Beauty of the beast: anticholinergic tropane alkaloids in therapeutics

Tropane alkaloids(TAs)are among the most valued chemical compounds known since pre-historic times.Poisonous plants from Solanaceae family(Hyoscyamus niger,Datura,Atropa belladonna,Scopolia lurida,Mandragora officinarum,Duboisia)and Erythroxylaceae(Erythroxylum coca)are rich sources of tropane alkaloids.These compounds possess the anticholinergic properties as they could block the neurotransmitter acetylcholine action in the central and peripheral nervous system by binding at either muscarinic and/or nicotinic receptors.Hence,they are of great clinical impor-tance and are used as antiemetics,anesthetics,antispasmodics,bronchodilator and mydriatics.They also serve as the lead compounds to generate more effective drugs.Due to the important pharmacological action they are listed in the WHO list of essential medicines and are available in market with FDA approval.However,being anticholinergic in action,TA medication are under the suspicion of causing dementia and cognitive decline like other medications with anticholinergic action,interestingly which is incorrect.There are published reviews on chemistry,biosynthesis,phar-macology,safety concerns,biotechnological aspects of TAs but the detailed information on anticholinergic mecha-nism of action,clinical pharmacology,FDA approval and anticholinergic burden is lacking.Hence the present review tries to fill this lacuna by critically summarizing and discussing the above mentioned aspects.

Antipsychotic and Anticholinergic Drug Prescribing Pattern in Psychiatry: Extent of Evidence-Based Practice in Bahrain

The aim of this study is to determine the antipsychotic prescribing pattern and the prevalence of concurrent anticholinergic prescribing in a psychiatric referral hospital. A retrospective audit of prescriptions issued for outpatients was carried out at the Psychiatric Hospital, the only facility that provides psychiatric services for both inpatients and outpatients in the Kingdom of Bahrain. Antipsychotic monotherapy was prescribed for 89.2% patients, whereas polytherapy with two- and three-drugs in 10.4 and 0.4%, respectively. Atypical antipsychotics were prescribed more often (67.7%) than typical antipsychotics. Risperidone and haloperidol were the most frequently prescribed antipsychotics. Long-acting risperidone injection was the only depot preparation prescribed. The mean antipsychotic dose expressed as chlorpromazine equivalent (CPZeq;mg/day) was 242 (220 for monotherapy and 414 for polytherapy). The prevalence of high dose antipsychotic (mean CPZeq > 1000 mg/day) was 1.8%, prescribed at a mean CPZeq dose of 1531 (1925 for monotherapy and 1137 for polytherapy), mainly attributed to haloperidol. Anticholinergics were co-prescribed for almost two third of patients receiving antipsychotics, particularly for those on polytherapy (monotherapy 57.3%;poly-therapy 87.5%). Antipsychotic polytherapy, high dose and co-prescription of an oral with a depot antipsychotic preparation were strongly associated with concurrent prescription of anticholinergics. Procyclidine and orphenadrine were the most often prescribed anticholinergics. In Bahrain, antipsychotic monotherapy is a common practice for outpatients with psychotic disorders. Some of the antipsychotic polytherapies, dosage strategies, and high prevalence of anticholinergic use are therapeutic issues that need to be addressed to foster evidence-based prescribing practice.

An overlooked effect of systemic anticholinergics:alteration on accommodation amplitude

AIM： To investigate the effect of oral solifenacin succinate, tolterodine-L-tartarate and oxybutinin hydrochloride（HCl） on accommodation amplitude.·METHODS： Female overactive bladder syndrome（OAB）patients who were planned to use oral anticholinergics,patients that uses solifenacin succinate 5 mg（Group I,n =25）, tolterodine-L-tartarate 4 mg（Group II, n =25）,and oxybutinin HCl 5 mg b.i.d.（Group III, n =25） and age matched healthy female subjects（Group IV, n =25） were recruited and complete ophthalmological examination and accommodation amplitude assessment were done at baseline and 4wk after initiation of treatment.·RESULTS： The mean age of 100 consecutive female subjects was 51.6 ±5.7（40-60）y and there were no statistically significant difference with regard to the mean age（P =0.107） and baseline accommodation amplitude（P =0.148） between study groups. All treatment groups showed a significant decrease in accommodation amplitude following a 4-week course of anticholinergic treatment（P =0.008 in Group I, P =0.002 in Group II, P =0.001 in Group III）, but there was no statistically significant difference in Group IV（P =0.065）.·CONCLUSION： A 4-week course of oral anticholinergic treatment have statistically significant effect on accommodation amplitude. Clinicians should avoid both overestimating this result, as this would unnecessarily restrict therapeutic possibilities, and also underestimating it which may lead to drug intolerance.

