The effects of the cholinergic system on carrageenan-induced arthritis.

The cholinergic system has been found to make an anti-inflammatory effect through the cholinergic anti-inflammatory pathway (CAIP), which suppresses the production of pro-inflammatory cytokines by secreting acetylcholine, a major neurotransmitter. However, no studies have been conducted on the effects of CAIP on joint pain and inflammation. In this study, we investigated the effects of muscarinic acetylcholine receptors (mAChRs) in knee arthritis. To examine pain behavioral changes, atropine (or saline for sham control) was pretreated in the joint cavity of rats at 1 % carrageenan + 5, 10, and 30 µL and the dynamic weight-bearing evaluation was performed. Synovial membranes were collected and cyclooxygenase-2 (COX-2) and interleukin-1ß (IL-1ß) were measured using a western blot. Hematoxylin and eosin staining was performed. Compared to that of the sham group, the weight-bearing of the affected knee joint significantly increased in the 1 % carrageenan + 10 µL atropine group (p < 0.05). However, no significant changes were observed in the 1 % carrageenan + 5 and 30 µL atropine groups. COX-2 and IL-1ß and the number of inflammatory cells in synovial membrane significantly increased with 1 % carrageenan + 10 µL of atropine (p < 0.05). These results suggest that cholinergic system is involved in knee joint pain and inflammation and that mAChRs are potential therapeutic targets for knee joint arthritis.

Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials.

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

Pulegone Prevents Hypertension through Activation of Muscarinic Receptors and Cyclooxygenase Pathway in L-NAME-Induced Hypertensive Rats.

The current study was designed to determine pulegone's antihypertensive and vasoprotective activity in L-NAME-induced hypertensive rats. Firstly, the hypotensive dose-response relationship of pulegone was evaluated in normotensive anesthetized rats using the invasive method. Secondly, the mechanism involved in hypotensive activity was determined in the presence of pharmacological drugs such as atropine/muscarinic receptor blocker (1 mg/kg), L-NAME/NOS inhibitor (20 mg/kg), and indomethacin/COX inhibitor (5 mg/kg) in anesthetized rats. Furthermore, studies were carried out to assess the preventive effect of pulegone in L-NAME-induced hypertensive rats. Hypertension was induced in rats by administering L-NAME (40 mg/kg) orally for 28 days. Rats were divided into six groups which were treated orally with tween 80 (placebo), captopril (10 mg/kg), and different doses of pulegone (20 mg/kg, 40 mg/kg, and 80 mg/kg). Blood pressure, urine volume, sodium, and body weight were monitored weekly. After 28 days, the effect of pulegone on lipid profile, hepatic markers, antioxidant enzymes, and nitric oxide was estimated from the serum of treated rats. Moreover, plasma mRNA expression of eNOS, ACE, ICAM1, and EDN1 was measured using real-time PCR. Results show that pulegone dose-dependently decreased blood pressure and heart rate in normotensive rats, with the highest effect at 30 mg/kg/i.v. The hypotensive effect of pulegone was reduced in the presence of atropine and indomethacin, whereas L-NAME did not change its hypotensive effect. Concurrent treatment with pulegone for four weeks in L-NAME-treated rats caused a reduction in both systolic blood pressure and heart rate, reversed the reduced levels of serum nitric oxide (NO), and ameliorated lipid profile and oxidative stress markers. Treatment with pulegone also improved the vascular response to acetylcholine. Plasma mRNA expression of eNOS was reduced, whereas ACE, ICAM1, and EDN1 levels were high in the L-NAME group, which was facilitated by pulegone treatment. To conclude, pulegone prevented L-NAME-induced hypertension by demonstrating a hypotensive effect through muscarinic receptors and cyclooxygenase pathway, indicating its use as a potential candidate in managing hypertension.

Higher intake of medications for digestive disorders in children prenatally exposed to drugs with atropinic properties.

Childhood digestive disorders are a common occurrence and are sometimes unexplained. Maternal medication during the development of the foetus' digestive system may contribute to the increase in childhood digestive disorders, especially with drugs acting on the cholinergic system. This study investigated the association between prenatal exposure to drugs with atropinic properties and the use of digestive disorder medications in childhood (0-3 years). Children from POMME (PrescriptiOn Médicaments Mères Enfants), a French database of reimbursed drugs for pregnant women and their children, were included (N = 8 372). Each drug prescribed during antenatal life was assigned an atropinic score (0 = null, 1 = low, 3 = strong). The prenatal atropinic burden was calculated as the sum of atropinic scores of drugs prescribed. More than 30% (N = 2 652) of the children were prenatally exposed to atropinic drugs. They used significantly more digestive disorder medications than unexposed children (RRa = 1.11 [1.06; 1.16]). The strength of the association increased with the prenatal atropinic burden. Our results suggest long-term digestive effects after prenatal exposure to atropinic drugs.

