Flupenthixol
Thioxanthenes
Dopamine Antagonists
Trifluperidol
Encyclopedias as Topic
Antipsychotic Agents
Clopenthixol
Clozapine
Stimulation of P-glycoprotein-mediated drug transport by prazosin and progesterone. Evidence for a third drug-binding site. (1/89)
P-glycoprotein is a plasma membrane protein of mammalian cells that confers multidrug resistance by acting as a broad-specificity, ATP-dependent efflux transporter of diverse lipophilic neutral or cationic compounds. Previously, we identified two positively cooperative drug-binding sites of P-glycoprotein involved in transport [Shapiro, A. B. & Ling, V. (1997) Eur. J. Biochem. 250, 130-137]. The H site is selective for Hoechst 33342 and colchicine. The R site is selective for rhodamine 123 and anthracyclines. Substrate binding to one site stimulates transport by the other. In this paper, we show that prazosin and progesterone stimulate the transport of both Hoechst 33342 and rhodamine 123. Rhodamine 123 and prazosin (or progesterone) in combination stimulate Hoechst 33342 transport in an additive manner. In contrast, Hoechst 33342 and either prazosin or progesterone interfere with each other, so that the stimulatory effect of the combination on rhodamine 123 transport is less than that of each individually. Non-P-glycoprotein-specific effects of prazosin on membrane fluidity and permeability were excluded. These results indicate the existence of a third drug-binding site on P-glycoprotein with a positive allosteric effect on drug transport by the H and R sites. This allosteric site appears to be one of the sites of photoaffinity labeling of P-glycoprotein by [125I]iodoarylazidoprazosin [Safa, A. R., Agresti, M., Bryk, D. & Tamai, I. (1994) Biochemistry 33, 256-265] and is likely not to be capable of drug transport. (+info)Effects of flupenthixol and quadazocine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys. (2/89)
The simultaneous i.v. administration of heroin and cocaine, called "speedball," is often reported clinically, and identification of effective pharmacotherapies for polydrug abuse is a continuing challenge. This study compared the effects of treatment using combinations of dopamine and opioid antagonists with each antagonist alone on speedball self-administration by rhesus monkeys. Speedballs (0.01 mg/kg/inj cocaine and 0.0032 mg/kg/inj heroin) and food (1 g banana pellets) were available in four daily sessions on a second-order schedule of reinforcement [FR4 (VR16:S)]. Monkeys were treated for 10 days with saline or ascending 1:10 dose combinations of the dopamine antagonist flupenthixol and the opioid antagonist quadazocine. The combination of flupenthixol (0.018 mg/kg/day) + quadazocine (0.18 mg/kg/day) significantly reduced speedball self-administration in comparison to the saline treatment baseline (p < .05), whereas, the same doses of each antagonist alone had no significant effect on speedball-maintained responding. Treatment with 0.018 mg/kg/day flupenthixol + 0.18 mg/kg/day quadazocine produced a 3-fold rightward shift in the speedball (3:1 cocaine-heroin combination) dose-effect curve. Food-maintained responding was similar during treatment with saline and with flupenthixol + quadazocine combinations. These findings suggest that medication mixtures designed to target both the stimulant and opioid component of the speedball combination, may be an effective approach to polydrug abuse treatment. (+info)The interaction of neuroleptic and muscarinic agents with central dopaminergic systems. (3/89)
1. The effect of muscarinic and neuroleptic agents on the turning behaviour induced by methamphetamine and apomorphine in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine has been examined. 2. Turning towards the side of the lesion induced by (+)-methamphetamine (5 mg/kg) was inhibited by alpha-flupenthixol (1 mg/kg) and alpha-clopenthixol (8 mg/kg) but not by high doses of their beta-isomers. 3. Turning was inhibited by chlorpromazine (4 mg/kg) and pimozide (0.2 mg/kg). Thioridazine and clozapine (16 mg/kg) were ineffective. Turning in the same direction produced by scopolamine (10 mg/kg) was also inhibited by alpha-flupenthixol (1 mg/kg) and pimozide (0.25 mg/kg). 4. Turning produced by methamphetamine (5 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) even in the presence of methylatropine (5 mg/kg). 5. Turning away from the side of the lesion induced by apomorphine (0.1 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) but not by thioridazine or clozapine (16 mg/kg). 6. These results are discussed with regard to the mode of action of neuroleptic drugs in producing anti-psychotic effects and drug-induced Parkinsonism. (+info)Flupenthixol decanoate and relapse prevention in alcoholics: results from a placebo-controlled study. (4/89)
