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1.
Turk Psikiyatri Derg ; 33(2): 146-148, 2022.
Artigo em Inglês, Turco | MEDLINE | ID: mdl-35730516

RESUMO

Dear Editor, The costs of antipsychotic drugs (APDs) used in the treatment of mental disorders with psychosis are mentioned in treatment guidelines (APA 2021, NICE 2014). While the American Psychiatric Association guideline states that every specialist should make decisions according to the rules and conditions of their country and their region, the National Institute of Health and Clinical Excellence guideline emphasizes that drug costs must be taken into consideration in the treatment process. Classical or first-generation antipsychotic drugs (FAPDs) are relatively cheaper in terms of sales prices compared to atypical or second-generation antipsychotic drugs (SAPDs) with a slightly different effect mechanism. The price difference between the two drug groups can be so large that sometimes it may be necessary to consider whether the cost of a second-generation drug is worth its benefit. While deciding on the use of first-generation or second-generation drugs, a multifaceted assessment should be made, such as the patient's level of compliance with the treatment, the possibility of occurrence of side effects, the possible effects of these side effects on body health and treatment compliance, and whether or not the costs are covered. The most important criterion that determines the choice of medication for psychiatrists is of course the multi-dimensional benefit/harm ratio that the drug used will reveal in the long term. We think that in our country, which, in terms of economic indicators is not in a strong position as an importer of pharmaceutical raw materials from abroad, APDs' cost calculation should be considered because drug costs constitute an important part of the direct treatment costs of psychotic disorders in developing countries such as Turkey (Yildiz and Cerit 2006). We calculated the unit (mg) price based on the box prices of the APDs in use in 2020, thinking that it might work when calculating the cost of the illness using APDs as the main component of the treatment and calculated the annual average drug costs with the daily average dosage. Although the daily treatment dose varies with the stage of the illness and the individual characteristics of the patient, the average doses recommended for maintenance treatment were used here (Öztürk and Ulusahin 2018). The daily and annual cost calculations based on the assumption that the average maintenance treatment dose was used with the unit price obtained from (Drug Prices 2020) the drugs in the Turkish pharmaceutical market in September 2020 are shown in Table 1. A similar study was done in 2005 (Yildiz 2005). The purpose of this article is to redetermine the average costs of APDs in the Turkish pharmaceutical market every 15 years and to bring them to the attention of experts in terms of cost-effectiveness studies. When the costs in 2005 are examined, it is seen that the annual costs of the FAPDs were around 450 TRY, and the annual cost of oral preparations of SAPDs was 2,500 TRY (5 times the first generation). In 2005, there was only one depot of SAPD (risperidon consta) that allowed intramuscular (IM) administration, and its average annual cost was 5,400 TRY, 3 times more than the tablet form (1,700 TRY). In 2005, when the price of risperidone consta, which was the first second-generation depot APD, were compared with the prices of the first-generation depot drugs (fluphenazine = 380 TRY, flupentixol = 876 TRY, zuclopentixol = 730 TRY), the cost difference was 6-14 times. This almost-10-fold difference between the cost of the first and second generation APDs was remarkable. It is seen that this difference (risperidone consta = 10,807 TRY, fluphenazine = 916 TRY, flupentixol = 1,007 TRY, zuclopenthixol = 2,372 TRY, and haloperidol deconate 237 TRY) did not change in 2020. In 2020, the average RETHINKING THE COST OF ANTIPSYCHOTIC TREATMENT: THE AVERAGE COST OF THE DRUGS USED IN TURKEY IN 2020 2 Türk Psikiyatri Dergisi 2 Turkish Journal of Psychiatry Letter to the Editor 146 147 annual cost of oral use preparations of FAPDs is 925 TRY, while the average annual cost of oral forms of SAPDs is 2,580 TRY. The 5-fold difference observed in 2005 between the first and second-generation ones of the oral APDs decreased to 2.5 times in 2020. It is clear that while the difference between the cost of oral use of first- and second-generation drugs was halved in 2020, the difference between the costs of depot preparations applied with IM did not change. In 2005, the average dollar rate was 1.34 TRY, and in 2020 it was 7.02 TRY (Republic of Turkey Central Bank Exchange Rates, 2021). It is understood that the 5-fold increase in dollar exchange rate is not reflected in all drug prices in the same way. For example, there was a 3 to 4-fold increase in the prices of haloperidol, chlorpromazine, fluphenazine, trifluperazine and zuclopenthixol, while a less than two-fold increase in pimozide, flupenthixol, sulpiride, amisulpride and quetiapine and a decrease in the prices of clozapine, olanzapine, ziprasidone and risperidone in the tablet form. There is also a two-fold increase in the price of risperidone consta. The fluctuations in drug prices in 2005 and 2020 are shown in Table 2 in 500, 1,000, 2,000, 3,000 and 5,000 TRY brackets. It is noteworthy that while some drugs have moved into an upper price bracket in terms of annual costs, some have fallen into a lower price bracket. The prices of the second generation long-acting (depot) antipsycotic drugs (LA-APDs), which were not available in the Turkish pharmaceutical market in 2005, are quite high compared to others. In 2020, the annual cost of all of them, including risperidone consta, is over 10 thousand TRY. It is understood that the underlying reason for such price increase is the fact that the drug is wanted/sought after/new/marketed rather than the dollar exchange rate. For example, while there was a certain increase in the price of FAPDs, the increase in the price of some of the SAPDs (sulpiride, amisulpride, quetiapine tablet) was low, while the price of some others (clozapine, olanzapine, ziprasidone, risperidone tablet) decreased. It should also be taken into account that the effect of generic drugs entering the market during this period may have had an impact on price changes. It is noteworthy that while the annual cost of risperidone consta was approximately 3 times higher than the tablet form (5,400 TRY versus 1,700 TRY) in 2005, this difference reached 14 folds (10,807 TRY versus 742 TRY) in 2020. In 2005, the difference between the lowest daily cost (0.07 TRY) and the highest daily cost (14.80 TRY) was 211 times (Yildiz 2005), this difference had receded to 111 times (0.35 TRY versus 38.72 TRY) in 2020. Still a huge difference, isn't it? Table 1. Current Forms, Box Prices, Daily and Annual Costs in For Maintenance Treatment of Antipsychotic Drugs Available in the Pharmaceutical Market in September 2020 in Turkey No Generic name Trade name Dosage forms (mg) BV Price# TRY/Mg