Psychotropics in Your Medicine Cabinet: A Case Study of Dimenhydrinate Use.

: Reporting of intoxication and withdrawal from aberrant use of over-the-counter medication has been sparse and inconsistent in literature. Attributed to their anticholinergic properties, medications such as dimenhydrinate (Gravol) taken in supratherapeutic doses have been associated with euphoria, anxiolysis, and hallucinations. We present a case of a woman in her forties, with a psychiatric history of bipolar disorder, and complex concurrent medical history including familial Mediterranean fever (FMF), and fibromyalgia, admitted for withdrawal management of her intravenous dimenhydrinate use. As a result of her FMF, there were numerous hospital admissions and treatment which required intravenous access. Hence, a physician-inserted intravenous access port was placed on her chest. The port was maintained monthly with the help of a community agency. In this port, she was injecting 100 to 200 mg of dimenhydrinate hourly for its euphoric and calming effects, consuming upwards of 2400 mg/d. Comprehensive laboratory work-up and urine drug screening were unremarkable. Vital signs were stable. Her mental status at time of admission was lethargic, unfocused, but calm. Her withdrawal symptoms included severe nausea, vomiting, sedation, headaches, dizziness, anxiety, and muscle stiffness. Her detoxification was managed with benztropine and lorazepam, and was well tolerated. The patient was discharged to a community inpatient rehabilitation center. Urine drug testing before discharge was negative. This case draws attention to the addictive potential of dimenhydrinate and offers a regime for its medical withdrawal management. Additionally, this case highlights that screening and management of over-the-counter medications warrants further clinical consideration and investigation.

Preventive action of benztropine on platinum-induced peripheral neuropathies and 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.

Further delineation between typical and atypical dopamine uptake inhibitors: effects on food-maintained behavior and food consumption.

The present studies compared the acute effects of benztropine analogs (4-Cl-BZT, JHW 007, AHN 1-055), which are atypical dopamine uptake inhibitors, with those of the standard dopamine uptake inhibitors GBR 12909 and cocaine, on the reinforcing efficacy of food and food intake in male Sprague-Dawley rats. Repeated drug effects of JHW 007 on food intake were also determined. The number of ratios completed under a progressive-ratio schedule of food delivery was used as an index of reinforcing efficacy. Food intake was determined by measuring powdered laboratory-chow consumption during daily 40 min food-availability time periods. Under the progressive-ratio schedule, cocaine and GBR 12909 dose-dependently increased the number of ratios completed. JHW 007 decreased ratios completed, whereas neither 4-Cl-BZT nor AHN 1-055 increased ratios completed with a magnitude that approximated any of the increases produced by cocaine or GBR 12909. Acute administration of each drug dose-dependently decreased food intake; however, the benztropine analogs were more potent than cocaine and GBR 12909. A reduction in food intake emerged after repeated administration of a low dose of JHW 007. Future studies that compare JHW 007 with standard anorectic drugs (e.g. phentermine) and continue investigation of the repeated drug effects under similar experimental procedures are clearly warranted.

Persistence of racial disparities in prescription of first-generation antipsychotics in the USA.

PURPOSE: The aim of this study was to estimate the prevalence of first-generation antipsychotics (FGA) prescribed for treatment of psychiatric and neurological conditions and use of benztropine to reduce extrapyramidal side effects (EPS) by patient race/ethnicity in a nationally representative sample of adult outpatient visits. METHODS: The study sample included all outpatient visits (N = 8154) among patients aged 18-69 years where a prescription for one or more antipsychotics was recorded across 6 years of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (2005-2010). Use of FGA was compared by race/ethnicity using multiple logistic regression models accounting for patient and clinical characteristics stratified by neighborhood poverty rate. Frequency of EPS was determined by use of benztropine to reduce or prevent EPS. RESULTS: Black patients were significantly more likely than White patients to use FGA (odds ratio = 1.48, p = 0.040) accounting for psychiatric and neurological diagnoses, treatment setting, metabolic factors, neighborhood poverty, and payer source. Black patients were more than twice as likely as White patients to receive higher-potency FGA (haloperidol or fluphenazine), particularly in higher-poverty areas (odds ratio = 2.50, p < 0.001). Use of FGA, higher among Black than White patients, was positively associated with use of benztropine to reduce EPS. CONCLUSIONS: Racial disparities in the pharmacological treatment of severe mental disorders persist 30 years after the introduction of second-generation antipsychotics. The relatively high frequency of FGA of use among Black patients compared with White patients despite more Food and Drug Administration-approved indications and lower EPS risk for second-generation antipsychotics requires additional research.

