Behavioural effects of long-term administration of fencamfamine: neurochemical implications

The repeated effects of fencamfamine administration (10.0 mg/kg, i.p. single dose) were studied in male rats. Fencamfamine treatment increased stereotyped sniffing and decreased rearing behaviour. These changes occurred after 8 days of treatment and remained for 25 days. The fencamfamine repeated administration enhanced the homovanillic acid (HVA) level in the tubercullum olfactorium while the same treatment decreased the dihydroxyphenilacetic acid (DOPAC) and HVA striatal levels. The data suggest that long-term fencamfamine administration develops changes in the activity of parts of the DA systems which might be responsible for tolerance or sensitization to the effects of fencamfamine.     

The bed nucleus of stria terminalis and the amygdala as targets of antenatal glucocorticoids: implications for fear and anxiety responses

Rationale  

Several human and experimental studies have shown that early life adverse events can shape physical and mental health in adulthood. Stress or elevated levels of glucocorticoids (GCs) during critical periods of development seem to contribute for the appearance of neurospyschiatric conditions such as anxiety and depression, albeit the underlying mechanisms remain to be fully elucidated.     

Neonatal outcomes after oral administration of antenatal corticosteroid: A case report

The use of antenatal corticosteroids is associated with reduction in morbidity and mortality rates in preterm delivery. A 34 year-old pregnant woman, gravida 2 para1, was planned for elective cesarean section at 36 weeks of gestation as ultrasound study showed intrauterine growth retardation. She has idiopathic thrombocytopenia and anemia, with suspected hypoplastic anemia. Due to mother’s low platelet count, antenatal intramuscular corticosteroids injection was avoided. Instead, oral dexamethasone was given for fetal lung maturity. Baby’s Apgar score at 1-min and 5-min was 9 and 10, respectively. The baby girl did not develop respiratory distress syndrome. She had mild transient tachypnea of newborn that needed only mild respiratory support with nasal cannula in room air.     

风湿免疫科长期口服糖皮质激素患者的知信行现状及药学监护

目的： 分析风湿免疫科长期口服糖皮质激素患者的知信行（knowledge-attitude-practice，KAP）现状及其影响因素；考察药学监护对KAP的影响，促进糖皮质激素在临床的合理应用。方法： 选取某三甲医院风湿免疫科门诊长期口服糖皮质激素患者246例，随机分为干预组和对照组（1：1），入组时采用一般资料调查表、自行设计的疾病与用药知识问卷、汉化的患者服药信念特异性量表（Brief medication questionnaire，BMQ）、Morisky药物依从性量表（Morisky medication adherence scale，MMAS-8）分析KAP现状及其影响因素，临床药师对干预组患者薄弱方面进行针对性干预，对照组进行常规教育。6个月后比较两组患者的KAP维度改善情况、不良反应发生率和疾病控制情况。结果： 风湿免疫科长期口服糖皮质激素的患者知识得分（3.08±3.80）分，信念得分（0.96±2.95）分，行为得分（5.40±1.81）分，且自我管理知识、信念、行为三者之间均相关（P<0.01）。年龄和文化程度是影响患者自我管理知识的主要因素（P<0.01），病程是影响患者自我管理信念、行为得分的主要因素（P<0.01）。6个月后，干预组的KAP维度得分均较对照组有显著提高（P<0.05）；干预组的不良反应发生率低于对照组（52.03 %vs 57.72%）、疾病控制情况优于对照组（61.78 %vs 54.47%），但无统计学差异（P>0.05）。结论： 风湿免疫科长期口服糖皮质激素的患者自我管理KAP水平有待加强，临床药师针对其影响因素进行药学监护可显著提高其KAP水平，改善疾病控制水平。     