ADD Cost/d Cost/y 2005** 1 Haloperidol Norodol 5, 10, 20 tb 5/50 17.57 0.070 5 0.35 127 26 5, 10 amp 5/5 5.35 0.214 5 1.07 390 - 50, 150 LAI 50/1 9.80 0.196 1/15* 0.65 237 - 2 Chlorpromazine Largactil 25,100 tb 100/30 17.92 0.006 300 1.79 653 197 3 Fluphenazine Prolixin 25 LAI 25/1 17.57 0.703 1/7* 2.51 916 380 4 Trifluoperazine Stilizan 1, 2, 5 drj; 1 amp 5/30 14.52 0.096 10 0.97 354 91 5 Pimozide Nörofren 2 tb 2/30 19.33 0.322 4 1.29 470 365 6 Flupenthixol Fluanxol 3 drj 3/50 65.75 0.438 6 2.63 960 526 20 LAI 20/1 19.33 0.966 1/7* 2.76 1,007 876 7 Zuklopenthixol Clopixol 2, 10, 25 tb 2/50 38.65 0.386 20 7.72 2,817 701 200 LAI, 50 acu 200/1 45.55 0.227 1/7* 6.50 2,372 730 8 Sulpirid Dogmatil 200 tb 200/24 23.15 0.005 600 3.00 1,095 876 9 Amisulpirid Solian 200 tb 200/60 146.92 0.012 600 7.20 2,628 2,387 10 Quetiapine Seroquel 25, 50, 100, 200, 300, 400 tb 300/30 137.17 0.015 600 9.00 3,285 2,628 11 Clozapine Leponex 25, 100 tb 100/50 32.56 0.006 400 2.40 876 1,898 12 Olanzapine Zyprexa 5, 10, 20 tb 10/28 152.96 0.546 10 5.46 1,992 2,606 13 Ziprasidone Zeldox 20, 40, 60, 80 tb 60/56 189.89 0.056 120 6.72 2,452 3,541 14 Sertindole Serdolect 4, 12, 16, 20 tb 16/28 453.53 1.012 16 16.19 5,909 - 15 Risperidone Risperdal 1, 2, 3, 4 tb; 1 sol 2/20 20.34 0.508 4 2.03 741 1,719 Ris. Consta 25, 37.5, 50 LAI 37.5/1 444.17 11.840 1/15* 29.61 10,807 5,402 16 Paliperidone Invega 3, 6, 9 tb 6/28 213.15 1.268 6 7.61 2,777 - Xeplion 50, 75, 100, 150 LAI 100/1 1161.56 11.615 1/30* 38.72 14,132 - Trevicta 175, 263, 350, 525 LAI 350/1 3426.95 9.788 1/90* 38.08 13,899 - 17 Aripiprazole Abilify 5, 10, 15, 20 tb; 1 sol 20/28 113.25 0.404 20 8.08 2,949 - Abilify Main. 400 LAI 400/1 971.17 2.420 1/30* 32.37 11,815 - BV: Baseline value (in mg of the form and the number in the box), Price#: Box price of the base value in TRY, TRY/mg: Value per milligram in Turkish Lira, ADD: Average daily dose, Cost/d: Daily cost in TRY, Cost/y: Annual cost in TRY, mg: Milligram, tb: Tablet, drj: Dragee, amp: Ampoule, LAI: Long-acting injectable, acu: Acuphase, d: Day, TRY: Turkish Lira, *LAI per 7,15,30 or 90 days, **Annual cost in TRY in 2005. 148 Received: 14.01.2021, Accepted: 31.03.2021, Available Online Date: 07.01.2022 1Prof., 2Res. Assis., Kocaeli University School of Medicine, Department of Psychiatry, Kocaeli, Turkey. e-mail: myildiz60@yahoo.com https://doi.org/10.5080/u26315 The difference in 2005 between oral FAPDs prices and SAPDs prices seems to have halved in 2020. In 2020, the average daily treatment cost of oral drugs, whether for the first generation or the second generation, is 3 TRY (approximately the same for FAPDs applied with IM), while the daily cost of LA-SAPDs is around 33 TRY. It is seen that the difference between costs is approximately 11 times. This difference increases to 50 times for haloperidol deconate. From here, the following judgment can be made: in order for LA-SAPDs to be preferred, they must be at a value that willconstitute at least 11 times higher cost. This cost can and should be taken, especially for patients who are non-adherend with treatment and who do not adapt to LA-FAPDs. Because for clinicians, preventing the multi-dimensional destructiveness of psychosis in the individual, families and the society should be the priority. In this case, calculating the cost should not be a primary consideration. However, it is also known that patients who are non-adherend with treatment gain the ability to understand their illness and make consistent evaluations with its' results. If a psychosocial therapy has been carried out for a patient using IM medication for six months or a year, it is likely that this period provides insight and increases the level of treatment compliance. After one year of IM application, whether or not the patient will comply with oral treatment should be re-evaluated and the transition to oral treatment should be considered. If there is no problem in the patient's oral treatment compliance, it should be taken into account that the benefit of this transition will be at least 11-folds a year with this transition. Naturally, it will be necessary to apply IM for some patients for years. Moreover, there will be patients who need to switch from monthly administration of LA-SAPDs to quarterly usage patterns. However, we can say that most patients using LA-APDs will not need such use after a while, based on our clinical practice, although there is no study done in this field. With this study, we wanted to emphasize that while prescribing drugs used in the treatment of illnesses with psychotic symptoms, they should take into account the side effects of the drugs, as well as the daily, monthly, annual, and lifetime costs of the drugs. The principle of 'using an effective drug recommended for a specific disorder at the required dose, in sufficient time, at the lowest cost' adopted in the rational drug use guidelines should not be forgotten. It is expected that the modification of drug treatments, considering their costs as well as their efficiency, will contribute significantly to the country's economy in the long run. Mustafa Yildiz1, Emre Osman2 REFERENCES American Psychiatric Association (2021) The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Third edition. Washington, DC: American Psychiatric Association. Drug Prices. https://www.ilacrehberi.com/ilac-fihrist/ Accession date: 25th September 2020. National Institute for Health and Clinical Excellence (NICE) (2014) Psychosis and schizophrenia in adults: prevention and management. NICE Guideline CG178; https://www.nice.org.uk/guidance/cg178. Accession date: 4th April 2018. Öztürk MO, Ulusahin NA (2018) Mental Health and Disorders. 18th Edit. Ankara: Nobel Tip Kitapevleri. (In Turkish) Republic of Turkey Central Bank Exchange Rates. https://www.tcmb.gov.tr/kurlar/kurlar_tr.html Accession date: 10th January 2021. Yildiz M (2005) The cost of treatment of psychotic disorders. Turk Psikiyatri Derg 16:146-7. (In Turkish) Yildiz M, Cerit C (2006) Annual cost of treatment for schizophrenia: Estimation from a university hospital data in Turkey. Bulletin of Clinical Psychopharmacology 16:239-44. Table 2. Comparison of the Annual Costs of Antipsychotic Drugs Calculated By The Daily Standard Average Dose Use, at Certain Price Ranges, for the Years 2005 and 2020 Price bracket (TRY) 2005 2020 500 ↓ Haloperidol tb, amp, Trifluoperazine drj, Chlorpromazine tb, Pimozid tb, Fluphenazine LAI Haloperidol tb, amp, depo, Trifluoperazine drj, Pimozid tb 500-1,000 Flupenthixol drj, LAI, Zuklopenthixol tb, acu, LAI, Sulpirid tb Chlorpromazine tb, Fluphenazine LAI, Flupenthixol drj, LAI, Clozapine tb, Risperidone tb 1,000-2,000 Clozapine tb, Risperidone tb Olanzapine tb, Sulpirid tb 2,000-3,000 Amisulpirid tb, Olanzapine tb, Quetiapine tb Zuklopenthixol tb, acu, LAI, Amisulpirid tb, Ziprasidone tb, Paliperidone tb, Aripiprazole tb 3,000-5,000 Ziprasidone tb Quetiapine tb 5,000-10,000 Risperidone consta Sertindole tb 10,000 ↑ Risperidone consta, Paliperidone monthly, Paliperidone 3 monthly, Aripiprazole maintana tb: Tablet, drj: Dragee, amp: Ampoule, LAI: Long-acting injectable, acu: Acuphase.