Modulation of methamphetamine's locomotor stimulation and self-administration by JHW 007, an atypical dopamine reuptake blocker.

JHW 007 [N-(n-butil)-3α-[bis(4'-fluorophenil)methoxi]-tropane] belongs to the family of N-substituted benztropine (BZT) analogs, atypical dopamine transporter (DAT) blockers that are able to strongly modulate cocaine- and amphetamine-related behavior. In the present study, we tested in rats the ability of JHW 007 to alter the stimulant and reinforcing properties of methamphetamine (METH) using locomotor activity, fixed ratio and progressive ratio (PR) self-administration tests. The results showed that JHW 007 attenuated METH-induced locomotor stimulation in a dose-dependent manner and had no stimulant effects when administered alone. The BZT analog, given as a pre-treatment, attenuated METH self-administration without affecting responding for sucrose. In the PR tests JHW 007 produced an increase of the breaking point achieved for both METH- and sucrose self-administration, suggesting that the ability of the BZT analog to reduce self-administration may be linked to its ability to enhance the reinforcing properties of METH. Taken together, these data suggest that DAT inhibition with a high affinity blocker such as JHW 007 can exert differential effects on METH-associated behaviors, reducing METH-induced motor stimulation but augmenting METH׳s reinforcing effects.

The stereotypy-inducing effects of N-substituted benztropine analogs alone and in combination with cocaine do not account for their blockade of cocaine self-administration.

RATIONALE: Previous studies have demonstrated that several N-substituted 4', 4″-diF-benztropine (BZT) analogs with high dopamine transporter affinity selectively decreased cocaine self-administration without affecting food-maintained behavior in rats. OBJECTIVES: The present study examined if the decreases in cocaine self-administration are due to competition from excess behavioral activity (hyperlocomotion or stereotypy) induced by the BZT analogs alone or in combination with cocaine. RESULTS: Pretreatments with the typical dopamine uptake inhibitor methylphenidate [1.0, 3.2, and 10 mg/kg, intraperitoneally (i.p.)] dose-dependently shifted the cocaine self-administration dose-effect curve (0, 0.032, 0.1, 0.32, and 1.0 mg/kg/injection) leftward. The shift in the dose-effect curve was obtained at doses of methylphenidate that, when administered alone, also decreased food-maintained behavior and increased locomotor activity and stereotypy. In contrast, the N-substituted BZT analogs, JHW 007 (1.0, 3.2, and 10 mg/kg, i.p.), AHN 1-055 (10 mg/kg), and, AHN 2-005 (10 mg/kg), as previously reported, decreased the maximum for the cocaine self-administration dose-effect curve, and did so at doses that were virtually without effects on food-maintained behavior. Further, the BZT analogs alone had minimal effects on locomotor activity and stereotypies and did not appreciably change the effects of cocaine on these measures when administered in combination with cocaine. CONCLUSIONS: The present results suggest that the decrease in cocaine self-administration produced by the N-substituted BZT analogs is due to an antagonism of the reinforcing effects of cocaine rather than due to interference from competing behavioral overstimulation, and further supports the development of N-substituted BZT analogs as medications to treat cocaine abuse.

A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: potential relevance to attention deficit hyperactivity disorder.