Atropinic burden of drugs during pregnancy and psychological development of children: a cohort study in the EFEMERIS database.

AIM: The aim of this study was to evaluate the potential effect of in utero exposure to drugs with atropinic properties on infant psychological development using atropinic burden (AB) scales. METHODS: Women from the EFEMERIS cohort, a French database including prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes, delivering between 2004 and 2010 were included (n = 43 740). Each drug was classified as having no (score = 0), few (score = 1) or strong (score = 3) atropinic properties. AB per woman was calculated by adding the atropinic scores of drugs prescribed during pregnancy. AB was categorized as exposure or no exposure. Secondary analyses were performed by dividing the exposure into four scores = [0], [1-8], [9-17] and [≥18]. Data for psychological development were extracted from children's medical certificates completed at 9 and 24 months. RESULTS: Thirty-four% (n = 14 925) of women received at least one atropinic drug during pregnancy. Women with AB ≥1 were older and received more drugs during pregnancy than unexposed women. At 24 months, more infants of mothers with AB ≥1 had difficulties to 'name a picture' (ORa , 1.18, 95% CI 1.03, 1.36) and to 'understand instructions' (ORa , 1.61, 95% CI 1.13, , 2.30]) compared with infants of unexposed women. Analyses of four groups of exposure and analyses excluding women receiving psychotropics led to similar results. CONCLUSIONS: The study showed significant association between in utero exposure to drugs with atropinic properties and fewer infant cognitive acquisitions at 24 months. Further exploring the potential effect of simultaneous use of drugs with atropinic effects among pregnant women will bring into consideration whether such prescriptions could be inappropriate for the child.

Potentially inappropriate medication use among patients with Alzheimer disease in the REAL.FR cohort: be aware of atropinic and benzodiazepine drugs!

OBJECTIVE: Few studies have investigated potentially inappropriate medication (PIM) use in patients with Alzheimer's disease (AD). The aim of our study was to assess the prevalence of PIM in community-dwelling patients diagnosed with mild-to-moderate AD and identify the clinical factors associated with PIM prescriptions. METHODS: REAL.FR is a 4-year, prospective, multicenter French cohort of AD patients recruited in centers of expertise. We analyzed patient baseline data at entry into the study. PIMs were assessed using the Laroche list. A multivariate logistic regression was conducted to assess factors associated with PIMs. RESULTS: A total of 684 AD patients were enrolled in the study [mean age 77.9 ± 6.8 years, 486 (71.0 %) females]. According to the Laroche list, 46.8 % [95 % confidence interval (CI) 43.0-50.5 %] of the patients had at least one PIM. "Cerebral vasodilators" were the most widely used class of PIM, accounting for 24.0 % (95 % CI 20.9-27.3 %) of all prescriptions, followed by atropinic drugs (17.0 %, 95 % CI 14.1-19.8 %) and long half-life benzodiazepines (8.5 %, 95 % CI 6.4-10.6 %). Atropinic drugs were associated with cholinesterase inhibitors in 16 % of patients. In the multivariate analysis, only two factors, namely, female gender [odds ratio (OR) 1.5, 95 % CI 1.1-2.2] and polypharmacy (≥5 drugs; OR 3.6, 95 % CI 2.6-4.5) were associated with prescriptions for PIMs. CONCLUSIONS: These results reveal that approximately one out of two community-dwelling patients with mild-to-moderate AD treated by AD specialists use PIMs. They also indicate that the characteristics of the disease and the pharmacodynamic/pharmacokinetic profile of the drugs prescribed are not sufficiently taken into account by physicians when prescribing for AD patients.

Hyperinsulinemia instead of insulin resistance induces baroreflex dysfunction in chronic insulin-infused rats.