Intratracheal administration of glucocorticoids using surfactant as a vehicle

1. Glucocorticoids are an effective treatment in the amelioration of chronic lung disease in neonates. However, systemic administration of glucocorticoids to neonates is associated with significant side-effects that preclude them as an early intervention to prevent onset of the condition. Conversely, local intratracheal administration of glucocorticoids may prevent inflammatory insult to the lungs without the development of systemic side-effects. We therefore investigated whether local intratracheal delivery of corticosteroids could be facilitated using surfactant as a vehicle. 2. Addition of dexamethasone to either diluted or commercial artificial surfactant, Survanta (Abbott Industries, Sydney, NSW, Australia), did not alter the surface properties of the surfactant. 3. After intratracheal instillation to rats, radiolabelled dexamethasone in Survanta was well distributed throughout all four lobes of the lungs. A concentration gradient of the steroid was observed between the root and the peripheral sections of all lobes. 4. Our results suggest that surfactant is an effective vehicle for intratracheal delivery of glucocorticoids. Moreover, we propose that prophylactic intratracheal administration of glucocorticoids administered shortly after birth may prevent inflammatory insult to the lungs and thereby reduce the likelihood of chronic lung disease developing.     

Fenfluramine long-term administration and brain serotonin

Long-term administration of fenfluramine induced a decrease of brain 5-HT to the same extent as did an acute dose. 48 h after drug withdrawal, the brain serotonin level returned to the control value. The present study provides evidence to suggest that a degenerative lesion of 5-HT neurons is not involved in fenfluramine activity.     

Betamethasone pharmacokinetics after two prodrug formulations in sheep: implications for antenatal corticosteroid use.

Maternal administration of betamethasone to enhance fetal lung maturation for women who threaten preterm labor is common clinical practice. However, recommendations regarding the choice of betamethasone formulations for perinatal use are vague. The disposition of betamethasone from two commonly used antenatal formulations is poorly understood. We therefore designed a study to capture the true pharmacokinetic profiles of betamethasone from these fast acting and dual-release formulations. Betamethasone in sheep plasma was measured by a newly designed, highly sensitive liquid chromatography/tandem mass spectrometry assay after intramuscular injection (n = 4) of 0.25 mg/kg betamethasone phosphate and 0.5 mg/kg betamethasone phosphate/acetate formulations. Compartmental modeling was performed using the ADAPT II program. Betamethasone pharmacokinetics could be captured for 24 h for the phosphate and for 5 days for the phosphate/acetate formulations. The phosphate formulation profile had the appearance of a traditional Bateman function with a terminal half-life of 4 h, whereas the phosphate/acetate formulation produced a biexponential decline with a terminal half-life of 14 h. The latter is much longer than is commonly reported and has been missed in the literature due to assay limitations. Extrapolations to humans indicate that although both formulations might have similar therapeutic indices, the dual formulation might be associated with a lower safety profile. In light of this newly identified long terminal half-life for the betamethasone dual formulation, dosing practices for betamethasone in pregnancy need to be reassessed.     

长期应用APC导致药物依赖

患者女,68岁。10年前因体质较差,易患“感冒”,常服APC治疗。最初在有“感冒”症状时服用1片,3次/d或2次/d,不规律。后因“感冒”较频繁,反复出现鼻塞、头痛、无力、发冷(体温正常)等症状,十几天即“感冒”1次。因经济所限,未查过病因,每次均用APC治疗。用药后症状很快减轻或消失,自认为有疗效。1年多后,用药剂量逐渐增加,以至无感冒症状时也要服用,每天必服1～2片,否则即感全身不适,影响劳动。几年后增至2～3片/d。至今已服用APC 10余年,患者除有如前的“感冒”症状外,无其他器质性疾病。本例患者最初因患“感冒”而服用APC,由于服药…     

Effects of chronic antenatal and postnatal administration of narcotics on naloxone-induced anorexia in preweanling rats

Previous studies have reported age-related changes in opiate receptors and in their response to narcotics during the process of normal growth of the brain. By inducing alterations in this developmental sequence, the present study attempted to provide correlates of the opiate receptor system with naloxone-induced anorexia. Offspring of mothers treated with morphine (7.5 mg/kg twice daily, s.c.) or saline during pregnancy, and infants from untreated mothers given morphine (5 mg/kg), naltrexone (10 mg/kg) or saline subcutaneously on postnatal days 1-5, were tested at days 10, 12 and 14 for deprivation-induced milk consumption following an acute dose of naloxone (1 or 5 mg/kg, i.p.). Naloxone reduced the food intake of 10- and 12-day old infants chronically treated with morphine postnatally. At age 14, naloxone reduced the food consumed by all the pretreatment groups, and pretreatment with morphine altered the dose-response curves for feeding modulation induced by naloxone. Naloxone had no effect on the food consumed by 10- or 12-day old offspring of mothers treated with morphine or saline, or on those age-groups that received naltrexone chronically or saline pretreatments postnatally. The observed changes occurred in the absence of gross malformations, drug-withdrawal symptoms and differences in activity. These results demonstrate that opiate receptors may participate in feeding.     

