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Biochemical Pharmacology Jan 2008The discovery and development of medications to treat addiction and notably, cocaine addiction, have been frustrated by both the complexity of the disorder and the lack... (Review)
Review
The discovery and development of medications to treat addiction and notably, cocaine addiction, have been frustrated by both the complexity of the disorder and the lack of target validation in human subjects. The dopamine transporter has historically been a primary target for cocaine abuse medication development, but addictive liability and other confounds of such inhibitors of dopamine uptake have limited clinical evaluation and validation. Herein we describe efforts to develop analogues of the dopamine uptake inhibitors GBR 12909 and benztropine that show promising profiles in animal models of cocaine abuse that contrast to that of cocaine. Their unique pharmacological profiles have provided important insights into the reinforcing actions of cocaine and we propose that clinical investigation of novel dopamine uptake inhibitors will facilitate the discovery of cocaine-abuse medications.
Topics: Animals; Behavior, Animal; Benztropine; Cocaine-Related Disorders; Conditioning, Psychological; Disease Models, Animal; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Humans; Piperazines; Structure-Activity Relationship
PubMed: 17897630
DOI: 10.1016/j.bcp.2007.08.007 -
Acta Neuropathologica Communications Jan 2019The endogenous cholinergic system plays a key role in neuronal cells, by suppressing neurite outgrowth and myelination and, in some cancer cells, favoring tumor growth....
The endogenous cholinergic system plays a key role in neuronal cells, by suppressing neurite outgrowth and myelination and, in some cancer cells, favoring tumor growth. Platinum compounds are widely used as part of first line conventional cancer chemotherapy; their efficacy is however limited by peripheral neuropathy as a major side-effect. In a multiple sclerosis mouse model, benztropine, that also acts as an anti-histamine and a dopamine re-uptake inhibitor, induced the differentiation of oligodendrocytes through M1 and M3 muscarinic receptors and enhanced re-myelination. We have evaluated whether benztropine can increase anti-tumoral efficacy of oxaliplatin, while preventing its neurotoxicity.We showed that benztropine improves acute and chronic clinical symptoms of oxaliplatin-induced peripheral neuropathies in mice. Sensory alterations detected by electrophysiology in oxaliplatin-treated mice were consistent with a decreased nerve conduction velocity and membrane hyperexcitability due to alterations in the density and/or functioning of both sodium and potassium channels, confirmed by action potential analysis from ex-vivo cultures of mouse dorsal root ganglion sensory neurons using whole-cell patch-clamp. These alterations were all prevented by benztropine. In oxaliplatin-treated mice, MBP expression, confocal and electronic microscopy of the sciatic nerves revealed a demyelination and confirmed the alteration of the myelinated axons morphology when compared to animals injected with oxaliplatin plus benztropine. Benztropine also prevented the decrease in neuronal density in the paws of mice injected with oxaliplatin. The neuroprotection conferred by benztropine against chemotherapeutic drugs was associated with a lower expression of inflammatory cytokines and extended to diabetic-induced peripheral neuropathy in mice.Mice receiving benztropine alone presented a lower tumor growth when compared to untreated animals and synergized the anti-tumoral effect of oxaliplatin, a phenomenon explained at least in part by benztropine-induced ROS imbalance in tumor cells.This report shows that blocking muscarinic receptors with benztropine prevents peripheral neuropathies and increases the therapeutic index of oxaliplatin. These results can be rapidly transposable to patients as benztropine is currently indicated in Parkinson's disease in the United States.
Topics: Animals; Antineoplastic Agents; Benztropine; Cell Line, Tumor; Diabetic Nephropathies; Disease Models, Animal; Ganglia, Spinal; Hyperalgesia; Male; Mice, Inbred BALB C; Oxaliplatin; Peripheral Nervous System Diseases; Sciatic Nerve; Sensory Receptor Cells
PubMed: 30657060
DOI: 10.1186/s40478-019-0657-y -
Movement Disorders Clinical Practice Jul 2022To present a case of refractory medication-induced tremor successfully treated with deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (Vim) and... (Review)
Review
OBJECTIVE
To present a case of refractory medication-induced tremor successfully treated with deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (Vim) and to propose a medical and surgical treatment algorithm based on a systematical review of the literature.