Suggested Two Hypotheses on Dementia (“Anticholinergic Hypothesis” and “Cranial Skeletal Muscles Hypothesis”) and the Therapeutic Agent

The present study was conducted with the objective of further developing the cholinergic hypothesis and not using the prevalent amyloid beta plaque hypothesis or the tau protein hypothesis on dementia. The experiment was conducted on mice using anticholinergic drugs scopolamine and biperiden to investigate the root cause of dementia. First, we measured the mice serum for liquid chromatography-tandem mass spectrometry (LC-MS/MS) after administration of scopolamine and biperiden and found an accumulation of anticholinergic drugs metabolites in the body. The Y-maze test and measurement of LC-MS/MS in the cranial skeletal muscle cells showed that the Scopolamine metabolites have a significant effect on the cranial skeletal muscles, leading to the conclusion that Methocarbamol is an effective treatment for dementia.

Antidiarrheal potential of Distemonanthus benthamianus Baillon. extracts via inhibiting voltage-dependent calcium channels and cholinergic receptors

Objective:To evaluate spasmolytic mechanisms of aqueous and methanolic extracts from Distemonanthus benthamianus trunk-bark.Methods:Spasmolytic activities of extracts were evaluated in vitro on spontaneous and potassium chloride-induced jejunum contractions,or against cholinergic[acetylcholine(0.3μmol/L)]stimulations.High performance liquid chromatography analysis of both extracts was performed in reference to standard compounds.Results:Extracts developed concentration-dependent inhibitory activities.The methanolic extract,which revealed better activity,produced spasmolytic and myorelaxant effects at concentrations of 0.01-0.30 mg/mL with EC(50)of 0.06 and 0.09 mg/mL(95%CI:0.03-0.3 mg/mL),respectively.Its anticholinergic effect was obtained at the same concentrations with EC(50)of 0.11 mg/mL(95%CI:0.03-0.3 mg/mL).Chromatograms showed the presence of gallic acid in both extracts,rutin being only detected in the aqueous extract.Conclusions:Distemonanthus benthamianus extracts exhibit verapamil and atropine-like activities,thus highlighting calcium channels and muscarinic receptors blocking potentials,which may be conveyed by some phenolic compounds.These results confirm the antidiarrheal activity of Distemonanthus benthamianus extracts.

THE PREPARATION AND BIOACTIVITIES OF OPTICALANALOGS OF BAOGONGTENG A

objective We prepared optical analogs of Baogongteng A and investigated their bioactivities soas to find new effective hypotoxic drugs at M- receptors. Methods Racemic analogs of Baogongteng A wereresolved with chiral acid. Results Six chiral analogs of Baogongteng A were prepared. In mydriatic tests inrabbits, (+) - 32 - benzoyloxy - 6β - acetoxytropane and (+) - 32 - parachloro benzoyloxy- 6β- acetoxytropanepossess anticholinergic activities. Conclusion The configuration of enantiomers has significant influence on thebioactivity of analogs of Baogongteng A.