Flupenthixol, with its broad receptor profile, interacts with a variety of dopamine and serotonin binding sites which are important in the neurobiology of alcohol dependence. Its pharmacology, together with encouraging results from both animal studies and clinical trials with cocaine users, led us to postulate that flupenthixol would significantly prevent relapse in detoxified alcohol-dependent individuals. We conducted a prospective, randomized, double-blind, placebo-controlled, multi-centre trial with two parallel groups and appropriate statistical evaluation. Subjects met criteria for moderate to severe alcohol dependence (DSM-III-R), without any concomitant psychiatric disorder. After complete detoxification, 281 women and men received either 10 mg of flupenthixol decanoate or placebo as i.m. injection every second week for 6 months on an out-patient basis, followed by 6 months of follow-up. Efficacy was based on absolute abstinence, with relapse being defined as consumption of any alcohol after inclusion in the study. In contrast to the hypothesis, flupenthixol did not reduce, but was associated with more, relapses. Though well tolerated, relapse rates after 6 months of treatment were 85.2% (flupenthixol) versus 65.5% (placebo), a highly significant difference from the medication. Flupenthixol was also inferior to placebo with regard to other secondary criteria of efficacy (cumulative abstinence duration, relapse rate after 12 months). These results indicate that a 10 mg dose of flupenthixol decanoate does not have a beneficial effect on abstinence maintenance in alcohol-dependent individuals. (+info)Differential involvement of NMDA, AMPA/kainate, and dopamine receptors in the nucleus accumbens core in the acquisition and performance of pavlovian approach behavior. (5/89)
Stimuli paired with primary rewards can acquire emotional valence and the ability to elicit automatic, Pavlovian approach responses that have been shown to be mediated by the nucleus accumbens. The present experiment investigated the effects of infusions of glutamatergic or dopaminergic receptor antagonists into the core of the nucleus accumbens on the acquisition and performance of Pavlovian discriminated approach to an appetitive conditioned stimulus. Rats were trained on an autoshaping task in which a conditioned stimulus (CS+; a lever) was inserted into the operant chamber for 10 sec, after which a food pellet was delivered. Presentation of another lever (CS-) was never followed by food. Subjects developed a conditioned response of approaching and contacting the CS+ selectively, although food delivery was not in any way contingent on the animals' response. A triple dissociation in the effects of AP-5, LY293558 [(3SR, 4aRS, 6RS, 8aRS)-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline- 3-carboxylic acid], and alpha-flupenthixol infused into the nucleus accumbens core on the acquisition and performance of this conditioned response was observed. The AMPA/kainate receptor antagonist LY293558 disrupted discriminated approach performance but not acquisition, as evidenced by increased approaches to the CS-. In contrast, the NMDA receptor antagonist AP-5 impaired only the acquisition, but not performance, of autoshaping whereas the dopamine D1/D2 receptor antagonist alpha-flupenthixol decreased approaches to the CS+ during both acquisition and performance. The data are discussed with reference to dissociable interactions of these receptor types with limbic cortical and dopaminergic afferents to the nucleus accumbens core during the acquisition and expression of Pavlovian conditioned approach. (+info)Flow-injection chemiluminometric determination of some thioxanthene derivatives in pharmaceutical formulations and biological fluids using the [Ru(dipy)3(2+)]-Ce(IV) system. (6/89)
A flow-injection (FI) methodology using tris(2,2'-dipyridyl)ruthenium(II), [Ru(dipy)3(2+)], chemiluminescence (CL) was developed for the rapid and sensitive determination of three thioxanthene derivatives, namely zuclopenthixol hydrochloride, flupentixol hydrochloride and thiothixene. The method is based on the CL reaction of the studied thioxanthenes with [Ru(dipy)3(2+)] and Ce(IV) in a sulfuric acid medium. Under the optimum conditions, calibration graphs were obtained over the concentration ranges 0.002-6 migrograms/ml for zuclopenthixol hydrochloride, 0.5-15 micrograms/ml for flupentixol hydrochloride and 0.05-7.5 micrograms/ml for thiothixene. The limits of detection (s/n = 3) were 4.2 x 10(-9) mol/l zuclopenthixol hydrochloride, 2 x 10(-8) mol/l flupentixol hydrochloride and 4.5 x 10(-8) mol/l thiothixene. The method was successfully applied to the determination of these compounds in dosage forms and biological fluids. (+info)Rapid assessment of choice between cocaine and food in rhesus monkeys: effects of environmental manipulations and treatment with d-amphetamine and flupenthixol. (7/89)