Assuntos
Antipsicóticos , Clozapina , Monofosfato de Adenosina , Adulto , Amissulprida , Aripiprazol , Benzodiazepinas/efeitos adversos , Clorpromazina , Clopentixol , Clozapina/uso terapêutico , Flupentixol , Flufenazina , Haloperidol , Humanos , Olanzapina , Palmitato de Paliperidona , Preparações Farmacêuticas , Pimozida , Fumarato de Quetiapina , Risperidona , Sulpirida/uso terapêutico , Trifluoperazina
2.
Behav Brain Res ; 425: 113827, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35248650

RESUMO

Our aims were to assess the effect of melatonin on fluphenazine-induced hypokinesia during the light (ZT 9.5-10.5) and dark (ZT 17.5-18.5) phases in mice lacking endogenous pineal melatonin (C57BL/6 mouse), and to investigate the effects of the manipulation of environmental lighting in mice with a targeted deletion of the MT1 melatonin receptor. In both knockout (C57KO MT1) and wild type (C57WT) mice, fluphenazine (1 mg/kg) induced hypokinesia during the light phase (C57WT: M=105, SEM=31.2 s, n = 31; C57 MT1KO:M=118, SEM = 32.6 s, n = 29). During the light phase melatonin (10 mg/kg, sc) significantly reduced hypokinesia in both genotypes (C57WT: M=33.1, SEM=8.4 s; C57 MT1KO: M=33.3, SEM=13.0 s). In the dark, fluphenazine did not induce a substantial hypokinesia in either C57WT or C57 MT1KO mice. Manipulating the lightning environment during testing, experiments conducted during the light phase in a dark environment served to abolish the hypokinetic effect of fluphenazine in all groups regardless of melatonin treatment. Conversely, experiments conducted during the dark phase in a light environment showed mice to have hypokinetic effects by fluphenazine treatment in both C57WT (M=98.4, SEM=20.2 s) and C57 MT1KO (M=40.4 SEM=9.5 s) groups. These data suggest that fluphenazine-induced hypokinesia is more pronounced under light than dark conditions, and that melatonin is only able to counteract hypokinesia during the light phase. Importantly, our data suggest that the effect of melatonin on hypokinesia was not solely mediated by the MT1 melatonin receptor in the C57BL/6 mouse, leaving the possible activation of MT2 receptor as the mechanism of action which is regulated by the light/dark environment.


