Hypothalamic levels and utilization of noradrenaline and 5-hydroxytryptamine in the sodium-depleted rat

The present report investigated the time course of hypothalamic noradrenaline (NA) and 5-hydroxytryptamine (5-HT) metabolism in male rats with acute sodium depletion by intraperitoneal dialysis (IPD). The hypothalamic level and utilization of NA start to rise significantly 12 to 24 hrs after IPD. In contrast, 24 hrs after IPD, sodium-depleted rats allowed to drink sodium in a half hour drinking test significantly decreased NA steady state and utilization. Electrochemical stimulation of the pre-limbic cortex 5 hrs after IPD significantly increased the utilization but not the concentration of NA, whereas sodium replenishment decreased both of them. The metabolism of hypothalamic 5-HT was not affected 12-24 hrs after sodium depletion or by electrochemical stimulation, while both the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) increased significantly in sodium-depleted rats allowed to drink sodium. These results suggest that sodium deficiency promotes an increased hypothalamic NA utilization while failing to affect 5-HT metabolism.     

Scopolamine: Effects on fear or defense responses in the rat

In previous research scopolamine reduced fear or defense responses of rats to a cat, and removal of the rats' olfactory bulbs had the same effect. This suggested that scopolamine might have affected defense responses by blocking olfactory perception of the stimulus cat. The present experiments studied this possibility and explored further the effects of scopolamine on defense responses of the hooded rat. In Experiments 1 rats treated with scopolamine were found to be responsive to olfactory cues from a cat. When cat smell, but not a cat, was present in the apparatus, scopolamine-treated rats showed a large and significant suppression of food consumption. In Experiment 2 the effects of scopolamine on defense responses were shown to be generalizable to an inanimate stimulus, mechanical robot. Scopolamine caused significantly less freezing and avoidance and significantly shorter latencies to drink in the presence of the robot. One of the primary findings of the present research is that scopolamine has now been shown to reduce the defensive response of freezing in a variety of stimulus situations. This finding was thought to have important implications for the literature relating anticholinergic drugs and avoidance behavior.     

Anticholinergic agents prevent guinea-pig airway constriction induced by histamine,bradykinin and leukotriene C4: Relationship to circulating TXA2

Various doses of histamine, bradykinin and leukotriene C₄ caused bronchoconstriction in anaesthetized guinea-pigs which were breathing spontaneously or artificially ventilated; there was a simultaneous, dose-related increase of circulating TXA₂. The animals were prepared for continuous recording of extracororeal circulation in order to detect the appearance in the blood of bioassayable levels of TXA₂-like substance. Furthermore, a TXA₂ derivative, the mono-O-Me-TXB₂, was radioimmunoassayed. Atropine, oxytropium bromide and ipratropium bromide given in μmol doses prevented both the increased airway resistance and the release of TXA₂-like substance in the blood. Pirenzepine dihydrochloride was the least active of the drugs tested. The protecting activity of anticholinergics and the relationship with their ability to affect TXA₂-like substance generation suggest a new site of action for these drugs besides the blockade of muscarinic receptors.     

Changes in drug sensitivity following acute and chronic exercise

A number of factors are known to influence drug sensitivity. These include biological variables such as genetics, age, endocrine status and gender, as well as environmental variables such as operant schedules, ambient temperature and sleep deprivation. Additional factors function as either biological or environmental variables in different situations. For example, chronic drug administration can produce tolerance and cross tolerance and function as a biological variable. Acute administration of the same compound can function as an environmental variable. The present study examined exercise as both a biological and an environmental variable influencing drug sensitivity. Chronic exercise leads to relatively long term changes in physical fitness level, and functions as a biological variable. Fitness level did not influence drug sensitivity when physically conditioned animals and non-exercised control subjects were compared under rested conditions. Mild acute exercise, an environmental variable, increased sensitivity to muscarinic antagonists in the control subjects but not in the exercise trained animals. These results indicate that exercise state should be considered as an environmental variable capable of influencing drug response and that biological fitness level modifies this effect.     

Influence of anticholinergic drugs on after-discharges and activity of epileptogenic foci in rabbit hippocampus

The influence of M-anticholinergic drug Metamyzil and N-anticholinergic drug Gangleron on the thresholds of after-discharges (AD) and the activity of a penicillin-produced epileptogenic focus in the hippocampus was studied in rabbits with chronic bipolar electrodes implanted in the cortex and subcortical structures. Both anticholinergics increased AD thresholds under direct administration into hippocampus at the point of stimulation (1–160 mkg). Metamyzil induced a more marked effect than Gangleron. When injected into the area of epileptogenic focus in the hippocampus, both anticholinergics (15–20 mkg) did not influence the intensity of interictal epileptiform discharges but decreased the number of fits. Gangleron equally affected the activity of the epileptogenic focus under both conditions of intravenous (1–3 mg/kg) and direct administration into the hippocampus. Contrary to Gangleron, when Metamyzil was intravenously administered (0.5–2.5 mg/kg) it markedly depressed the ascending activating system of the reticular formation and intensified interictal epileptiform activity and fits. It was concluded that the blocking of cholinergic systems of the hippocampus on one hand prevents the circulation of excitement along neuron circuits and, on the other hand, it does not influence the interictal epileptiform discharges in the EEG, which suggests that the fluctuation of the membrane potential of epileptogenic neurons were not affected.     