Simple and Rapid Hollow Fiber Liquid Phase Microextraction Followed by High Performance Liquid Chromatography Method for Determination of Drug-protein Binding

A method was established using hollow fiber-liquid phase microextraction（HF-LPME） followed by high performance liquid chromatography（HPLC） to determine the concentration of the free（unbound） drug in the solution of the drug and protein. Measurements of drug-protein binding ratios and free drug concentrations were then analyzed with the Klotz equation to determine the equilibrium binding constant and number of binding sites for drug-protein interaction. The optimized method allows one to perform the efficient extraction and separation of free drug from protein-bound drug, protein, and other interfering substances. This approach was used to characterize the binding of the anticholinergic drugs atropine sulfate and scopolamine hydrobromide to proteins in human plasma and bovine serum albumin（BSA）. The results demonstrate the utility of HF-LPME method for measuring free drug concentrations in protein-drug mixtures and determining the protein binding parameters of a pharmacologically important class of drugs.

Anisocoria in a 10-month old girl in the immediate preoperative setting: can you proceed with surgery?

We report the case of a 10-month old girl with a significant past medical history who presented for elective sur-gery with a new-onset fixed, dilated pupil. We briefly review the diagnostic approach to such patients and provide guidelines for managing these patients in the immediate preoperative setting.

Comparative assessment of efficacy and safety of different treatment for de novo overactive bladder children: A systematic review and network meta-analysis

Objective:To compare these managements focusing on the efficacy and safety to treat overactive bladder(OAB)in children through network meta-analysis(NMA).Methods:We searched PubMed,Embase,the Cochrane Library Central Register of Controlled Trials(CENTRAL)and the reference lists up to May 1st,2017.Data from eligible randomized controlled trails(RCT)studies including three different treatment options were extracted.The primary outcome was maximal voiding volume(MVV).We performed pairwise metaanalyses by random effects model and NMA by Bayesian model.We used the Grading of Recommendations,Assessment,Development and Evaluations(GRADE)framework to assess the quality of evidence contributing to each network estimate.Results:Six RCTs(462 patients)comparing three different interventions fulfilled the inclusion criteria.A low risk of bias was shown for the majority of the study items.The results of NMA showed that compared with antimuscarinic drugs,Parasacral transcutaneous electrical nerve stimulation was associated with significant improvement in the MVV(mean difference[MD]=58.50,95% confidential interval[CI]:45.95-69.52),followed by urotherapy group(MD=21.03,95%CI:11.85-29.97).When it comes to the constipation,antimuscarinic drugs exerted significant benefit than PTENS(odds ratio[OR]:0.22,95%CI:0.01-0.46).No significant difference was found between other treatments.Conclusion:Compared with antimuscarinic drugs,PTENS was associated with significant better efficacy considering MVV,but more constipation events in de novo OAB children.Antimuscarinic drugs showed remarkably better efficacy considering MVV and comparable safety profile compared with urotherapy.Clinicians should take all known safety and compliance of patients into account when choosing an optimal strategy.

The advantages of penehyclidine hydrochloride over atropine in acute organophosphorus pesticide poisoning:A meta-analysis

Background:Penehyclidine hydrochloride(PHC)has been used for many years as an anticholinergic drug for the treatment of acute organophosphorus pesticide poisoning(AOPP).The purpose of this meta-analysis was to explore whether PHC has advantages over atropine in the use of anticholinergic drugs in AOPP.Methods:We searched Scopus,Embase,Cochrane,PubMed,ProQuest,Ovid,Web of Science,China Science and Technology Journal Database(VIP),Duxiu,Chinese Biomedical literature(CBM),WanFang,and Chinese National Knowledge Infrastructure(CNKI),from inception to March 2022.After all qualified randomized controlled trials(RCTs)were included,we conducted quality evaluation,data extraction,and statistical analysis.Statistics using risk ratios(RR),weighted mean difference(WMD),and standard mean difference(SMD).Results:Our meta-analysis included 20,797 subjects from 240 studies across 242 different hospitals in China.Compared with the atropine group,the PHC group showed decreased mortality rate(RR=0.20,95%confidence intervals[CI]:0.16–0.25,P<0.001),hospitalization time(WMD=-3.89,95%CI:-4.37 to-3.41,P<0.001),overall incidence rate of complications(RR=0.35,95%CI:0.28–0.43,P<0.001),overall incidence of adverse reactions(RR=0.19,95%CI:0.17–0.22,P<0.001),total symptom disappearance time(SMD=-2.13,95%CI:-2.35 to-1.90,P<0.001),time for cholinesterase activity to return to normal value 50–60%(SMD=-1.87,95%CI:-2.03 to-1.70,P<0.001),coma time(WMD=-5.57,95%CI:-7.20 to-3.95,P<0.001),and mechanical ventilation time(WMD=-2.16,95%CI:-2.79 to-1.53,P<0.001).Conclusion:PHC has several advantages over atropine as an anticholinergic drug in AOPP.