Assuntos
Melatonina , Glândula Pineal , Animais , Ritmo Circadiano , Flufenazina/efeitos adversos , Hipocinesia/induzido quimicamente , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glândula Pineal/metabolismo , Receptor MT1 de Melatonina/genética , Receptor MT2 de Melatonina/genética
3.
J Clin Pharm Ther ; 47(4): 562-566, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34750842

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Long-acting injectable (LAI) antipsychotics are an integral part of mental health treatment. Modifying an LAI regimen poses several challenges because of the extended half-life of the drug. CASE SUMMARY: An acutely psychotic patient with schizoaffective disorder received aripiprazole lauroxil without resolution of symptoms. She was started on a previously successful regimen of oral fluphenazine. Due to continued psychosis, oral carbamazepine was initiated to expedite the LAI's metabolism allowing subsequent doses of fluphenazine to impart activity. WHAT IS NEW AND CONCLUSION: Potent cytochrome enzyme inducers may help in transitioning patients from LAI antipsychotics to other therapies.


Assuntos
Antipsicóticos , Esquizofrenia , Aripiprazol , Benzodiazepinas , Carbamazepina/uso terapêutico , Preparações de Ação Retardada , Feminino , Flufenazina/uso terapêutico , Humanos , Esquizofrenia/tratamento farmacológico
4.
Am J Psychiatry ; 178(5): 424-436, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33596679

RESUMO

OBJECTIVE: This study compared relapse prevention and acceptability of long-acting injectable (LAI) antipsychotics in the maintenance treatment of adults with nonaffective psychoses. METHODS: The authors searched MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, and online registers for randomized controlled trials published until June 2020. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse rate and all-cause discontinuation ("acceptability"). The quality of included studies was rated with the Cochrane Risk of Bias tool, and the certainty of pooled estimates was measured with GRADE (Grading of Recommendations Assessment, Development, and Evaluation). RESULTS: Of 86 eligible trials, 78 (N=11,505) were included in the meta-analysis. Regarding relapse prevention, most of the 12 LAIs included outperformed placebo. The largest point estimates and best rankings of LAIs compared with placebo were found for paliperidone (3-month formulation) and aripiprazole. Moderate to high GRADE certainty for superior relapse prevention compared with placebo was also found for (in descending ranking order) risperidone, pipothiazine, olanzapine, and paliperidone (1-month formulation). In head-to-head comparisons of LAIs, only haloperidol was inferior to aripiprazole, fluphenazine, and paliperidone. For acceptability, most LAIs outperformed placebo, with moderate to high GRADE certainty for (in descending ranking order) zuclopenthixol, aripiprazole, paliperidone (3-month formulation), olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). In head-to-head comparisons, only LAI aripiprazole had superior acceptability to other LAIs (bromperidol, fluphenazine, paliperidone [1-month formulation], pipothiazine, and risperidone). CONCLUSIONS: LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine, and paliperidone (1-month formulation) showed the highest effect sizes and certainty of evidence for both relapse prevention and acceptability. Results from this network meta-analysis should inform frontline clinicians and guidelines.


Assuntos
Antipsicóticos/administração & dosagem , Aceitação pelo Paciente de Cuidados de Saúde , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Aripiprazol/administração & dosagem , Clopentixol/administração & dosagem , Preparações de Ação Retardada , Flupentixol/administração & dosagem , Flufenazina/administração & dosagem , Haloperidol/administração & dosagem , Humanos , Injeções Intramusculares , Metanálise em Rede , Olanzapina/administração & dosagem , Palmitato de Paliperidona/administração & dosagem , Fenotiazinas/administração & dosagem , Risperidona/administração & dosagem , Prevenção Secundária
5.
J Appl Toxicol ; 41(1): 82-94, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32852120

RESUMO

Drug repositioning is an approach that could accelerate the clinical use of compounds in different diseases. The goal is to take advantage of the fact that approved drugs have been tested on humans and detailed information is available on their pharmacology, toxicity and formulation. It can significantly reduce the costs and time needed to implement necessary therapies on the market. In recent years, phenothiazines are being tested for cancer, viral, bacterial, fungal and other diseases. Most research focuses on chlorpromazine as a model drug in this class, but other drugs such as fluphenazine, perphenazine and prochlorperazine have been proven to inhibit the viability of different cancer cell lines. In this study, we performed an extensive literature search to find and summarize all papers on the chosen phenothiazines and their potential in treating different types of cancerin vitro for further animal/clinical trials. Fluphenazine, perphenazine and prochlorperazine possess anticancer activity towards different types of human cancer. The antitumor activity is mainly mediated by an effect of the drugs on the cell cycle, proliferation or apoptosis. Possible molecular targets of phenothiazine derivatives are the drug's efflux pumps (ABCB1 and P-glycoprotein) and two parallel pathways (AKT and Wnt) regulated by the D2 receptor antagonists. The drugs have the potential to reduce the viability of human cancer cell lines, fragment the DNA, stimulate apoptosis, inhibit cell migration and invasiveness as well as impair the production of reactive oxygen species. In addition, due to the sedative and antiemetic properties antipsychotics can be used as an adjuvant for the treatment of chemotherapy side effects.