BACKGROUND: The present study was undertaken to compare the effects of chronic hyperinsulinemia with or without insulin resistance on the autonomic control of heart rate (HR) in rats. METHODS: Male Sprague-Dawley rats were implanted subcutaneously with insulin (3 mU/kg x min) or vehicle-filled osmotic minipumps for 8 weeks. Insulin-infused rats were further divided into insulin resistant (IR) and insulin sensitive (IS) groups according to the results of the homeostasis model assessment method and euglycemic hyperinsulinemic clamp study. Autonomic function in HR control was indicated by arterial baroreflex sensitivity (BRS) after a bolus injection of phenylephrine or sodium nitroprusside. RESULTS: Compared with those in control group, plasma insulin levels were elevated about threefold and 1.5-fold in the IR and IS groups at the end of week 8, respectively. Blood glucose level remained basal in the IR group, but was significantly lower in the IS group. The elevated mean arterial pressure (MAP) observed in IR was not exhibited in IS. The HR and BRS in reflex tachycardia were significantly increased in the IR and IS groups, but the BRS in reflex bradycardia was not different among all rats. Propranolol eliminated the tachycardia and enhanced BRS responses in both groups. Methylatropine further accelerated tachycardia and diminished the enhanced BRS in the IR group. However, in IS, the enhanced BRS remained after methylatropine was given. The intrinsic HR was similar among all groups. The baseline MAP, HR, and BRS in reflex tachycardia were significantly correlated to plasma insulin levels but not to the Si value, an index of insulin sensitivity. CONCLUSIONS: The present results demonstrate that hyperinsulinemia but not insulin resistance is a dominant contributing factor to the development of arterial baroreflex abnormalities in this chronic hyperinsulinemic model, which may simultaneously enhance sympathetic nerve activity and possibly vagal withdrawal if insulin resistance coexisted.

[Potential of the anticholinergic drug troventol in the treatment and diagnosis of bronchial asthma]. / Vozmozhnosti antikholinergicheskogo preparata troventola v lechenii i diagnostike bronkhial'noi astmy.

A study was made of potentialities of the Soviet drug troventol in the diagnosis and treatment of bronchial asthma. 143 patients suffering from bronchial asthma and 38 patients with pollenosis were examined for external respiratory function using a microprocessor spiroanalyzer, the immunological status and clinical symptoms. The importance of carrying out the diagnostic test with troventol in revealing latent bronchospasm was established, the bronchodilatory effect of troventol at the level of the large bronchi was demonstrated as was a decrease of the emotional manifestations together with the immunomodulatory effect. Beneficial results were attained in 67.8% of cases, satisfactory in 16.8%, and unsatisfactory in 15.4%. Untoward effects in the form of tachycardia were recorded in 3.5% of patients, bradycardia in 5.6%, dry mouth in 16.1% of patients.

Side effects of therapeutic drugs against organophosphate poisoning.

The possible side effects of therapeutic drugs against organophosphate poisoning were investigated. First, dose-effect curves were obtained with atropine sulphate (AS), P2S, obidoxime, aprophen, N-methylatropine nitrate and HI-6. The first three drugs are currently used in the therapy of organophosphate poisoning, the others are potentially useful candidates. Automated tests measuring open field behavior, motor coordination and shuttlebox performance, as well as neurophysiological techniques such as the quantified EEG (qEEG) and visual evoked responses were used. The sign-free doses of these compounds were determined; it appeared that open field behavior and the qEEG were the most sensitive methods for these drugs. Subsequently, these two methods were used to investigate the effects of the combinations of AS and P2S, AS and obidoxime or AS and HI-6, each compound given in a sign-free dose. Synergistic or additive effects were found with the combination of AS and P2S, which were smaller with the combination of AS and obidoxime and absent with the combination of AS and HI-6. These results indicate that the untimely use (false alarm, panic) of the current drug combinations may cause undesirable side effects.

Supraventricular tachycardia caused by nebulised ipratropium bromide.

A 71 year old patient developed a supraventricular tachycardia after the administration of nebulised ipratropium bromide.

Bladder outflow obstruction induced by ipratropium bromide.

Three cases are described in which bladder outflow obstruction was produced by ipratropium bromide, a widely used anticholinergic bronchodilator which has been regarded as virtually free from systemic side effects. Many patients treated with ipratropium bromide are elderly males in whom prostatic hypertrophy is common and in these circumstances, large doses should be used with caution.

Irritant contact facial dermatitis due to nebulizer therapy.

A case is reported of a patient with long-standing, severe airflow obstruction requiring long-term nebulizer therapy developing a facial dermatitis in the area bounded by the nebulizer mask. The facial dermatitis seems to be the result of the combined irritancy of the nebulizer solutions and moisture, and prophylactic measures are suggested for patients requiring long-term nebulizer therapy.