METHODS
Patient data were retrospectively collected. A systematic search was performed in PubMed, Embase, and Cochrane Library. Subjective and objective data were pooled for analysis by classifying them into 5 predefined categories(no, minimal, moderate, good, and excellent effects).
RESULTS
The patient presented with lithium-induced bilateral progressive hand tremor lasting 25 years. After DBS, he reported excellent tremor suppression until the last follow-up (36 months after Vim-DBS). For the review, 34 of 140 studies were included and evaluated (178 unique subjects, 31 different treatments). A good-to-excellent tremor suppression (50%-100%) in at least 50% of subjects was achieved using propranolol (12 studies, 50% of 56 subjects), tetrabenazine (5 studies, 51% of 13 subjects), and metoprolol (4 studies, 75% of 8 subjects). The effect of benztropine and diphenhydramine was none or only minimal to moderate (up to 50% improvement; both: 3 studies, 50% of 4 patients). One article reported minimal-to-moderate effectiveness after DBS of the ventral oral posterior nucleus of the thalamus. Methods were highly heterogeneous. All studies scored grade III or IV quality of evidence, which was insufficient for recommendations (level U).
CONCLUSION
Treatment decision making should be performed on a case-by-case basis considering the low level of evidence, and we propose a practically oriented treatment algorithm. Propranolol, tetrabenazine, and metoprolol might be effective. For selected and refractory cases, DBS might be considered.
PubMed: 35844282
DOI: 10.1002/mdc3.13463 -
Cancers Feb 2020Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids...
Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a 3D tumoroid-based screening system. We screened six pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with a matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and the properties of cancer stem cells/cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited the tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.
PubMed: 32102440
DOI: 10.3390/cancers12020523 -
The Primary Care Companion For CNS... Aug 2023To evaluate real-world treatment patterns for patients initiating benztropine and to understand treatment approaches in patients with drug-induced movement disorders...
To evaluate real-world treatment patterns for patients initiating benztropine and to understand treatment approaches in patients with drug-induced movement disorders from a health care provider perspective. A retrospective claims analysis was conducted among patients with evidence of benztropine initiation from January 2017 through March 2020 to assess treatment patterns and patient health care resource utilization. Subsequently, a 30-minute, United States-based online survey fielded from December 2021 to January 2022 was sent to physicians, nurse practitioners, and physician assistants who reported a primary care or psychiatry specialty currently treating drug-induced movement disorders and prescribed benztropine. The health care claims analysis included 112,542 patients. Polypharmacy and multiple comorbidities were frequent characteristics in this population; 54.1% of patients had ≥ 2 comorbidities at baseline, and 59.1% had claims for > 10 medications. Benztropine was used for > 3 months in > 50% of the population. Health care costs and resource utilization were high, with mean all-cause pharmacy and outpatient costs totaling $11,755. Survey results from 349 primary care or psychiatry health care providers indicated that benztropine is often used in non-tardive dyskinesia drug-induced movement disorders but frequently continued for > 3 months or used in tardive dyskinesia. In this study, psychiatry providers prescribed benztropine in line with guideline recommendations more often than primary care providers; however, < 40% indicated familiarity with 2020 American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia. These complementary analyses suggest that benztropine is used long-term in non-tardive dyskinesia drug-induced movement disorders and in tardive dyskinesia despite risks of worsening tardive dyskinesia or adverse effects. .
Topics: Humans; Benztropine; Insurance Claim Review; Retrospective Studies; Movement Disorders; Tardive Dyskinesia; Health Personnel
PubMed: 37671827
DOI: 10.4088/PCC.22m03472 -
The Cochrane Database of Systematic... Jul 2016This is an update of an earlier review that considered both neuropathic pain and fibromyalgia (Issue 6, 2014), which has now been split into separate reviews for the two... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an update of an earlier review that considered both neuropathic pain and fibromyalgia (Issue 6, 2014), which has now been split into separate reviews for the two conditions. This review considers neuropathic pain only.Opioid drugs, including oxycodone, are commonly used to treat neuropathic pain, and are considered effective by some professionals. Most reviews have examined all opioids together. This review sought evidence specifically for oxycodone, at any dose, and by any route of administration. Separate reviews consider other opioids.
