- Replacement treatment during extinction training with the atypical dopamine uptake inhibitor, JHW-007, reduces relapse to methamphetamine seeking. [Journal Article]
- NLNeurosci Lett 2018 Feb 13; 671:88-92
- There are currently no approved medications to effectively counteract the effects of methamphetamine (METH), reduce its abuse and prolong abstinence from it. Data accumulated in recent years have sho...
There are currently no approved medications to effectively counteract the effects of methamphetamine (METH), reduce its abuse and prolong abstinence from it. Data accumulated in recent years have shown that a range of N-substituted benztropine (BZT) analogues possesses psychopharmacological features consistent with those of a potential replacement or "substitute" treatment for stimulant addiction. On the other hand, the evidence that antidepressant therapy may effectively prevent relapse to stimulant seeking is controversial. Here, we compared in rats the ability of the BZT analogue and high affinity dopamine (DA) reuptake inhibitor, JHW-007, and the antidepressant, trazodone, administered during extinction sessions after chronic METH self-administration, to alter METH-primed reinstatement of drug seeking. The data showed that trazodone produced paradoxical effects on lever pressing during extinction of METH self-administration, decreasing active, but increasing inactive, lever pressing. JHW-007 did not have any observable effects on extinction training. Importantly, JHW-007 significantly attenuated METH-primed reinstatement, whereas trazodone enhanced it. These findings lend support to the candidacy of selective DA uptake blockers, such as JHW-007, as potential treatments for METH addiction, but not to the use of antidepressant medication as a single therapeutic approach for relapse prevention.
- Use of Selective Serotonin Reuptake Inhibitor and Midodrine in a Patient With Autonomic Instability 2/2 Compressive Squamous Cell Carcinoma and Pain. [Journal Article]
- JIJ Investig Med High Impact Case Rep 2018 Jan-Dec; 6:2324709617749621
- A rare cause of reflex syncope is metastatic cancers involving the head and neck. These can irritate the glossopharyngeal nerve and lead to glossopharyngeal neuralgia with associated syncope. This ty...
A rare cause of reflex syncope is metastatic cancers involving the head and neck. These can irritate the glossopharyngeal nerve and lead to glossopharyngeal neuralgia with associated syncope. This type of syncope is difficult to treat since it commonly involves both a vasodepressor and cardioinhibitory response, and typically requires removal of the irritative focus. We report a case of a 52-year-old male who presented from home with syncope. He endorsed a 5-week history of progressively worsened positional headaches and dramatic 40-pound weight loss with night sweats over 6 months. In the emergency department, his heart rate was noted to drop into the 20s with associated hypotension 60/31 mm Hg. Heart rate and blood pressure increased with intravenous atropine. Physical examination revealed a large ulcerative lesion in the left tonsillar area. After biopsy of the lesion, a diagnosis of stage IV squamous cell carcinoma of the neck was made; computed tomography angiogram and positron emission tomography/computed tomography confirmed involvement in the posterior tongue extending to the left palatine tonsil in addition to the left jugular chain. The patient was started on cisplatin and radiation therapy, but continued to have episodes of syncope associated with bradycardia and hypotension. After a failed trial of benztropine, the patient was started on sertraline and midodrine with resolution of syncope. This could be a potential treatment option in those with compressive mixed syncope who are not candidates for surgery or chemotherapy or are awaiting definitive treatment.
- Anticholinergic medication for antipsychotic-induced tardive dyskinesia. [Review]
- CDCochrane Database Syst Rev 2018 01 17; 1:CD000204
- 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.
- Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus Infection. [Journal Article]
- JMJ Med Chem 2018 Feb 08; 61(3):724-733
- Here, we show that four chemically divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprot...
Here, we show that four chemically divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprotein. Binding of these drugs destabilizes the protein, suggesting that this may be the mechanism of inhibition, as reported for the anticancer drug toremifene and the painkiller ibuprofen, which bind in the same large cavity on the glycoprotein. Crystal structures show that the position of binding and the mode of interaction within the pocket vary significantly between these compounds. The binding constants (Kd) determined by thermal shift assay correlate with the protein-inhibitor interactions as well as with the antiviral activities determined by virus cell entry assays, supporting the hypothesis that these drugs inhibit viral entry by binding the glycoprotein and destabilizing the prefusion conformation. Details of the protein-inhibitor interactions of these complexes and their relation with binding affinity may facilitate the design of more potent inhibitors.
- Reducing Anticholinergic Medication Burden in Patients With Psychotic or Bipolar Disorders. [Journal Article]
- JCJ Clin Psychiatry 2017 Nov/Dec; 78(9):e1270-e1275
- CONCLUSIONS: In this interdisciplinary, collaborative QI project, patients whose anticholinergic burden was reduced experienced a significant improvement in side effects, memory, and quality of life.
- Stability-Indicating UPLC and TLC-Densitometric Methods for Determination of Benztropine Mesylate and Its Carcinogenic Degradation Product. [Journal Article]
- JCJ Chromatogr Sci 2017 Oct 01; 55(9):961-968
- Two accurate, precise and highly selective stability-indicating methods were adopted for simultaneous determination of benztropine mesylate (BNZ) in presence of its hepatotoxic and carcinogenic degra...