新型抗胆碱药物在慢性阻塞性肺疾病治疗中的研究状况

近年来,慢性阻塞性肺疾病(COPD)发病率不断上升,病死率逐渐增加,严重威胁着全世界患者的生命健康。由于胆碱能神经及其受体的变化在COPD的发病过程中起重要的作用,因此抗胆碱药物是目前治疗COPD的主要药物之一。本文主要对已有的以及目前仍在研发的抗胆碱药物进行综述。

Evaluation of the efficacy and safety of tiotropium bromide （5 μg） inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease

Background A pharmacokinetic study in an Asian population showed that tiotropium 5 μg via Respimat leads to the same plasma levels compared to 18 μg via HandiHaler.The objective of the trial was to compare the efficacy and safety of longterm treatment （1 year） with tiotropium bromide （5 μg） via Respimat（R） with placebo in patients with chronic obstructive pulmonary disease （COPD）.Methods A total of 3991 patients were randomized in this double-blind,placebo controlled,parallel group study,while in China 338 patients （309 males,29 females） received either tiotropium bromide （n=167） or placebo （n=171）.Tiotropium bromide solution or matching placebo was delivered via Respimat（R） at a dosage of 5 μg （2 x 2.5 μg/puff） once daily for 48 weeks.Co-primary endpoints were trough forced expiratory volume in one second （FEV1） and the time to first exacerbation.Results Statistically significant improvements in trough FEV1 and trough forced vital capacity （FVC） in the tiotropium group were achieved at weeks 4,24,and 48 compared with those in the placebo group.A statistically significant difference （P=0.0027） in favour of tiotropium was also observed for the time to first exacerbation.The total numbers of exacerbations during treatment were 90 and 128 in the tiotropium and placebo groups,respectively,with a rate ratio of 0.69 （P=0.0164）.The difference between the treatment groups in the adjusted mean changes from baseline of St.George Respiratory Questionnaire （SGRQ） total score was-3.9 （95% Cl：-7.5,-0.2） and was of statistical significance （P=0.0367）.The incidences of serious adverse events （SAEs） in the tiotropium and placebo groups were 16.2% and 17.0%,respectively.Seven deaths occurred whilst patients were on treatment,four in the tiotropium group and three in the placebo group,all of which were assessed as non-related study drugs by the investigators.Conclusions Tiotropium significantly improved lung function and quality of life,delayed the time to first exacerbation,reduced the number of exacerbations.Overall,tiotropium was well tolerated.

Molecular Pharmacology of Antinicotinic Activity of Cholinolytic Drugs

Anticholinergic drugs have been widely used for many years in neurological researchand clinical therapy of many diseases, such as parkinsonism, stomachache and theorganophosphorus agents poisoning. But these drugs are antagonists of muscarinicreceptors(M-receptors) and can hardly be used in the treatment of soman poisoning,because it is known in our institute that the potent antimuscarinic and certainantinicotinic activities are necessary for a highly effective drug against Soman poi-soning. In our previous works, we developed a theoretical model for the drug-receptorinteraction deduced from a conformation-activity relationship (CAN) of classic

Sleep-based therapy:A new treatment for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is a worldwide problem with no effective treatment.Patients usually die of respiratory failure.The basic pathological process of ALS is the degeneration and necrosis of motor neurons.Neuroglial cell dysfunction is considered closely related to the development of ALS.Sleep plays an important role in repairing the nervous system,and sleep disorders can worsen ALS.Herein,we review the pathogenesis of ALS and the neuroprotective mechanism of sleep-based therapy.Sleep-based therapy could be a potential strategy to treat ALS.