Single-dose tolerance to the behavioral effects of dibutyryl cyclic AMP in mice

The behavioral effects of varying doses of intraperitoneally administered dibutyryl cyclic AMP, cyclic AMP, adenosine, 5-AMP, and butyric acid were studied in male ICR mice. Behavioral parameters 25 min following treatment included measurement of spontaneous locomotor activity (SLMA) and rotarod performance, the latter providing an indication of neuromuscular coordination. Dibutyryl cyclic AMP produced a dose-related inhibition of SLMA with the largest dose, 75 mg/kg, decreasing activity by 89%. Adenosine and 5-AMP produced maximal inhibition of approximately 50–80% of SLMA at doses ranging from 75–250 mg/kg, while cyclic AMP decreased SLMA by 58% at only the highest dose, 250 mg/kg. Butyric acid failed to produce alterations in SLMA at doses ranging from 25–250 mg/kg. No compound altered neuromuscular coordination. Single-dose tolerance to the inhibitory effect of dibutyryl cyclic AMP on SLMA developed within 3 h and lasted at least 7 days. Adenosine failed to produce tolerance while cyclic AMP and 5-AMP exhibited only a slightly reduced effect following a second injection at intervals of 4 and 24 h. These results suggest that exogenous administration of dibutyryl cyclic AMP and its metabolites exert centrally mediated behavioral effects with selective development of single-dose tolerance to the dibutyryl derivative.     

In vivo toxicological evaluation of polymeric nanocapsules after intradermal administration

Polymeric nanocarriers have shown great promise as delivery systems. An alternative strategy has been to explore new delivery routes, such as intradermal (i.d.), that can be used for vaccines and patch-based drug delivery. Despite their many advantages, there are few toxicity studies, especially in vivo. We report a safety assessment of biodegradable poly(ɛ-caprolactone) lipid-core nanocapsules (LNC) with a mean size of 245 ± 10 nm following single and repeated intradermal injections to Wistar rats. Suspensions were prepared by interfacial deposition of polymer. The animals (n = 6/group) received a single-dose of saline solution (1.2 ml/kg) or LNC (7.2 × 10¹² LNC/kg), or repeated-doses of two controls, saline solution or Tween 80 (0.9 ml/kg), or three different concentrations of LNC (1.8, 3.6, and 5.4 × 10¹² LNC/kg) for 28 consecutive days. Clinical and physiological signs and mortality were observed. Samples of urine, blood, and tissue were used to perform toxicological evaluation. There were no clinical signs of toxicity or mortality, but there was a slight decrease in the relative body weights in the Tween 80–treated group (p < 0.01) after repeated administration. No histopathological alterations were observed in tissues or significant changes in blood and urinary biomarkers for tissue damage. Mild alterations in white blood cells count with increases in granulocytes in the Tween-80 group (p < 0.05) were found. Genotoxicity was evaluated through the comet assay, and no statistical difference was observed among the groups. Therefore, we conclude that, under the conditions of these experiments, biodegradable LNC did not present appreciable toxicity after 28 consecutive days of intradermal administration and is promising for its future application in vaccines and patch-based devices for enhancing the delivery of drugs.     

Inactivated influenza virions are a flexible vaccine platform for eliciting protective antibody responses against neuraminidase

Most seasonal influenza vaccines are produced using hemagglutinin (HA) surface antigens from inactivated virions. However, virions are thought to be a suboptimal source for the less abundant neuraminidase (NA) surface antigen, which is also protective against severe disease. Here, we demonstrate that inactivated influenza virions are compatible with two modern approaches for improving protective antibody responses against NA. Using a DBA/2J mouse model, we show that the strong infection-induced NA inhibitory (NAI) antibody responses are only achieved by high dose immunizations of inactivated virions, likely due to the low viral NA content. Based on this observation, we first produced virions with higher NA content by using reverse genetics to exchange the viral internal gene segments. Single immunizations with these inactivated virions showed enhanced NAI antibody responses and improved NA-based protection from a lethal viral challenge while also allowing for the development of natural immunity to the heterotypic challenge virus HA. Second, we combined inactivated virions with recombinant NA protein antigens. These combination vaccines increased NA-based protection following viral challenge and elicited stronger antibody responses against NA than either component alone, especially when the NAs possessed similar antigenicity. Together, these results indicate that inactivated virions are a flexible platform that can be easily combined with protein-based vaccines to improve protective antibody responses against influenza antigens.     