Fertility and early embryonic development toxicity of penequine hydrochloride in mice.

Penequine hydrochloride, a novel anticholinergic agent, was developed as an effective treatment for organophosphorus intoxication. The potential for penequine hydrochloride to induce fertility and early embryonic developmental toxicity was evaluated in AMMS-1 mice. Totally 320 healthy, sexual mature and nulliparous AMMS-1 mice were orally treated with the chemical in drinking water at dose levels of 0, 2.5, 12.5 and 62.5 mg/L from 60 days before cohabitation to successful copulation in 160 males and from two weeks before cohabitation to GD 6 in 160 females, respectively. All the parental mice were observed for body weights, water consumption and any abnormal change during treatment period. Caesarean sections were carried out on day 14 of pregnancy in half assumed-pregnant females, and all the intrauterine data were recorded. Pups naturally delivered by the other half females were weighed, and examined for viability, sex ratio and gross malformations. About 7 days after cohabitation period, all the paternal males were examined for epididymal and testicular weights, sperm number and sperm motility. The decreases in fertility/fecundity indices and maternal weight gain were found at high-dose level in both caesarean sections and natural delivery observations. The primary developmental toxicity of the chemical included decreases in relative organ (epididymis, liver and lung) weights at mid- and high-dose levels in pups on postnatal day (PND) 35. The cause of both the decreased fertility/fecundity indices in F0 males and the decreased relative organ weights in F1 pups are not well known but are presently under investigation. Under the experimental conditions, penequine hydrochloride did not produce any adverse effects (expect the decreases in certain relative organ weights) up to and including 12.5 mg/L (2.53 mg/kg/day in males and 2.19 mg/kg/day in females) corresponding to approximately 72 times above anticipated dosage in human.     

抗胆碱能药在休克治疗中的炎性抑制作用

脓毒性休克和创伤失血性休克均可能发展为全身性炎性反应综合征,甚至多器官功能障碍综合征,导致预后不良和死亡。近年来,抗胆碱能药防治休克-复苏后肺部炎性反应的作用机制研究较为活跃,主要集中在对炎性细胞和炎性介质的干预上。长托宁(盐酸戊乙奎醚)是一种新型的抗胆碱能药物,与阿托品和山莨菪碱相比有更多的优点而受到重视,但有关用药的剂量与时间,尚需进一步研究。     

Hospital and emergency department utilization associated with treatment for chronic obstructive pulmonary disease in a managed-care Medicare population

Abstract

Background:

Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition with high morbidity and mortality among older and disabled adults. Few studies have examined the comparative effectiveness of maintenance therapies for chronic obstructive pulmonary disease (COPD) in this vulnerable population.     

Use of Anticholinergic Drugs and its Relationship With Psychological Well-Being and Mortality in Long-Term Care Facilities in Helsinki

Objectives

To assess the burden of drugs with anticholinergic properties (DAPs) and associated factors in long-term care facilities and to explore how psychological well-being and mortality are associated with the use of DAPs.

Anticholinergic Burden is Associated With Increased Mortality in Older Patients With Dependency Discharged From Hospital

ObjectivesTo determine whether anticholinergic burden may predict differently 1-year mortality in older patients discharged from acute care hospitals with or without dependency in basic activities of daily living (BADL).DesignProspective observational study.Setting and participantsOur series consisted of 807 patients aged 65 years or older consecutively discharged from 7 acute care geriatric wards throughout Italy between June 2010 and May 2011.MeasuresOverall anticholinergic burden was assessed by the anticholinergic cognitive burden (ACB) score. Dependency was rated by BADL, and dependency in at least 1 BADL was considered as a potential mediator in the analysis. The study outcome was all-cause mortality during 12-months of follow-up.ResultsPatients included in the study were aged 81.0 ± 7.4 years, and 438 (54.3%) were female. During the follow-up period, 177 out of 807 participants (21.9%) died. After adjusting for potential confounders, discharge ACB score = 2 or more was significantly associated with the outcome among patients with dependency in at least 1 BADL [hazard ratio (HR) 2.25 95% confidence (CI) 1.22‒4.14], but not among independent ones (HR 1.06 95% CI 0.50‒2.34). The association was confirmed among dependent patients after adjusting for the number of lost BADL at discharge (HR 2.20 95% CI 1.18‒4.04) or ACB score at 3-month follow-up (HR 2.18 95% CI 1.20‒3.98), as well as when considering ACB score as a continuous variable (HR 1.28 95% CI 1.11‒1.49). The interaction between ACB score at discharge and BADL dependency was highly significant (P < .001).Conclusions/ImplicationsACB score at discharge may predict mortality among older patients discharged from an acute care hospital carrying at least 1 BADL dependency. Hospital physicians should be aware that prescribing anticholinergic medications in this population may have negative prognostic implications and they should try to reduce anticholinergic burden at discharge whenever possible.