OBJECTIVES
To assess the analgesic efficacy and adverse events of oxycodone for chronic neuropathic pain in adults.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from inception to 6 November 2013 for the original review and from January 2013 to 21 December 2015 for this update. We also searched the reference lists of retrieved studies and reviews, and two online clinical trial registries. This update differs from the earlier review in that we have included studies using oxycodone in combination with naloxone, and oxycodone used as add-on treatment to stable, but inadequate, treatment with another class of drug.
SELECTION CRITERIA
We included randomised, double-blind studies of two weeks' duration or longer, comparing any dose or formulation of oxycodone with placebo or another active treatment in chronic neuropathic pain.
DATA COLLECTION AND ANALYSIS
Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio and numbers needed to treat for one additional event, using standard methods.We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table.
MAIN RESULTS
The updated searches identified one additional published study, and one clinical trial registry report. We included five studies reporting on 687 participants; 637 had painful diabetic neuropathy and 50 had postherpetic neuralgia. Two studies used a cross-over design and three used a parallel group design; all studies used a placebo comparator, although one study used an active placebo (benztropine). Modified-release oxycodone (oxycodone MR) was titrated to effect and tolerability. One study used a fixed dose combination of oxycodone MR and naloxone. Two studies added oxycodone therapy to ongoing, stable treatment with either pregabalin or gabapentin. All studies had one or more sources of potential major bias.No study reported the proportion of participants experiencing 'substantial benefit' (at least 50% pain relief or who were very much improved). Three studies (537 participants) in painful diabetic neuropathy reported outcomes equivalent to 'moderate benefit' (at least 30% pain relief or who were much or very much improved), which was experienced by 44% of participants with oxycodone and 27% with placebo (number needed to treat for one additional beneficial outcome (NNT) 5.7).All studies reported group mean pain scores at the end of treatment. Three studies reported a greater pain intensity reduction and better patient satisfaction with oxycodone MR alone than with placebo. There was a similar result in the study adding oxycodone MR to stable, ongoing gabapentin, but adding oxycodone MR plus naloxone to stable, ongoing pregabalin did not show any additional effect.More participants experienced adverse events with oxycodone MR alone (86%) than with placebo (63%); the number needed to treat for an additional harmful outcome (NNH) was 4.3. Serious adverse events (oxycodone 3.4%, placebo 7.0%) and adverse event withdrawals (oxycodone 11%, placebo 6.4%) were not significantly different between groups. Withdrawals due to lack of efficacy were less frequent with oxycodone MR (1.1%) than placebo (11%), with a number needed to treat to prevent one withdrawal of 10. The add-on studies reported similar results.We downgraded the quality of the evidence to very low for all outcomes, due to limitations in the study methods, heterogeneity in the pain condition and study methods, and sparse data.
AUTHORS' CONCLUSIONS
There was only very low quality evidence that oxycodone (as oxycodone MR) is of value in the treatment of painful diabetic neuropathy or postherpetic neuralgia. There was no evidence for other neuropathic pain conditions. Adverse events typical of opioids appeared to be common.
Topics: Adult; Aged; Analgesics, Opioid; Constipation; Delayed-Action Preparations; Diabetic Neuropathies; Disorders of Excessive Somnolence; Dizziness; Female; Humans; Male; Middle Aged; Nausea; Neuralgia, Postherpetic; Oxycodone; Randomized Controlled Trials as Topic
PubMed: 27465317
DOI: 10.1002/14651858.CD010692.pub3 -
Paediatrics & Child Health May 2022Sialorrhea in children can be associated with adverse physical and social effects. Treatment using anticholinergic medications has been shown to offer symptomatic...
BACKGROUND
Sialorrhea in children can be associated with adverse physical and social effects. Treatment using anticholinergic medications has been shown to offer symptomatic relief, but there is no consensus regarding which treatment is the most efficacious.