Efficacy and safety of single-dose mizoribine for patients with rheumatoid arthritis: results at 6 months after switching from a multiple-dose regimen without a change in total daily dose

Abstract

To determine the efficacy and safety of single-dose mizoribine (MZR) for patients with rheumatoid arthritis (RA), a 6-month, single-arm, open-label, prospective observation study was performed. In patients who had been taking MZR at 100–150 mg/day in 2–3 divided portions continuously for at least 3 months, and who had shown a lack of clinical response, or escape (defined as a lack of response at the time of switching, even if some form of response had been shown before that), multiple-dose administration was switched to single-dose administration without changing the total daily dose. Efficacy was assessed in terms of the disease activity score, using the 28-joint count and erythrocyte sedimentation rate (DAS 28-ESR). Of the 34 enrolled patients, 28 met all the eligibility criteria and were assessed for efficacy, and finally 26 patients were able to receive the single-dose regimen throughout the full 6 months. The DAS28-ESR showed a significant decrease from 2 months after switching, and 46.4% of the 28 patients finally achieved a good or moderate response (3 and 10 patients, respectively). With regard to safety, no serious adverse events were observed. In conclusion, the administration of MZR at 100 or 150 mg in a single dose is thought to be a useful alternative form of MZR therapy.     

Single-dose kinetics of the neuroleptic drug perazine in psychotic patients

Eight male and two female unmedicated psychotic patients received 100 mg perazine orally and seven blood samples were taken within 25 h. Plasma levels of perazine and its demethylated metabolite were analyzed by HPLC with electrochemical detection. They exhibited large interindividual variations, with maximal concentrations as well as AUC values of perazine differing more than 10-fold. From the decay of plasma levels during the last 12–18 h half-lives were estimated to be between 7.5 and 16 h; they did not correlate with AUC. There was a significant positive correlation between AUC and age. Desmethylperazine was consistently present at lower concentrations than the parent drug during the first 12 h.     

Efficacy and safety of single therapeutic and supratherapeutic doses of indacaterol versus salmeterol and salbutamol in patients with asthma

ABSTRACT

Objective: This study compared the bronchodilator efficacy and safety of indacaterol with placebo, salbutamol and salmeterol, in patients with persistent asthma, at single therapeutic and supratherapeutic doses.

Research design and methods: This was a randomised, open-label crossover study in adult subjects with asthma (forced expiratory volume in 1 second [FEV₁] ≥?60% predicted). In part A, patients (n = 20) received single doses of indacaterol 200?µg, salbutamol 200?µg, salmeterol 50?µg and placebo. In part B, patients (n = 19) received single doses of indacaterol 1000?µg, salbutamol 1000?µg, salmeterol 250?µg and placebo.

Main outcomes measures; Results: For the primary endpoint, FEV₁ area under the effect curve during 0–24?h, indacaterol 200?µg was statistically superior to placebo and salbutamol. Indacaterol 200?µg FEV₁ was higher than placebo (5?min to 24?h), salbutamol 200?µg (4–24?h), and salmeterol 50?µg (5 and 15?min and 22 and 24?h). Few adverse events were reported; all were mild or moderate in severity. Initial changes were observed in glucose, potassium, heart rate and QTc interval, but all values remained within normal ranges. Values matched placebo levels after a shorter time for indacaterol 1000?µg than for salmeterol 250?µg.