Assuntos
Antineoplásicos/uso terapêutico , Antipsicóticos/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Reposicionamento de Medicamentos , Flufenazina/uso terapêutico , Neoplasias/tratamento farmacológico , Perfenazina/uso terapêutico , Proclorperazina/uso terapêutico , Humanos , Técnicas In Vitro
6.
Mol Cell Neurosci ; 109: 103562, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32987141

RESUMO

Abnormal dendritic arbor development has been implicated in a number of neurodevelopmental disorders, such as autism and Rett syndrome, and the neuropsychiatric disorder schizophrenia. Postmortem brain samples from subjects with schizophrenia show elevated levels of NOS1AP in the dorsolateral prefrontal cortex, a region of the brain associated with cognitive function. We previously reported that the long isoform of NOS1AP (NOS1AP-L), but not the short isoform (NOS1AP-S), negatively regulates dendrite branching in rat hippocampal neurons. To investigate the role that NOS1AP isoforms play in human dendritic arbor development, we adapted methods to generate human neural progenitor cells and neurons using induced pluripotent stem cell (iPSC) technology. We found that increased protein levels of either NOS1AP-L or NOS1AP-S decrease dendrite branching in human neurons at the developmental time point when primary and secondary branching actively occurs. Next, we tested whether pharmacological agents can decrease the expression of NOS1AP isoforms. Treatment of human iPSC-derived neurons with d-serine, but not clozapine, haloperidol, fluphenazine, or GLYX-13, results in a reduction in endogenous NOS1AP-L, but not NOS1AP-S, protein expression; however, d-serine treatment does not reverse decreases in dendrite number mediated by overexpression of NOS1AP isoforms. In summary, we demonstrate how an in vitro model of human neuronal development can help in understanding the etiology of schizophrenia and can also be used as a platform to screen drugs for patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Dendritos/ultraestrutura , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia , Neurônios/citologia , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Células Cultivadas , Clozapina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Flufenazina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/fisiologia , Haloperidol/farmacologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Canais Iônicos/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Células-Tronco Neurais/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligopeptídeos/farmacologia , Técnicas de Patch-Clamp , Isoformas de Proteínas/fisiologia , Esquizofrenia/etiologia , Esquizofrenia/genética , Serina/farmacologia
7.
Eur J Pharmacol ; 887: 173553, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949606

RESUMO

In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.


Assuntos
Antipsicóticos/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fenotiazinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Vírus de RNA/efeitos dos fármacos , Animais , Antipsicóticos/uso terapêutico , Antivirais/uso terapêutico , COVID-19 , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Flufenazina/farmacologia , Flufenazina/uso terapêutico , Humanos , Pandemias , Perfenazina/farmacologia , Perfenazina/uso terapêutico , Fenotiazinas/uso terapêutico , Proclorperazina/farmacologia , Proclorperazina/uso terapêutico , SARS-CoV-2 , Tioridazina/farmacologia , Tioridazina/uso terapêutico
8.
SLAS Discov ; 25(10): 1123-1140, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32804597

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of pandemic coronavirus disease 2019 (COVID-19). So far, no approved therapy has been developed to halt the spread of the pathogen, and unfortunately, the strategies for developing a new therapy will require a long time and very extensive resources. Therefore, drug repurposing has emerged as an ideal strategy toward a smart, versatile, quick way to confine the lethal disease. In this endeavor, natural products have been an untapped source for new drugs. This review represents the confederated experience of multidisciplinary researchers of 99 articles using several databases: Google Scholar, Science Direct, MEDLINE, Web of Science, Scopus, and PubMed. To establish the hypothesis, a Bayesian perspective of a systematic review was used to outline evidence synthesis. Our docking documentation of 69 compounds and future research agenda assumptions were directed toward finding an effective and economic anti-COVID-19 treatment from natural products. Glucosinolate, flavones, and sulfated nitrogenous compounds demonstrate direct anti-SARS-CoV-2 activity through inhibition protease enzymes and may be considered potential candidates against coronavirus. These findings could be a starting point to initiate an integrative study that may encompass interested scientists and research institutes to test the hypothesis in vitro, in vivo, and in clinics after satisfying all ethical requirements.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Flufenazina/farmacologia , Glucosinolatos/farmacologia , SARS-CoV-2/genética , Antivirais/química , Teorema de Bayes , Produtos Biológicos/química , Produtos Biológicos/farmacologia , COVID-19/etiologia , Coronavirus/genética , Flufenazina/química , Predisposição Genética para Doença , Variação Genética , Genoma Viral , Glucosinolatos/química , Interações Hospedeiro-Patógeno , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Simulação de Acoplamento Molecular , Uso Off-Label , Pneumonia Viral/etiologia , Estudos Retrospectivos , SARS-CoV-2/patogenicidade
9.
Mol Syst Biol ; 16(7): e9628, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32729248

RESUMO

The COVID-19 pandemic caused by SARS-CoV-2 has is a global health challenge. Angiotensin-converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID-19 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2-upregulating drugs, while antineoplastic agents are enriched for ACE2-downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID-19, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Células A549 , Enzima de Conversão de Angiotensina 2 , Betacoronavirus , Bleomicina/farmacologia , COVID-19 , Dexametasona/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Cloridrato de Erlotinib/farmacologia , Flufenazina/farmacologia , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Células MCF-7 , Pandemias , Peptidil Dipeptidase A , SARS-CoV-2 , Biologia de Sistemas , Regulação para Cima , Vemurafenib/farmacologia
12.
Elife ; 92020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32167471

RESUMO

Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.