OBJECTIVE
To examine the effectiveness of anticholinergic medications for sialorrhea in children.
METHODS
A systematic review was carried out in Medline, EMBASE, Cochrane, Scopus, and the Web of Science from inception until April 29, 2020. Studies reporting original data on the efficacy of anticholinergic medications in the management of sialorrhea in children aged 0 to 17 years of age were included. This review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards. Data on study design, setting, population, pharmacologic intervention(s), comparator(s), outcomes, and results were extracted and summarized.
RESULTS
The search strategy identified 2,800 studies of which 27 articles were included in the synthesis, including five randomized controlled trials. Each anticholinergic undergoing experimental study (glycopyrrolate, scopolamine/hyoscine, trihexyphenidyl/benzhexol, benztropine, and atropine) showed evidence of efficacy. Adverse side effects were common. Significant heterogeneity exists in the studies' methodology and the variability of outcome measures used between studies precluded a meta-analysis.
CONCLUSIONS
Glycopyrrolate, scopolamine/hyoscine, trihexyphenidyl/benzhexol, benztropine, and atropine have all shown efficacy in the treatment of sialorrhea in children. The small number of reports and the variability in study design precluded a meta-analysis. More studies are needed with uniformity in outcome measures to help guide evidence-based decision making. A guidance table is presented.
PubMed: 35599670
DOI: 10.1093/pch/pxab051 -
The Cochrane Database of Systematic... Jan 2018Antipsychotic (neuroleptic) medication is used extensively to treat people with serious mental illnesses. However, it is associated with a wide range of adverse effects,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Antipsychotic (neuroleptic) medication is used extensively to treat people with serious mental illnesses. However, it is associated with a wide range of adverse effects, including movement disorders. Because of this, many people treated with antipsychotic medication also receive anticholinergic drugs in order to reduce some of the associated movement side-effects. However, there is also a suggestion from animal experiments that the chronic administration of anticholinergics could cause tardive dyskinesia.
OBJECTIVES
To determine whether the use or the withdrawal of anticholinergic drugs (benzhexol, benztropine, biperiden, orphenadrine, procyclidine, scopolamine, or trihexylphenidyl) are clinically effective for the treatment of people with both antipsychotic-induced tardive dyskinesia and schizophrenia or other chronic mental illnesses.
SEARCH METHODS
We retrieved 712 references from searching the Cochrane Schizophrenia Group's Study-Based Register of Trials including the registries of clinical trials (16 July 2015 and 26 April 2017). We also inspected references of all identified studies for further trials and contacted authors of trials for additional information.
SELECTION CRITERIA
We included reports identified in the search if they were controlled trials dealing with people with antipsychotic-induced tardive dyskinesia and schizophrenia or other chronic mental illness who had been randomly allocated to (a) anticholinergic medication versus placebo (or no intervention), (b) anticholinergic medication versus any other intervention for the treatment of tardive dyskinesia, or (c) withdrawal of anticholinergic medication versus continuation of anticholinergic medication.
DATA COLLECTION AND ANALYSIS
We independently extracted data from included trials and we estimated risk ratios (RR) with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE.
MAIN RESULTS
The previous version of this review included no trials. We identified two trials that could be included from the 2015 and 2017 searches. They randomised 30 in- and outpatients with schizophrenia in the USA and Germany. Overall, the risk of bias was unclear, mainly due to poor reporting: allocation concealment was not described; generation of the sequence was not explicit; studies were not clearly blinded; and outcome data were not fully reported.Findings were sparse. One study reported on the primary outcomes and found that significantly more participants allocated to procyclidine (anticholinergic) had not improved to a clinically important extent compared with those allocated to isocarboxazid (MAO-inhibitor) after 40 weeks' treatment (1 RCT, n = 20; RR 4.20, 95% CI 1.40 to 12.58; very low quality evidence); that there was no evidence of a difference in the incidence of any adverse effects (1 RCT, n = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence); or acceptability of treatment (measured by participants leaving the study early) (1 RCT, n = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence). The other trial compared anticholinergic withdrawal with anticholinergic continuation and found no evidence of a difference in the incidence of acceptability of treatment (measured by participants leaving the study early) (1 RCT, n = 10; RR 2.14, 95% CI 0.11 to 42.52; very low quality evidence).No trials reported on social confidence, social inclusion, social networks, or personalised quality of life - outcomes designated important to patients. No studies comparing either i. anticholinergics with placebo or no treatment, or ii. studies of anticholinergic withdrawal, were found that reported on the primary outcome 'no clinically important improvement in TD symptoms and adverse events'.
