal Medicine, Tokushima University). The results were presented in part at the 19th General Meeting of the Japanese Society for Gastroenterological Surgery in February, 1982     

Methotrexate Hepatotoxicity in Psoriasis—Comparison of Different Dose Regimens

Liver histological appearances were studied in 44 patients treated for psoriasis with methotrexate. Cirrhosis was found in six and hepatic fibrosis in another 11. Of these 17 patients 12 had received methotrexate by a regimen of frequent small dosage, two had been treated by a regimen of intermittent large dosage, while three had been treated at different times by both methods. The prevalence of cirrhosis and fibrosis was significantly greater in patients treated by frequent small dosage than in those treated by intermittent large dosage, though the dose level (mg/month) was similar in both groups. Hepatic fibrosis, sometimes preceding cirrhosis, seems to develop invariably if treatment with small frequent dosage is sufficiently prolonged. In the few circumstances in which this drug is indicated for psoriasis intermittent large dosage is the treatment regimen of choice.     

CORTISONE IN TREATMENT OF BRONCHIAL ASTHMA

Twenty patients with intractable asthma were treated with cortisone on various dosage schedules. Results indicated that a rapid improvement in the asthmatic state may be expected in four to five days with high level dosage of the hormone—usually a total dose exceeding 200 mg. per day at the beginning. If treatment is discontinued after a week, relapse usually will occur within a period of eight days. If small doses are given two or three times weekly, following initial response, relapse may not occur for 20 or 30 days. The interspersed administration of ACTH during an attempt to discontinue cortisone apparently was of no value. It therefore appears that cortisone control of intractable asthma is dependent on large dosage until clinical improvement is obtained, then approximately 100 mg. two or three times a week for maintenance of a reasonable state of health.     

WR2721 protection of bone marrow in 131I-labeled antibody therapy.

The use of phosphorothioate radioprotectors such as WR2721 in radioimmunotherapy is attractive because radiation delivered to tumors is usually separated in time from that delivered to the marrow and most normal organs, making protection of tumors of little consequence. However, to be effective radioprotectors must provide continuous protection against radiation of varying dose rates. To evaluate the potential of radioprotectors in radioimmunotherapy we treated normal mice with graded amounts of WR2721 in combination with an LD90/30 (26 MBq) of 131I-labeled antibody. A regimen of 15 doses of WR2721, 200 mg/kg prior to antibody infusion followed by 100 mg/kg ip every 4 h for a total of 72 h, was the maximum tolerated dosage schedule. With this schedule, treatment with radioprotectors failed to prolong survival or delay myelosuppression from the 131I-labeled antibody. In contrast, this regimen of radioprotector provided partial protection from a single treatment of 10 Gy total-body radiation given at 0.2 Gy/min. Protection 30 min after the final dose of WR2721 was greater than 3 h after the 14th dose (60 min prior to the final dose). These results suggest that the potential role of phosphorothioate radioprotectors in a radioimmunotherapy is limited because of the difficulty in achieving continuous protection with nontoxic amounts of drug and possibly because of a limited effect on low-dose-rate radiation.     

The role of the peritoneal cavity in successful treatment of a murine lymphoma with chemotherapy and non-specific immunostimulation

Summary The influence of the route of administration and treatment schedule of a yeast immunoadjuvant, Candida albicans (CA) on the degree of success achieved with an immunochemotherapy regimen in a virus-induced murine lymphoma has been evaluated. To this end, histocompatible CD2F1 mice received IP or IV inoculations of LSTRA lymphoma cells and were subjected to various treatments with inactivated CA and bis, 1, chloroethyl nitrosourea (BCNU).The results showed that CA may significantly increase the antitumor efficiency of BCNU when (a) the tumor is inoculated IP and not IV; (b) CA is administered before (on day –14) and after (on days +1 and/or day +8) LSTRA challenge; (c) CA is given IP as a post-tumor treatment.To ascertain whether the immunoadjuvant effect was anatomically restricted to the peritoneal cavity (PC), spreading of IP injected lymphoma was studied by means of LSTRA cells labeled with 3–5iodo-deoxyuridine ¹²⁵I (¹²⁵IUdR) and tumor bioassay in spleen, lung, kidney, liver, and PC of recipient mice. The results showed that IP tumor challenge led to early (1 h) generalized neoplasia in both untreated and CA-pretreated hosts.Therefore, the combined antitumor effects of chemotherapy and CA are not restricted to the PC but rather the result of systemic immunity. In conclusion, in our system the PC seems to be a preferential site for eliciting generalized antilymphoma host responses markedly amplified by selected schedules of immunoadjuvant administration.     