Central cholinergic receptor supersensitivity after long-term atropine administration

Rats were treated with a single dose of atropine (AT) at 5 mg/kg, or every day for 14 or 31 days with the same dose of AT, 3 h after the single dose and 24 h after the last dose of chronically administered AT, 10 g of ACh was injected intracerebroventricularly, and two tests were used to examine the behavior of the animals. The tremorigenic effect of oxotremorine was also measured in mice treated with 10 mg/kg of AT for 1 month. It was shown that a single dose of AT antagonized ACh-induced behavior. The long-term treatment with AT enhanced the depressive behavior of ACh in rats and the tremorigenic effect of oxotremorine in mice. The results suggest that long-term blockade of central cholinergic receptors induces their hypersensitivity.     

Effects of short-term and long-term theobromine administration to male dogs

Thirty-three dogs were each given a single oral dose of theobromine which ranged from 15 to 1000 mg/kg. Three dogs died, one each given theobromine 300, 500, and 1000 mg/kg. Ten dogs were continued on theobromine (75 to 150 mg/kg/day) for periods of 21 or 28 days; seven died and the others were killed with pentobarbital sodium. None had thymic or testicular atrophy, as has been reported in rats, but a degenerative, fibrotic cardiomyopathy limited to the right atrial appendage occurred in 6 of these 10 dogs. Theobromine was given to two groups of dogs for 1 year in doses of 25 and 50 mg/kg/day, respectively. Other dogs were given theobromine 25 or 50 mg/kg/day for 4 months and the dose was then increased to 100 or 150 mg/kg/day for 8 months. Three dogs (one each at 50, 100, and 150 mg/kg/day) died during the course of the year. The right atrial appendage of one, the dog at 100 mg/kg/day, was obliterated by fibrosis, but no heart lesions were found in the other two dogs. At the end of 1 year all surviving dogs including controls were killed and subjected to complete necropsies. As in the short-term study, the only gross and microscopic change associated with theobromine was a fibrotic lesion in the right atrium of the heart, in three of five dogs given theobromine 150 mg/kg/day and in two of the four dogs given 100 mg/kg/day. Plasma theobromine concentrations were determined during the last 2 months of the year. While right atrial cardiomyopathy occurred in dogs given theobromine 100 or 150 mg/kg/day, a clear relationship between dose, plasma concentration, frequency, and severity of the lesion could not be determined.     

Pharmacodynamic effects of bezafibrate and niacin combination: implications of the mode of administration

The goal of this investigation was to optimize antilipid therapy by utilizing the combined activity of two lipid-lowering agents, niacin and bezafibrate, and improve their efficacy by targeting them to their presumed presystemic site(s) of action. Thus, continuous duodenal (IGI) administration of the drug combination should augment their efficacy in comparison with intermittent oral treatment. Three hyperlipidemic rat models were studied: Models A and B were based on cholesterol-enriched diets and Model C was based on on acute hyperlipidemia induced by triton injection. Continuous IGI administration of the drug combination [bezafibrate, 30mg/kg/day, and niacin, 40 mg/kg/day for 3 days (Models A and B) or for 18 h (Model C)] produced significantly greater lowering of total cholesterol and triglycerides and elevation of high-density lipoprotein (HDL) cholesterol in comparison with intermittent oral administration of the same doses either given individually or in combination (Models A and B). Similar results were found in Model C for the IGI administration of the drug combination in contrast to oral and also to intravenous infusions. The results indicate that the combination of bezafibrate and niacin produces a significant hypolipidemic response, with major site(s) of action located presystemically. Because a slow-release matrix tablet of the drug combination resulted in a similar magnitude of effect as the IGI administration, the present study provides a pharmacodynamic rationale for the use of a slow-release low-dose niacin-bezafibrate combination.     