AUTHORS' CONCLUSIONS
Based on currently available evidence, no confident statement can be made about the effectiveness of anticholinergics to treat people with antipsychotic-induced tardive dyskinesia. The same applies for the withdrawal of such medications. Whether the withdrawal of anticholinergics may benefit people with antipsychotic-induced TD should be evaluated in a parallel-group, placebo-controlled randomised trial, with adequate sample size and at least 6 weeks of follow-up.
Topics: Antipsychotic Agents; Biperiden; Cholinergic Antagonists; Dyskinesia, Drug-Induced; Humans; Isocarboxazid; Procyclidine; Randomized Controlled Trials as Topic; Schizophrenia; Withholding Treatment
PubMed: 29341071
DOI: 10.1002/14651858.CD000204.pub2 -
International Journal of Molecular... Jul 2021Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS...
Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.
Topics: Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Colonic Neoplasms; Drug Synergism; Drug Therapy, Combination; Female; Fluorouracil; Humans; Paclitaxel; Tumor Cells, Cultured
PubMed: 34299028
DOI: 10.3390/ijms22147408 -
Journal of Neurochemistry Nov 2008The widely abused psychostimulant cocaine is thought to elicit its reinforcing effects primarily via inhibition of the neuronal dopamine transporter (DAT). However, not...
Interaction of cocaine-, benztropine-, and GBR12909-like compounds with wild-type and mutant human dopamine transporters: molecular features that differentially determine antagonist-binding properties.
The widely abused psychostimulant cocaine is thought to elicit its reinforcing effects primarily via inhibition of the neuronal dopamine transporter (DAT). However, not all DAT inhibitors share cocaine's behavioral profile, despite similar or greater affinity for the DAT. This may be due to differential molecular interactions with the DAT. Our previous work using transporter mutants with altered conformational equilibrium (W84L and D313N) indicated that benztropine and GBR12909 interact with the DAT in a different manner than cocaine. Here, we expand upon these previous findings, studying a number of structurally different DAT inhibitors for their ability to inhibit [(3)H]CFT binding to wild-type, W84L and D313N transporters. We systematically tested structural intermediates between cocaine and benztropine, structural hybrids of benztropine and GBR12909 and a number of other structurally heterologous inhibitors. Derivatives of the stimulant desoxypipradrol (2-benzhydrylpiperidine) exhibited a cocaine-like binding profile with respect to mutation, whereas compounds possessing the diphenylmethoxy moiety of benztropine and GBR12909 were dissimilar to cocaine-like compounds. In tests with specific isomers of cocaine and tropane analogues, compounds with 3alpha stereochemistry tended to exhibit benztropine-like binding, whereas those with 3beta stereochemistry were more cocaine-like. Our results point to the importance of specific molecular features--most notably the presence of a diphenylmethoxy moiety--in determining a compound's binding profile. This study furthers the concept of using DAT mutants to differentiate cocaine-like inhibitors from atypical inhibitors in vitro. Further studies of the molecular features that define inhibitor-transporter interaction could lead to the development of DAT inhibitors with differential clinical utility.
Topics: Animals; Asparagine; Aspartic Acid; Benztropine; Binding, Competitive; Cell Line, Transformed; Cocaine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Drug Interactions; Humans; Leucine; Models, Molecular; Mutation; Piperazines; Protein Binding; Protein Structure, Tertiary; Sodium; Structure-Activity Relationship; Transfection; Tritium; Tryptophan
PubMed: 18786172
DOI: 10.1111/j.1471-4159.2008.05667.x