The present study describes a procedure that permits rapid assessment of environmental and pharmacological factors that may influence the choice between cocaine and food in rhesus monkeys. Daily 2 h sessions were divided into five components. During each component, monkeys (N=4) chose between i.v. cocaine (0-0.1 mg/kg/injection) and food (0, 1, or 3 food pellets). Up to 10 reinforcers were available during each component, and different discriminative stimuli were associated with each magnitude of each reinforcer. Cocaine choice was directly related to cocaine dose, and a cocaine choice dose-effect curve could be determined in a single experimental session. The choice between cocaine and food was influenced by the schedules of cocaine and food reinforcement, the magnitude of the food reinforcer, and the amount of noncontingent food provided outside the experimental session. These results confirm and extend previous findings with other choice procedures and validate the sensitivity of the present procedure to environmental manipulations. The choice between cocaine and food could also be influenced by treatment with candidate pharmacotherapies for cocaine abuse and dependence. The "agonist" medication d-amphetamine produced rightward shifts in the cocaine choice dose-effect curve and decreased cocaine choice, whereas the "antagonist" medication flupenthixol had little effect on cocaine choice. Overall, these results suggest that this choice procedure may be useful for the evaluation of both environmental determinants of cocaine use and candidate pharmacotherapies for the treatment of cocaine abuse. (+info)Allosteric modulation of human P-glycoprotein. Inhibition of transport by preventing substrate translocation and dissociation. (8/89)
The human multidrug transporter P-glycoprotein (Pgp, ABCB1) contributes to the poor bioavailability of many anticancer and antimicrobial agents as well as to drug resistance at the cellular level. For rational design of effective Pgp inhibitors, a clear understanding of its mechanism of action and functional regulation is essential. In this study, we demonstrate that inhibition of Pgp-mediated drug transport by cis-(Z)-flupentixol, a thioxanthene derivative, occurs through an allosteric mechanism. Unlike competitive inhibitors, such as cyclosporin A and verapamil, cis-(Z)-flupentixol does not interfere with substrate ([(125)I]iodoarylazidoprazosin) recognition by Pgp, instead it prevents substrate translocation and dissociation, resulting in a stable but reversible Pgp-substrate complex. cis-(Z)-Flupentixol-induced complex formation requires involvement of the Pgp substrate site, because agents that either physically compete (cyclosporin A) for or indirectly occlude (vanadate) the substrate-binding site prevent formation of the complex. Allosteric modulation by cis-(Z)-flupentixol involves a conformational change in Pgp detectable by monoclonal antibody UIC2 binding to a conformation-sensitive external epitope of Pgp. The conformational change observed is distinct from that induced by Pgp substrates or competitive inhibitors. A single amino acid substitution (F983A) in TM12 of Pgp that impairs inhibition by cis-(Z)-flupentixol of Pgp-mediated drug transport also affects stabilization of the Pgp-substrate complex as well as the characteristic conformational change. Taken together, our results describe the molecular mechanism by which the Pgp modulator cis-(Z)-flupentixol allosterically inhibits drug transport. (+info)Flupenthixol is an antipsychotic medication that belongs to the chemical class of diphenylbutylpiperidines. It has potent dopamine D2 receptor blocking activity and moderate serotonin 5-HT2A receptor blocking activity, which makes it effective in managing various psychiatric disorders.
Flupenthixol is primarily used for the treatment of chronic schizophrenia and other related psychotic disorders. It can help alleviate symptoms such as hallucinations, delusions, thought disorders, and hostility. Additionally, flupenthixol may also be used off-label to manage depression, anxiety, and aggression in individuals with developmental disabilities or dementia.
The medication is available in two forms: immediate-release tablets (Flupenthixol decanoate) for short-term use and a long-acting depot injection (Flupenthixol dihydrochloride) that can be administered every 2-4 weeks, providing sustained therapeutic levels of the drug.