Impact of antenatal exposure of mice to fenfluramine on cardiac development and long-term growth of the offspring

The objective of this investigation was to determine, in a placebo-controlled manner, whether antenatal exposure to formulations of fenfluramine and dexfenfluramine impacted cardiac development and long-term growth of exposed mice offspring. One hundred forty-four CD-1 mice were randomized to six treatment groups (n=23 or 25) to obtain, per group, 5 gravids for killing on gestational day (GD) 15 and < or =10 deliveries for assessing growth of the offspring. Either fenfluramine preparation was administered in feed bars in two doses: 1 and 3.2 times the equivalent human daily dosage according to body surface area. The drugs were given from 2 weeks before mating until GD 15. The mice ingested each drug at target values, averaging 10.5+/-0.3 and 31.8+/-1.9 mg/kg/d for fenfluramine and 5.0+/-0.2 and 16.2+/-0.4 mg/kg/d for dexfenfluramine. The drug concentration was about 36% in the fetal brain compared with the adult brain. The maternal and the offspring hearts, including mitral and aortic valves, of fenfluramine-exposed mice were indistinguishable from the placebo-exposed mice. The duration of gestation and the litter size were the same between the treatment groups. The mean body weights, body lengths, and head circumferences and early functional testing did not differ significantly between the fenfluramine or dexfenfluramine-exposed offspring and the placebo-exposed offspring. There were no significant treatment differences in growth measured as body weights to PND 120. Neither fenfluramine formulation, given before conception and during gestation, impacted cardiac development and long-term growth of the mice offspring.     

Pharmacology of glucocorticoids: beyond receptors

Glucocorticoid hormones are important regulators of homeostasis. They are used clinically as highly effective anti-inflammatory compounds and have been prescribed for more than fifty years for a variety of conditions. They mediate their genomic actions by binding to two different intracellular receptors in target cells. The pharmacology of glucocorticoids largely depends on ligand concentration and receptor expression levels in target tissue. However, their genomic actions also critically depend on coactivators and corepressors recruitment. We discuss how various non-receptor factors affect glucocorticoid potency and efficacy with respect to their genomic effects. Differential recruitment of coregulators may account for many ligand- and cell-specific effects of glucocorticoids. This is best illustrated by the recent identification of selective glucocorticoid receptor agonists that induce distinct conformational changes to the receptors resulting in altered protein–protein interactions and consequently different regulation of gene expression. We conclude that these new molecular insights will contribute to the design of safer glucocorticoids that retain full pharmacological properties with reduced side-effects.     

A pharmacokinetic analysis of long-term administration of rubidium chloride

When a substance with a long biologic half-life is administered over an extended period with a varying dose schedule, many concerns about safety arise. In the case of rubidium chloride, which has been reported to have antidepressive activity, some of these concerns are related to the potential for unanticipated accumulation in the intracellular fluid, where replacement of more than 40% of the potassium ions is associated with toxicity in animals. A pharmacokinetic model of rubidium distribution, based on a three-compartment system, is in accord with the empirical data from previous human trials. By comparison of predicted with observed plasma rubidium levels, a sudden change in the ratio of intra- to extracellular distribution of rubidium can be detected, and availability of this warning signal of potentially toxic intracellular accumulation can be useful during extended administration.     

Enhanced interleukin production after long-term administration of erythromycin stearate

The effects of erythromycin stearate (10 mg/kg/day) were studied on productions of interleukin (IL)-1 and -2 in mice after a long-term treatment. A 28-day treatment resulted in higher levels of IL-1 production by macrophages and of IL-2 production by splenocytes, while a 7-day treatment did not increase them. T-cell growth factor activity of IL-2 preparation prepared on day 28 of treatment as determined by HT-2 cell proliferation was reduced by about 40% in the presence of anti-murine IL-4 monoclonal antibodies, while control IL-2 activity was not reduced. Furthermore, a 28-day treatment with erythromycin stearate increased concanavalin A-induced blastogenesis of splenocytes significantly. These results suggest that long-term treatment with erythromycin stearate can stimulate host defense by increasing interleukin production.