Assuntos
Agonistas dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Macrófagos/metabolismo , Cloridrato de Raloxifeno/farmacologia , Animais , Benzilisoquinolinas/farmacologia , Cálcio/metabolismo , Agonistas dos Canais de Cálcio/química , Canais de Cálcio/genética , Flufenazina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Ionomicina/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , NADP/análogos & derivados , NADP/metabolismo , Fosfatos de Fosfatidilinositol/farmacologia , Imagem Individual de Molécula , Sódio/metabolismo
13.
J Antimicrob Chemother ; 75(5): 1187-1193, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32011702

RESUMO

BACKGROUND: In recent decades, Candida glabrata has emerged as a frequent cause of life-threatening fungal infection. In C. glabrata, echinocandin resistance is associated with mutations in FKS1/FKS2 (ß-1,3-glucan synthase). The calmodulin/calcineurin pathway is implicated in response to antifungal stress and calcineurin gene disruption specifically reverses Fks2-mediated resistance of clinical isolates. OBJECTIVES: We evaluated the impact of calmodulin inhibition by fluphenazine in two caspofungin-resistant C. glabrata isolates. METHODS: C. glabrata isolates were identified by ITS1/ITS4 (where ITS stands for internal transcribed spacer) sequencing and the echinocandin target FKS1/FKS2 genes were sequenced. Susceptibility testing of caspofungin in the presence of fluphenazine was performed by a modified CLSI microbroth dilution method. The effect of the fluphenazine/caspofungin combination on heat stress (37°C or 40°C), oxidative stress (0.2 and 0.4 mM menadione) and biofilm formation (polyurethane catheter) was analysed. A Galleria mellonella model using blastospores (1 × 109 cfu/mL) was developed to evaluate the impact of this combination on larval survival. RESULTS: F659del was found in the FKS2 gene of both resistant strains. In these clinical isolates, fluphenazine increased susceptibility to caspofungin and reduced their thermotolerance. Furthermore, the fluphenazine/caspofungin combination significantly impaired biofilm formation in an in vitro polyurethane catheter model. All these features participated in the increasing survival of infected G. mellonella after combination treatment in comparison with caspofungin alone. CONCLUSIONS: In a repurposing strategy, our findings confirm that calmodulin could provide a relevant target in life-threatening fungal infectious diseases.


Assuntos
Candida glabrata , Flufenazina , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Biofilmes , Calmodulina/genética , Candida glabrata/genética , Caspofungina , Farmacorresistência Fúngica , Equinocandinas/farmacologia , Flufenazina/farmacologia , Testes de Sensibilidade Microbiana , Virulência
14.
Arch. Soc. Esp. Oftalmol ; 95(2): 84-89, feb. 2020. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-195331

RESUMO

La dopamina es sintetizada por la tirosina hidroxilasa y es considerada como una catecolamina mayor en la retina de los vertebrados, incluyendo el pez cebra. Sin embargo, se conoce poco sobre la función del receptor de dopamina D2 (DRD2) en la fisiología retiniana. Por lo tanto, para dilucidar el papel del DRD2 en el desarrollo y la función de los ojos en el pez cebra, los peces fueron expuestos a la flufenazina, quinpirol, o la combinación de ambos, y luego se evaluó el tamaño del ojo, el diámetro del nervio óptico (ONd) y la adaptación visual al fondo. Los resultados mostraron que la flufenazina (flufenazina, antagonista DRD2) disminuyó el tamaño del ojo y el diámetro del nervio óptico seguido de una interrupción de la función visual. La adición de quinpirol (quinpirol, agonista DRD2) invirtió los efectos causados por flufenazina, lo que implica que DRD2 es necesario para el desarrollo y la función normal del ojo en el pez cebra. Considerando el papel de las neuronas dopaminérgicas en el desarrollo y la función de la retina, la disfunción de las vías de señalización de las neuronas dopaminérgicas en la retina puede causar anormalidades visuales, particularmente en la participación de la dopamina en la regulación de la respuesta de la luz


Dopamine is synthesized by tyrosine hydroxylase and is considered as a major catecholamine in the vertebrate retina, including zebrafish. However, little is known about the role of dopamine D2 receptor (DRD2) in retinal physiology. Therefore, to elucidate the role of DRD2 in the eye development and function in zebrafish, fish were exposed to fluphenazine, quinpirole, or combination of both. Subsequently, the eye size, optic nerve diameter (ONd), and visual background adaptation were evaluated. The results showed that fluphenazine (fluphenazine, DRD2 antagonist) decreased eye size and optic nerve diameter followed by disruption of visual function. The addition of Quinpirole (quinpirole, DRD2 agonist) reversed the effects caused by fluphenazine, implying that DRD2 is necessary for normal eye development and function in zebrafish. Considering the role of dopaminergic neurons in retinal development and function, dysfunction of dopaminergic neuron signaling pathways in the retina may cause visual abnormalities, particularly in the involvement of dopamine in regulating light response


Assuntos
Animais , Antagonistas dos Receptores de Dopamina D2/farmacologia , Olho/embriologia , Fenômenos Fisiológicos Oculares , Receptores de Dopamina D2/fisiologia , Olho/anatomia & histologia , Olho/crescimento & desenvolvimento , Flufenazina/farmacologia , Imuno-Histoquímica , Tamanho do Órgão , Quimpirol/farmacologia
15.
Arch Soc Esp Oftalmol (Engl Ed) ; 95(2): 84-89, 2020 Feb.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31955999

RESUMO

Dopamine is synthesized by tyrosine hydroxylase and is considered as a major catecholamine in the vertebrate retina, including zebrafish. However, little is known about the role of dopamine D2 receptor (DRD2) in retinal physiology. Therefore, to elucidate the role of DRD2 in the eye development and function in zebrafish, fish were exposed to fluphenazine, quinpirole, or combination of both. Subsequently, the eye size, optic nerve diameter (ONd), and visual background adaptation were evaluated. The results showed that fluphenazine (fluphenazine, DRD2 antagonist) decreased eye size and optic nerve diameter followed by disruption of visual function. The addition of Quinpirole (quinpirole, DRD2 agonist) reversed the effects caused by fluphenazine, implying that DRD2 is necessary for normal eye development and function in zebrafish. Considering the role of dopaminergic neurons in retinal development and function, dysfunction of dopaminergic neuron signaling pathways in the retina may cause visual abnormalities, particularly in the involvement of dopamine in regulating light response.