As with any medication, flupenthixol should be used under the close supervision of a healthcare professional due to potential side effects and interactions with other drugs. Common side effects include extrapyramidal symptoms (involuntary muscle movements), sedation, weight gain, and sexual dysfunction. Rare but serious adverse reactions may include neuroleptic malignant syndrome, tardive dyskinesia, and metabolic disorders.
Thioxanthenes are a group of heterocyclic organic compounds that contain a thioxanthene nucleus, which is a six-membered ring containing five carbon atoms and one sulfur atom. Thioxanthenes are structurally related to phenothiazines and have been used in the synthesis of various pharmaceutical drugs, particularly antipsychotic medications.
In medical terms, thioxanthenes refer to a class of antipsychotic drugs that are used to treat various psychiatric disorders such as schizophrenia and related conditions. These drugs work by blocking dopamine receptors in the brain, which helps to reduce the symptoms of psychosis such as hallucinations, delusions, and disordered thinking.
Some examples of thioxanthene antipsychotics include chlorprothixene, thiothixene, and flupenthixol. Like other antipsychotic medications, thioxanthenes can have side effects such as extrapyramidal symptoms (EPS), which are movement disorders that can cause stiffness, tremors, or spasms. Other potential side effects of thioxanthenes may include sedation, orthostatic hypotension, and weight gain.
Dopamine antagonists are a class of drugs that block the action of dopamine, a neurotransmitter in the brain associated with various functions including movement, motivation, and emotion. These drugs work by binding to dopamine receptors and preventing dopamine from attaching to them, which can help to reduce the symptoms of certain medical conditions such as schizophrenia, bipolar disorder, and gastroesophageal reflux disease (GERD).
There are several types of dopamine antagonists, including:
1. Typical antipsychotics: These drugs are primarily used to treat psychosis, including schizophrenia and delusional disorders. Examples include haloperidol, chlorpromazine, and fluphenazine.
2. Atypical antipsychotics: These drugs are also used to treat psychosis but have fewer side effects than typical antipsychotics. They may also be used to treat bipolar disorder and depression. Examples include risperidone, olanzapine, and quetiapine.
3. Antiemetics: These drugs are used to treat nausea and vomiting. Examples include metoclopramide and prochlorperazine.
4. Dopamine agonists: While not technically dopamine antagonists, these drugs work by stimulating dopamine receptors and can be used to treat conditions such as Parkinson's disease. However, they can also have the opposite effect and block dopamine receptors in high doses, making them functionally similar to dopamine antagonists.
Common side effects of dopamine antagonists include sedation, weight gain, and movement disorders such as tardive dyskinesia. It's important to use these drugs under the close supervision of a healthcare provider to monitor for side effects and adjust the dosage as needed.
Trifluperidol is a potent, long-acting typical antipsychotic drug that is primarily used in the management of chronic schizophrenia. It belongs to the chemical class of diphenylbutylpiperidines and has strong antagonist activity at dopamine D2 receptors.
The medical definition of Trifluperidol can be stated as follows:
Trifluperidol (INN, BAN), also known as Etrafon, Stelazine, or Trilafon, is a potent antipsychotic medication used to treat chronic schizophrenia and related psychotic disorders. It has a high affinity for dopamine D2 receptors and exhibits strong antagonist activity, which contributes to its therapeutic effects in managing positive symptoms of schizophrenia such as hallucinations, delusions, and disorganized thinking.
Trifluperidol is available in oral and injectable forms, with the latter being used for more rapid symptom control or when oral administration is not feasible. Its long-acting properties make it suitable for once-daily dosing, although its use has declined in recent years due to the availability of newer atypical antipsychotic medications with fewer side effects.
Like other typical antipsychotics, Trifluperidol can cause extrapyramidal symptoms (EPS), including akathisia, dystonia, parkinsonism, and tardive dyskinesia, as well as other adverse effects such as sedation, orthostatic hypotension, and weight gain. Its use should be monitored closely to minimize these risks and optimize therapeutic outcomes.
An encyclopedia is a comprehensive reference work containing articles on various topics, usually arranged in alphabetical order. In the context of medicine, a medical encyclopedia is a collection of articles that provide information about a wide range of medical topics, including diseases and conditions, treatments, tests, procedures, and anatomy and physiology. Medical encyclopedias may be published in print or electronic formats and are often used as a starting point for researching medical topics. They can provide reliable and accurate information on medical subjects, making them useful resources for healthcare professionals, students, and patients alike. Some well-known examples of medical encyclopedias include the Merck Manual and the Stedman's Medical Dictionary.