Conclusions: In this single-dose, open-label study, indacaterol 200?µg provided effective 24‐h bronchodilation, with a longer duration than salmeterol 50?µg and a good overall safety profile. The sustained bronchodilation of indacaterol 1000?µg was not associated with sustained systemic adverse effects.     

Preclinical safety evaluation of IFNalpha2a-NGR

IFNalpha2a-NGR is an antitumor agent of bacterial origin. The report presents the preclinical toxicity studies with IFNalpha2a-NGR in mice, rats and monkeys. The single-dose toxicity study showed no effect on general signs, body weight, food consumption, ophthalmology, hematology and clinical chemistry and necropsy analysis. In repeated-dose toxicity studies, increase in HB was noted both in rat and monkey, showed that IFNalpha2a-NGR may not cause the suppression of hematopoiesis. Decrease in AST, A/G, GLU, T-Bil in rat and AST, TP, GLO in monkey were noted, accompanied by increase in TP and GLB in rat and BUN in monkey. All the clinical chemistry changes were mild, reversible and considered to be incidental, since no related abnormal parameters or results were found. Increase in spleen and thymus organ-to-body weight ratios and decrease in menses were mild, reversible and likely related to pharmacology activity of IFNalpha2a. Ames, chromosomal aberration and bone marrow micronulecus test were conducted and the results were negative. The degree of irritation caused by various concentration of IFNalpha2a-NGR was determined to be the same as that induced by normal saline. In conclusion, preclinical safety studies that IFNalpha2a-NGR was well tolerated at pharmacologically active doses in mice, rats and monkeys.     

吗啡在产妇自控硬膜外镇痛与单次硬膜外镇痛对剖宫产产妇子宫缩复的影响

目的　探讨单次和持续少量吗啡注入硬膜外腔对剖宫产术后产妇子宫缩复、产后出血量的影响。方法　 2 44例孕产妇随机分为两组各 12 2例 ,Ⅰ组术毕单次量吗啡、甲氧氯普胺、新斯的明、生理盐水稀释后注入硬膜外腔 ,Ⅱ组术毕与硬膜外导管连接设置好的PCEA装置。结果　子宫缩复率分别为 77 0 4%、90 98% (P <0 0 5 )。两组出血量≥ 5 0 0ml者分别占 17 2 1%和 3 2 7%。催产素追加率分别为 13 93%和 1 6 3% ,最大追加剂量 6 0IU～ 80IU。组间比较P <0 0 1,差异显著。结论　单次注射吗啡 ,抑制子宫收缩 ,增加产后出血量及催产素追加率。PCEA为持续给药 ,使吗啡和局麻药协同 ,降低两药副反应 ,符合药代动力学给药规律和个体化用药原则 ,对子宫缩复无影响     

儿童单纯性尿路感染两种治疗疗法的比较

目的 分析单剂抗菌治疗与10d疗法对儿童单纯性尿路感染(UTI)的治疗效果,为儿童单纯性尿路感染的临床治疗提供参考.方法 对医院2010年6月-2012年6月收治的117例单纯性尿路感染患儿的临床资料进行回顾性分析,根据治疗方法将其分为单剂治疗组52例和10 d疗法组65例,在治疗4、11d两个时间点观察治疗结果.结果 单剂治疗组中,治疗4d后尿细菌培养阳性患者38例,阳性率73.08％;10 d疗法组中,治疗4d尿细菌培养阳性患儿47例,阳性率72.31％,两组治疗效果差异无统计学意义；治疗11 d后,单剂治疗组与10 d疗法组尿细菌培养阳性率分别为69.23％、58.45％,两组治疗效果比较,差异有统计学意义(P＜0.05)；单剂治疗组与10 d疗法组药物不良反应发生率及复发率分别为7.69％、15.38％及15.38％、3.08％.结论 对于儿童尿路感染的治疗,10 d疗法治疗效率较高,复发率低,适用儿童尿路感染患儿或是选用单剂抗菌治疗无效的儿童尿路感染患儿临床选用.