Assuntos
Antagonistas dos Receptores de Dopamina D2/farmacologia , Olho/embriologia , Fenômenos Fisiológicos Oculares , Receptores de Dopamina D2/fisiologia , Animais , Olho/anatomia & histologia , Olho/crescimento & desenvolvimento , Flufenazina/farmacologia , Imuno-Histoquímica , Tamanho do Órgão , Quimpirol/farmacologia
16.
Spectrochim Acta A Mol Biomol Spectrosc ; 227: 117563, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31689607

RESUMO

Phenothiazines are very effective antipsychotic drugs, which also have anticancer and antimicrobial activities. Despite being used in human treatment, the molecular mechanism of the biological actions of these molecules is not yet understood in detail. The role of the interactions between phenothiazines and proteins or lipid membranes has been much discussed. Herein, fourier-transform infrared (FTIR) spectroscopic studies were used to investigate the effect of three phenothiazines: fluphenazine (FPh); chlorpromazine (ChP); and propionylpromazine (PP) on the structures of a positively charged poly-l-lysine (PLL) peptide, a negatively charged dipalmitoylphosphatidylcholine/dipalmitoylphosphatidylglycerol (DPPC/DPPG) membrane, and on the mutual interactions between electrostatically associated PLL molecules and DPPC/DPPG membranes. Phenothiazine-induced alterations in the secondary structure of PLL, the conformational state (trans/gauche) of the hydrocarbon lipid chains, and the hydration of the DPPC/DPPG membrane interface were studied on the basis of amide I' vibrations, antisymmetric and symmetric stretching vibrations of the CH2 groups of the lipid hydrocarbon chains (νsCH2), and stretching vibrations of the lipid C=O groups (νC = O), respectively. It was shown that in the presence of negatively charged DPPC/DPPG membranes, the phenothiazines were able to modify the secondary structure of charged PLL molecules. Additionally, the effect of PLL on the structure of DPPC/DPPG membranes was also altered by the presence of the phenothiazine molecules.


Assuntos
1,2-Dipalmitoilfosfatidilcolina/metabolismo , Antipsicóticos/farmacologia , Clorpromazina/farmacologia , Flufenazina/farmacologia , Fosfatidilgliceróis/metabolismo , Promazina/análogos & derivados , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Polilisina/metabolismo , Promazina/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
17.
Artigo em Português | Coleciona SUS, Coleciona SUS, CONASS, SES-GO | ID: biblio-1118711

RESUMO

Tecnologia: Palmitato de Paliperidona (PP) é um antipsicótico injetáveis de efeito prolongado (AIEP). Indicação: Tratamento sintomático da esquizofrenia. Objetivo: Comparar a eficácia, segurança e efetividade terapêutica entre PP e outros AIEP para o tratamento de esquizofrenia em adultos. Pergunta: O PP é mais eficaz e seguro que os outros AIEP (Decanoato de Haloperidol, Enantato de Flufenazina, Decanoato de Zuclopentixol, Risperidona-IEP) para o tratamento sintomático de esquizofrenia em adultos? Métodos: Levantamento bibliográfico, com estratégias estruturadas de busca, na base de dados PUBMED. Foi feita avaliação da qualidade metodológica das revisões sistemáticas (RS), ensaios clínicos randomizados (ECR) e dos estudos observacionais de efetividade no mundo real (EOEMR) com as ferramentas Assessing the Methodological Quality of Systematic Reviews (AMSTAR), Delphi List e Newcastle-Ottawa Scale (NOS), respectivamente. Resultados: Foram selecionadas 3 RS, 1 ECR e 3 EOEMR. Conclusão: PP (de aplicação mensal) tem similar eficácia e segurança com a Risperidona-IEP para o tratamento de esquizofrenia, exceto que provoca menor incidência de sintomas extrapiramidais. PP e Decanoato de Haloperidol são similares na eficácia e segurança para o tratamento de esquizofrenia, inclusive no risco de sintomas extrapiramidais (discinesias tardias e parkinsonismo), exceto que PP tem menor incidência de acatisia. PP é similar aos outros AIEP nos vários desfechos de eficácia e segurança terapêutica, inclusive mortalidade


Technology: Paliperidone palmitate (PP) is a long-acting injectable (LAI) antipsychotics. Indication: Symptomatic treatment of schizophrenia. Objective: To compare the therapeutic efficacy, safety and effectiveness in the real world between PP and other LAI antipsychotics for the treatment of schizophrenia in adults. Question: Is PP more effective and safer than other LAI antipsychotics (Haloperidol Decanoate, Fluphenazine Enanthate, Zuclopentixol Decanoate, Risperidone-LAI), for the symptomatic treatment of schizophrenia? Methods: Bibliographic survey, with structured search strategies, in the PUBMED database. Na evaluation was made of the methodological quality of systematic reviews (SR), randomized clinical trials (RCT) and observational studies (OS) of effectiveness in the real world with Assessing the Methodological Quality of Systematic Reviews (AMSTAR), Delphi List and Newcastle-Ottawa Scale (NOS) tools, respectively. Results: 3 SR, 1 RCT and 3 OE were included. Conclusion: PP (monthly dose presentation) has similar efficacy and safety with Risperidone-LAI for the treatment of schizophrenia, except that it causes a lower incidence of extrapyramidal symptoms. PP and Haloperidol Decanoate are similar in efficacy and safety for the treatment of schizophrenia, including the risk of extra-pyramidal symptoms (tardive dyskinesias and parkinsonism), except that PP has a lower incidence of akathisia. PP has similar outcomes of efficacy and safety to the other LAI antipsychotics, including mortality risk