Drugs used to treat attention deficit hyperactivity disorder (ADHD) improve prefrontal cortex (PFC)-dependent cognitive function. The majority of ADHD-related treatments act either as dual norepinephrine (NE) and dopamine (DA) reuptake inhibitors (psychostimulants) or selective NE reuptake inhibitors (SNRIs). Certain benztropine analogs act as highly selective DA reuptake inhibitors while lacking the reinforcing actions, and thus abuse potential, of psychostimulants. To assess the potential use of these compounds in the treatment of ADHD, we examined the effects of a well-characterized benztropine analog, AHN 2-005, on performance of rats in a PFC-dependent delayed-alternation task of spatial working memory. Similar to that seen with all drugs currently approved for ADHD, AHN 2-005 dose-dependently improved performance in this task. Clinically-relevant doses of psychostimulants and SNRIs elevate NE and DA preferentially in the PFC. Despite the selectivity of this compound for the DA transporter, additional microdialysis studies demonstrated that a cognition-enhancing dose of AHN 2-005 that lacked locomotor activating effects increased extracellular levels of both DA and NE in the PFC. AHN 2-005 produced a larger increase in extracellular DA in the nucleus accumbens, although the magnitude of this was well below that seen with motor activating doses of psychostimulants. Collectively, these observations suggest that benztropine analogs may be efficacious in the treatment of ADHD or other disorders associated with PFC dysfunction. These studies provide a strong rationale for future research focused on the neural mechanisms contributing to the cognition-enhancing actions and the potential clinical utility of AHN 2-005 and related compounds. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Substituting a long-acting dopamine uptake inhibitor for cocaine prevents relapse to cocaine seeking.

The treatment of cocaine addiction remains a challenge. The dopamine replacement approach in cocaine addiction involves the use of a competing dopaminergic agonist that might suppress withdrawal and drug craving in abstinent individuals. Although it has long been postulated that such an approach may be therapeutically successful, preclinical or clinical evidence showing its effectiveness to prevent relapse is scant. We used in rats a procedure that involved substitution of the N-substituted benztropine analog 3α-[bis(4'-fluorophenyl)methoxy]-tropane (AHN-1055), a long-acting dopamine uptake inhibitor (DUI), for cocaine. Maintenance treatment was self-administered. After extinction, reinstatement of drug seeking was induced by cocaine priming. We measured the contents of brain-derived neurotrophic factor (BDNF), c-Fos and Fas-associated death domain (FADD) proteins in the medial prefrontal cortex (mPFC) following reinstatement. DUI, but not amphetamine, substitution led to extinction of active lever presses, as did saline substitution. DUI substitution significantly reduced cocaine-induced reinstatement of drug-seeking behavior, which was strongly elicited after saline substitution. Rats passively yoked to DUI also showed reduced cocaine-primed reinstatement. Reductions in drug seeking during reinstatement were matched by downward shifts in the contents of BDNF, c-Fos and FADD proteins in the mPFC, which were elevated in relapsing rats. These data indicate that DUI substitution not only leads to extinction of self-administration behavior but also prevents reinstatement of drug seeking induced by cocaine re-exposure. Thus, DUI substitution therapy using compounds with low abuse potential, even if received passively in the context previously paired with drug taking, may provide an effective treatment for stimulant addiction.

Olanzapine and benztropine as a cause of ischemic colitis in a 27-year-old man.

Ischemic colitis is a rare adverse effect of antipsychotic medications and is most commonly associated with the phenothiazine class of antipsychotics and atypical antipsychotics such as clozapine and olanzapine. The risk is further increased when antipsychotics are taken in conjunction with anticholinergics. A 27-year-old man with a history of bipolar disorder and depression presented to the emergency department with 6 days of constipation, abdominal pain, nausea, and nonbloody vomiting. He later developed multiple episodes of hematochezia and fever. Within the preceding 2 weeks, his medication regimen of divalproex sodium, aripiprazole, and trihexyphenidyl, had been changed to olanzapine, benztropine, and bupropion. The patient's physical examination showed diffuse abdominal tenderness, guarding, and distension and laboratory tests revealed a leukocytosis. A computed tomographic scan of the abdomen/pelvis showed colitis extending from the splenic flexure to the sigmoid colon, without evidence of perforation. A colonoscopy revealed severe ischemic colitis involving the descending and sigmoid colon, which was confirmed on biopsy. Given the temporal association between the new medications and onset of symptoms, the patient's ischemic colitis was likely caused by olanzapine or the combination of olanzapine and benztropine, likely secondary to their anticholinergic properties. Thus, providers should take a thorough history and counsel patients regarding the risks of constipation when starting antipsychotic medications, particularly those with anticholinergic activity. Despite the fact that ischemic colitis is such a rare adverse effect of antipsychotic medications, it is important to consider because of its potentially fatal outcomes.