Chronosynergistic effects of lighting schedule-shift and cefodizime on plasmacytoma growth and host survival time

Lighting regimen shifts can modify the effects of cefodizime, for the purpose of a chronoimmunomodulation. Two experiments were carried out on male and female LOU rats inoculated subcutaneously with plasmacytoma cells. Some rats were kept on their original LD12:12 regimen, whereas others, after tumor implantation, were subjected every second day to 6-h shifts, instituted, in alternation, as advance or delay. Daily treatment with cefodizime or placebo started when, overall, about 50% of the animals had developed a palpable tumor. A subgroup of animals contributed daily smears for the determination of the estrus cycle and further provided core temperature and activity data by telemetry. In Experiment I, the repeated shifting of the LD regimen was associated with survival time prolongation (p less than 0.05), irrespective of drug administration. Moreover, in those (female) rats repeatedly exposed to shifts of the lighting schedule, cefodizime was found to prolong survival time (p less than 0.05). The effects of cefodizime vs placebo on survival time were found to be circadian stage-dependent. In Experiment II, differing from Experiment I in the initial conditions before the institution of the shifts, cefodizime treatment was associated with a prolongation of survival time of the female rats kept on a fixed LD12:12 regimen. Both male and female rats again showed a circadian stage-dependence of the cefodizime effect. These results suggest that interactions between synchronizers of rhythms (such as shifts of the lighting regimen, the latter simulating the daily routine) and immunomodulating agents such as cefodizime may be optimized to improve treatment strategies against cancer and other diseases.     

Control of severe pain with sustained-release morphine tablets v. oral morphine solution.

Recently a sustained-release morphine sulfate tablet (MS Contin [MSC]) was introduced in Canada. In a randomized double-blind crossover trial we compared MSC given every 12 hours with a morphine sulfate solution (MSS) given every 4 hours to 17 patients suffering from chronic severe pain. After titration of the morphine dosage to optimize the analgesic effect, each patient received 10 days of therapy with either MSC or MSS, then 10 days of therapy with an equal daily dose of the other formulation. Both preparations provided effective pain control, with minimal side effects. There was no significant difference between MSC and MSS in pain scores on a visual analogue scale (VAS), severity scores for tiredness and nausea, amount of supplemental morphine needed for break-through pain or patient preference. The plasma morphine concentrations tended to be greater during treatment with MSC. The study had an 89% probability of detecting a clinically significant difference in VAS pain scores. We conclude that an individualized, twice-daily regimen of MSC is as effective as MSS given every 4 hours for control of severe pain. The twice-daily regimen has several advantages: it provides for an uninterrupted night''s sleep, it is substantially more convenient than the six doses per day required with MSS, and it should help reduce both medication errors and noncompliance.     