Assuntos
Humanos , Esquizofrenia/tratamento farmacológico , Antipsicóticos/uso terapêutico , Palmitato de Paliperidona/uso terapêutico , Clopentixol/uso terapêutico , Risperidona/uso terapêutico , Medicina Baseada em Evidências , Flufenazina/uso terapêutico , Haloperidol/uso terapêutico
18.
Anticancer Res ; 39(7): 3757-3765, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262902

RESUMO

BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment. MATERIALS AND METHODS: Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. RESULTS: Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine-nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gp-overexpressing drug-resistant KBV20C cells. CONCLUSION: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drug-resistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.


Assuntos
Antimitóticos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Inibidores da Protease de HIV/farmacologia , Cetonas/farmacologia , Lopinavir/farmacologia , Nelfinavir/farmacologia , Vincristina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Flufenazina/farmacologia , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Ritonavir/farmacologia
19.
Appl Microbiol Biotechnol ; 103(16): 6701-6709, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201451

RESUMO

Candida albicans causes a high mortality rate in immunocompromised individuals, but the increased drug resistance challenges the current antifungal therapeutics. Fluphenazine (FPZ), a commonly used antipsychotic medication, can induce the expression of drug efflux pumps in C. albicans and, thus, may interfere with the therapeutic efficacy of antifungals, such as fluconazole (FLC) and amphotericin B (AmB). Here, we investigated the combined effects of FLC/FPZ and AmB/FPZ against C. albicans in vitro and in a systemic candidiasis mouse model. The antifungal activity of FLC was significantly reduced when supplemented with FPZ. The inhibitory effects of FLC on the expression of the Candida virulence-related genes ALS3 and HWP1 were antagonized by FPZ. However, FPZ enhanced the susceptibility of C. albicans to AmB and further downregulated the expression of ALS3 and HWP1 in a synergistic manner with AmB. FPZ also enhanced the gene expression of ERG11, a key gene of the ergosterol biosynthesis pathway that has been associated with the activities of both FLC and AmB. In our mammalian infection model, mice treated with FLC/FPZ showed notably poor living status and increased fungal burden in their kidneys and brains compared with those treated with FLC alone. Conversely, the combined application of AmB/FPZ significantly improved the survival rate, attenuated the weight loss and reduced the organ fungal burdens of the infected mice. These data suggest that FPZ antagonized the therapeutic efficacy of FLC but enhanced the antifungal activity of AmB in the treatment of candidiasis.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Antipsicóticos/farmacologia , Candida albicans/efeitos dos fármacos , Interações Medicamentosas , Fluconazol/farmacologia , Flufenazina/farmacologia , Anfotericina B/administração & dosagem , Estruturas Animais , Animais , Antifúngicos/administração & dosagem , Antipsicóticos/administração & dosagem , Candidíase/tratamento farmacológico , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Fluconazol/administração & dosagem , Flufenazina/administração & dosagem , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Camundongos , Resultado do Tratamento
20.
J Psychopharmacol ; 33(8): 1015-1029, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31219367

RESUMO

BACKGROUND: The functional role of dopamine D1 and D2 receptors in gambling disorder (GD) remains unclear. AIMS: This study aimed to investigate the role of D1 activation and the moderating effects of impulsivity, a trait linked with weaker D2-mediated inhibition of dopamine release, in GD subjects. METHODS: Thirty (nine female) non-comorbid GD subjects with low (LI), moderate (MI), or high impulsivity (HI) received the preferential D2 antagonist haloperidol (HAL; 3 mg) or the mixed D1-D2 antagonist fluphenazine (FLU; 3 mg), on separate sessions before a 15-minute slot machine game or amphetamine (AMPH; 20 mg), in a placebo-controlled, double-blind, counterbalanced design. RESULTS: On their own, HAL and FLU led to linear increases and decreases, respectively, in desire to gamble across increasing levels of impulsivity. The slot machine and AMPH each evoked an inverted-U pattern of desire to gamble across increasing impulsivity. HAL reversed this effect of the game, whereas FLU did not alter post-game desire. HAL and FLU decreased and increased psychostimulant-like effects of the game, respectively, in LI and MI subjects, but consistently reduced these effects in HI subjects. HAL also altered the salience of negative affective words on a reading task, such that greater salience of negative words coincided with lower post-game desire to gamble. CONCLUSIONS: D1 receptors appear to gauge the incentive value of gambling in GD subjects. D1 activation has negative reinforcing effects in HI gamblers and positive reinforcing effects in LI gamblers. Medications that activate D1 could curtail chasing in HI gamblers. D1 blockade could benefit HI gamblers whose main concern is craving.


Assuntos
Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Jogo de Azar/tratamento farmacológico , Jogo de Azar/fisiopatologia , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Adulto , Anfetamina/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Método Duplo-Cego , Feminino , Flufenazina/uso terapêutico , Haloperidol/uso terapêutico , Humanos , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Reforço Psicológico
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