A dopamine transport inhibitor with markedly low abuse liability suppresses cocaine self-administration in the rat.

RATIONALE: N-substituted benztropine analogs are potent dopamine uptake inhibitors that display pharmacokinetic/dynamic properties consistent with the profile of a substitute medication for cocaine addiction. OBJECTIVES: The purpose of the present experiments was to characterize in rats the addictive-like properties of one such analog, 3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane (AHN-1055), incorporating probes of its stimulant and incentive/motivational effects and of its ability to influence cocaine self-administration. METHODS: We used open field activity and drug self-administration assays. To examine the effects of AHN-1055 on locomotor behavior, the analog was administered alone (0, 1, 3, and 10 mg/kg intraperitoneally) and in combination with cocaine (15 mg/kg i.p.). The influence of AHN-1055 on cocaine's intake was studied by administering the analog (0, 3, and 10 mg/kg i.p.) before the start of the self-administration sessions. To compare the addictive-like properties of AHN-1055 and cocaine, progressive ratio performance and abstinence-induced context-conditioned relapse were evaluated. RESULTS: AHN-1055 evoked robust and sustained locomotor activity when administered alone and increased cocaine-induced locomotor stimulation. Notably, the analog showed by comparison to cocaine weak reinforcing efficacy in a modified progressive ratio schedule of drug reinforcement, and contrary to cocaine, it showed no ability to promote context-conditioned relapse to drug seeking following stable self-administration and abstinence. Further, AHN-1055 treatment blocked cocaine intake dose-dependently in rats with a steady history of cocaine self-administration without reducing responding for sucrose, a natural reward. CONCLUSIONS: These findings demonstrate essential psychopharmacological differences between AHN-1055 and cocaine and highlight important properties of the analog as a possible pharmacotherapy in cocaine addiction.

The dopamine uptake inhibitor 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane reduces cocaine-induced early-gene expression, locomotor activity, and conditioned reward.

Benztropine (BZT) analogs, a family of high-affinity dopamine transporter ligands, are molecules that exhibit pharmacological and behavioral characteristics predictive of significant therapeutic potential in cocaine addiction. Here, we examined in mice the effects of 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane (AHN-1055) on motor activity, conditioned place preference (CPP) and c-Fos expression in the striatum. AHN-1055 produced mild attenuation of spontaneous locomotor activity at a low dose (1 mg/kg) and weak stimulation at a higher dose (10 mg/kg). In parallel, the BZT analog significantly increased c-Fos expression in the dorsolateral caudoputamen at the high dose, whereas producing marginal decreases at low and moderate doses (1, 3 mg/kg) in both dorsal and ventral striatum. Interaction assays showed that cocaine's ability to stimulate locomotor activity was decreased by AHN-1055 treatment, but not by treatment with D-amphetamine. Such reduced ability did not result from an increase in stereotyped behavior. Another dopamine uptake inhibitor, nomifensine, decreased cocaine-induced locomotor activity but evoked by itself intense motor stereotypies. Remarkably, the BZT analog dose-dependently blocked cocaine-induced CPP without producing CPP when given alone, and blocked in conditioned mice cocaine-stimulated early-gene activation in the nucleus accumbens and dorsomedial striatum. These observations provide evidence that AHN-1055 does not behave as a classical psychomotor stimulant and that some of its properties, including attenuation of cocaine-induced striatal c-Fos expression, locomotor stimulation, and CPP, support its candidacy, and that of structurally related molecules, as possible pharmacotherapies in cocaine addiction.

Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats: comparisons with monoamine uptake inhibitors.

Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producing behavioral effects predicting abuse liability. The present study compared reinforcing effects of intravenous BZT analogs with those of standard monoamine uptake inhibitors and the effects of their oral pretreatment on cocaine self-administration. Responding of rats was maintained by cocaine [0.032-1.0 mg/kg/injection (inj)] or food reinforcement under fixed-ratio five-response schedules. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine or substituted methylphenidate, with lower rates maintained at lower and higher doses. The N-methyl BZT analog, AHN 1-055 (3alpha-[bis(4'-fluorophenyl)methoxy]-tropane), also maintained responding (0.1 mg/kg/inj), although maximal rates were less than those with cocaine. Responding was not maintained above vehicle levels by the N-allyl, AHN 2-005 (N-allyl-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane), and N-butyl, JHW 007 [N-(n-butyl)-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane], BZT analogs, and it was not maintained with nisoxetine or citalopram. Presession treatment with methylphenidate (3.2-32 mg/kg) dose-dependently shifted the cocaine self-administration dose-effect curve leftward, whereas nisoxetine and citalopram effects were not significant. An intermediate dose of AHN 1-055 (32 mg/kg) increased responding maintained by low cocaine doses and decreased responding maintained by higher doses. A higher dose of AHN 1-055 completely suppressed cocaine-maintained responding. Both AHN 2-005 and JHW 007 dose-dependently (10-32 mg/kg) decreased cocaine self-administration, shifting its dose-effect curve down. Decreases in cocaine-maintained responding occurred at doses of methylphenidate and BZT analogs that left food-maintained responding unchanged. During a component in which injections were not available, methylphenidate and AHN 1-055, but not AHN 2-005 or JHW 007, increased response rates. These findings further support the low abuse liability of BZT analogs and their potential development as medications for cocaine abuse.

Formulation and biopharmaceutical evaluation of transdermal patch containing benztropine.

Benztropine (BZ) is a potent muscarinic receptor antagonist that has been used for the treatment of Parkinson disease. However, the oral administration of BZ is often limited because of its many dose-related side effects. In this study, BZ was formulated into drug-in adhesive (DIA) patches in an attempt to overcome these problems. The effects of the formulation factors including pressure-sensitive adhesive (PSA), enhancer, the loading amount of the drug and patch thickness on the skin permeation of the drug were evaluated using excised rat skin. The optimized patch contained 10% BZ in Duro-Tak 2525 as a PSA at a thickness of 100 microm. The pharmacokinetic characteristics of the optimized DIA patch were determined after the transdermal application to rabbits. The calculated relative bioavailability of BZ in the DIA patch was 54% compared to the oral administration of BZ mesylate. This suggests that the transdermal application of BZ in a DIA patch may be used for the treatment of Parkinson disease.

Polypharmacy and EPS in a child; a case report.

Extrapyramidal symptoms (EPSs) (dystonic reaction, rigidity, and akathisia) occur as a result of D2 receptor blockade. Selective serotonin-reuptake inhibitors (SSRIs) have been reported to induce extrapyramidal signs and symptoms but tricyclic antidepressants have been rarely reported. Among the side effects attributed to valproic acid administration, the production of EPS is very rare, particularly in children. In this paper we present a case (10-year-old girl) under multiple pharmacologic treatment who developed EPSs (oculogyric crisis) shortly after the adjunct of imipramine to a combination of methylphenidate and valproic acid. Oculogyric crisis occurred on the third day of this combination treatment and these symptoms included ocular pain and sustained upward gaze. Benztropine 2 mg i.m. resulted in rapid relief of oculogyric crisis symptoms.

Benztropine pretreatment does not affect responses to acute cocaine administration in human volunteers.

Benztropine (Cogentin ) was evaluated for its ability to block cocaine's physiological and subjective effects in humans. In healthy, recreational users of cocaine, placebo, or benztropine (1, 2, and 4 mg orally) was given 2 hr before subjects self-administered 0.9 mg/kg of cocaine intranasally. Measurements were made for 2 hr following cocaine administration, and plasma cocaine and cocaine metabolites were assayed. Cocaine produced typical increases in heart rate and alterations in self-reports measured by visual analog scales (VAS). Benztropine alone did not produce changes on any of these measures. Responses to cocaine with and without benztropine pretreatment were similar: benztropine did not change cocaine's effects. This study of one of the tropane-ring analogs that is approved for human use suggests this compound does not alter cocaine-induced effects, but just as importantly, does not produce any adverse behavioral or physiological effects. The exact therapeutic application of benztropine as a possible adjunct treatment for cocaine abuse in humans require further exploration.

Adjunctive topiramate in ultradian cycling bipolar disorder: case report with 3-year follow-up.

A patient with a treatment-refractory bipolar disorder with ultradian cycling responded to adjunctive topiramate. Response was maintained during 3-year follow-up.