Antipsychotic agents are a class of medications used to manage and treat psychosis, which includes symptoms such as delusions, hallucinations, paranoia, disordered thought processes, and agitated behavior. These drugs work by blocking the action of dopamine, a neurotransmitter in the brain that is believed to play a role in the development of psychotic symptoms. Antipsychotics can be broadly divided into two categories: first-generation antipsychotics (also known as typical antipsychotics) and second-generation antipsychotics (also known as atypical antipsychotics).
First-generation antipsychotics, such as chlorpromazine, haloperidol, and fluphenazine, were developed in the 1950s and have been widely used for several decades. They are generally effective in reducing positive symptoms of psychosis (such as hallucinations and delusions) but can cause significant side effects, including extrapyramidal symptoms (EPS), such as rigidity, tremors, and involuntary movements, as well as weight gain, sedation, and orthostatic hypotension.
Second-generation antipsychotics, such as clozapine, risperidone, olanzapine, quetiapine, and aripiprazole, were developed more recently and are considered to have a more favorable side effect profile than first-generation antipsychotics. They are generally effective in reducing both positive and negative symptoms of psychosis (such as apathy, anhedonia, and social withdrawal) and cause fewer EPS. However, they can still cause significant weight gain, metabolic disturbances, and sedation.
Antipsychotic agents are used to treat various psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder with psychotic features, delusional disorder, and other conditions that involve psychosis or agitation. They can be administered orally, intramuscularly, or via long-acting injectable formulations. The choice of antipsychotic agent depends on the individual patient's needs, preferences, and response to treatment, as well as the potential for side effects. Regular monitoring of patients taking antipsychotics is essential to ensure their safety and effectiveness.
Clopenthixol is a type of antipsychotic medication that is primarily used to manage and treat symptoms associated with various mental health disorders, such as schizophrenia and other psychotic disorders. It belongs to a class of drugs known as "typical" or "first-generation" antipsychotics, which work by blocking dopamine receptors in the brain.
Clopenthixol has potent activity at both dopamine D2 and serotonin 5-HT2 receptors, which contributes to its efficacy in treating positive symptoms of schizophrenia, such as hallucinations and delusions, as well as negative symptoms, like apathy and social withdrawal. It is also used off-label for the treatment of agitation and aggression in individuals with dementia or intellectual disabilities.
The medication is available in two forms: immediate-release tablets (Clopenthixol decanoate) and a long-acting injectable form (Clopenthixol decanoate). The long-acting injection is typically administered every 2-4 weeks, while the oral tablet is taken daily.
Like all medications, clopenthixol can have side effects, which may include extrapyramidal symptoms (EPS), such as Parkinsonism, akathisia, and dystonia; weight gain; metabolic changes; sexual dysfunction; and cardiovascular issues. It is essential to monitor patients taking clopenthixol for these potential adverse effects and adjust the treatment plan accordingly.
It's important to note that clopenthixol should only be prescribed and administered under the supervision of a qualified healthcare professional, and patients should follow their instructions carefully to ensure safe and effective use.
Clozapine is an atypical antipsychotic medication that is primarily used to treat schizophrenia in patients who have not responded to other antipsychotic treatments. It is also used off-label for the treatment of severe aggression, suicidal ideation, and self-injurious behavior in individuals with developmental disorders.
Clozapine works by blocking dopamine receptors in the brain, particularly the D4 receptor, which is thought to be involved in the development of schizophrenia. It also has a strong affinity for serotonin receptors, which contributes to its unique therapeutic profile.
Clozapine is considered a medication of last resort due to its potential side effects, which can include agranulocytosis (a severe decrease in white blood cell count), myocarditis (inflammation of the heart muscle), seizures, orthostatic hypotension (low blood pressure upon standing), and weight gain. Because of these risks, patients taking clozapine must undergo regular monitoring of their blood counts and other vital signs.
Despite its potential side effects, clozapine is often effective in treating treatment-resistant schizophrenia and has been shown to reduce the risk of suicide in some patients. It is available in tablet and orally disintegrating tablet formulations.