Two accurate, precise and highly selective stability-indicating methods were adopted for simultaneous determination of benztropine mesylate (BNZ) in presence of its hepatotoxic and carcinogenic degradation product, benzophenone (BPH) either in pure form or in the pharmaceutical formulation without any preliminary separation steps. The first method is a thin layer chromatography (TLC)-densitometric method that depended on separation of BNZ from its degradate on TLC aluminum plates precoated with silica gel 60 F254 as the stationary phase using a developing system consisted of hexane:methylene chloride:triethylamine (5:5:0.6, by volume) and scanning the separated bands at 235 nm. Linear regression analysis data for the calibration plots of BNZ and BPH showed perfect linear relationships over the concentration range of 1.5-10 and 1-10 μg band-1, respectively. The second method is (UPLC) method, at which the mixture was separated on a reversed phase C8 analytical column (1.9 μm ps, 50 mm × 2.1 i.d.) using a mobile phase of acetonitrile: aqueous sodium dodecyl sulfate (50:50, v/v) Adjusted to pH = 3 with phosphoric acid, at a flow rate of 0.5 mL min-1. Quantification was achieved at 210 nm based on peak area and linear calibration curves over the concentration ranges of (20-200 μg mL-1) and (5-50 μg mL-1) for BNZ and BPH, respectively, were obtained. The investigated methods were successfully applied to available dosage form and method validation has been carried out. The results obtained by applying the proposed methods were statistically analyzed and compared with those obtained by reported one and no significant differences were obtained regarding both accuracy and precision.
- Behavioral economic analysis of the effects of N-substituted benztropine analogs on cocaine self-administration in rats. [Journal Article]
- PPsychopharmacology (Berl) 2018; 235(1):47-58
- CONCLUSIONS: The current findings, obtained using a behavioral economic assessment, suggest that BZT analogs selectively decrease the reinforcing effectiveness of cocaine.
- Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes. [Journal Article]
- JMJ Mol Graph Model 2017; 76:143-151
- The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and a...
The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design.
- The Transcriptome of Type I Murine Astrocytes under Interferon-Gamma Exposure and Remyelination Stimulus. [Journal Article]
- MMolecules 2017 May 15; 22(5)
- Astrocytes are considered to be an important contributor to central nervous system (CNS) disorders, particularly multiple sclerosis. The transcriptome of these cells is greatly affected by cytokines ...
Astrocytes are considered to be an important contributor to central nervous system (CNS) disorders, particularly multiple sclerosis. The transcriptome of these cells is greatly affected by cytokines released by lymphocytes, penetrating the blood-brain barrier-in particular, the classical pro-inflammatory cytokine interferon-gamma (IFNγ). We report here the transcriptomal profiling of astrocytes treated using IFNγ and benztropine, a putative remyelinization agent. Our findings indicate that the expression of genes involved in antigen processing and presentation in astrocytes are significantly upregulated upon IFNγ exposure, emphasizing the critical role of this cytokine in the redirection of immune response towards self-antigens. Data reported herein support previous observations that the IFNγ-induced JAK-STAT signaling pathway may be regarded as a valuable target for pharmaceutical interventions.
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- σ Receptor Effects of N-Substituted Benztropine Analogs: Implications for Antagonism of Cocaine Self-Administration. [Journal Article]
- JPJ Pharmacol Exp Ther 2017; 362(1):2-13
- Several N-substituted benztropine (BZT) analogs are atypical dopamine transport inhibitors as they have affinity for the dopamine transporter (DAT) but have minimal cocaine-like pharmacologic effects...
Several N-substituted benztropine (BZT) analogs are atypical dopamine transport inhibitors as they have affinity for the dopamine transporter (DAT) but have minimal cocaine-like pharmacologic effects and can block numerous effects of cocaine, including its self-administration. Among these compounds, N-methyl (AHN1-055), N-allyl (AHN2-005), and N-butyl (JHW007) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane were more potent in antagonizing self-administration of cocaine and d-methamphetamine than in decreasing food-maintained responding. The antagonism of cocaine self-administration (0.03-1.0 mg/kg per injection) with the above BZT analogs was reproduced in the present study. Further, the stimulant-antagonist effects resembled previously reported effects of pretreatments with combinations of standard DAT inhibitors and σ1-receptor (σ1R) antagonists. Therefore, the present study examined binding of the BZT analogs to σRs, as well as their in vivo σR antagonist effects. Each of the BZT analogs displaced radiolabeled σR ligands with nanomolar affinity. Further, self-administration of the σR agonist DTG (0.1-3.2 mg/kg/injection) was dose dependently blocked by AHN2-005 and JHW007 but potentiated by AHN1-055. In contrast, none of the BZT analogs that were active against DTG self-administration was active against the self-administration of agonists at dopamine D1-like [R(+)-SKF 81297, (±)-SKF 82958 (0.00032-0.01 mg/kg per injection each)], D2-like [R(-)-NPA (0.0001-0.0032 mg/kg per injection), (-)-quinpirole (0.0032-0.1 mg/kg per injection)], or μ-opioid (remifentanil, 0.0001-0.0032 mg/kg per injection) receptors. The present results indicate that behavioral antagonist effects of the N-substituted BZT analogs are specific for abused drugs acting at the DAT and further suggest that σR antagonism contributes to those actions.