Potent CYP17 inhibitors: improved syntheses, pharmacokinetics and anti-tumor activity in the LNCaP human prostate cancer model

A facile preparation of azolyl steroids, VN/85-1 and VN/87-1 (potent inhibitors of CYP17) has been developed. This process without tedious chromatographic separations improved the overall yields from 55 and 45% to 70 and 65% for VN/85-1 and VN/87-1, respectively. Pharmacokinetic studies of VN/85-1 were conducted in male SCID mice. Following subcutaneous (s.c.) administration of 100mg/kg of VN/85-1, peak plasma level of 16.73 microg/ml occurred after 45 min, and the compound was cleared rapidly with a t(1/2) of 52.34 min. The bioavailability of VN/85-1 after s.c. administration was 83.0%. VN/85-1 was also rapidly metabolized to the corresponding 3-oxo-4-ene analog, 17-(1H-imidazol-1-yl)androsta-4,16-diene-3-one (VN/108-1). In our attempt to optimize the anti-tumor efficacy of these two CYP17 inhibitors, we studied their anti-tumor efficacies in male SCID mice bearing LNCaP tumor xenografts, utilizing various drug doses and drug scheduling. Three times a day dose regimen (3 x dose regimen) of VN/85-1 was more effective than a once daily dose. In contrast, 3 x dose regimen doses of VN/87-1 were less effective than the once daily dose. However, at their effective dosage regimes, VN/85-1 and VN/87-1 were each as effective as castration and more effective than finasteride or casodex, an anti-androgen used for prostate cancer (PC) therapy. For all of the treatments, there was a strong correlation between the tumor volumes and other associated parameters, such as, tumor weights, and serum testosterone (T) and PSA levels. These results indicate that VN/85-1 or VN/87-1 may be useful in the treatment of hormone-dependent prostate cancer.     

Antiangiogenic effect of low-dose cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinoma

Angiogenesis is now known to play an important role in both growth and metastasis of lung cancer. The intense interest in angiogenesis has led to a re-examination of the activity of many established cytotoxic agents. Some results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses increases the antiangiogenic activity of the drugs. In the present study, we investigated the efficacy of the combination of low-dose cyclophosphamide and ginsenoside Rg3 for the antiangiogenic effect on Lewis lung carcinoma. Our findings suggest that continuous low-dose regimen of CTX increases the efficacy of targeting the tumor microvasculature, which produces therapeutic activity with decreased toxicity. The effects of the low-dose schedule of CTX may be further enhanced by concurrent administration of angiogenic inhibitor ginsenoside Rg3. As an antiangiogenic method, this regimen has the advantage of a reduced susceptibility to drug resistance mechanisms and improved animal survival.     

Corticosteroid plus β<Subscript>2</Subscript>-agonist in a single inhaler as reliever therapy in intermittent and mild asthma: a proof-of-concept systematic review and meta-analysis

Background

Current guidelines recommend a single inhaler maintenance and reliever therapy (SMART) regimen for moderate to severe asthma. However, evidence for the inhaled corticosteroid plus fast-onset-acting β₂-agonist (ICS/FABA) as reliever therapy in management of intermittent and mild asthma patients is lacking.

Objective

To systematically explore efficacy and safety of the proof-of-concept of the ICS plus FABA regimen in a single inhaler as reliever therapy across children and adults with intermittent and mild persistent asthma.

Methods

We searched online bibliographic databases for randomized controlled trials (RCTs) involving the as-needed use of ICS/FABA as monotherapy in intermittent or mild asthma patients. The primary outcomes were exacerbations and the hazard ratio (HR) of the time to first exacerbation.

Results

Six RCTs (n?=?1300) met the inclusion criteria. Compared with the as-needed FABA regimen, the as-needed use of ICS/FABA as monotherapy statistically reduced exacerbations (RR?=?0.56, P?=?0.001). Compared with regular ICS regimen, the as-needed ICS/FABA therapy had slightly higher risk of exacerbations (RR?=?1.39, P?=?0.011). The HR for time to first exacerbations in the ICS/FABA regimen was significant lower when compared with FABA regimen (HR?=?0.52, P?=?0.002) but had no difference when compared with ICS regimen (HR?=?1.30, P?=?0.286). The corticosteroid exposure in the daily ICS regimen was 2- to 5-fold compared with as-needed use of ICS/FABA regimen.

Conclusions

Our analysis shows that the ICS/FABA as a symptom-driven therapy may be a promising alternative regimen for the patients with intermittent or mild asthma, but it needs further real-world RCTs to confirm these findings.