RESUMEN
BACKGROUND: Prochlorperazine maleate (PCM) is a phenothiazine antipsychotic used in the treatment of nausea, vomiting and vertigo. It is BCS class II drug with only 12.5% bioavailability. Patents data on PCM had shown work on conjugation and matrix formulation which suggested idea for the present work design. OBJECTIVE: The objective of this study was to enhance solubility of drug and to optimize gastro retentive floating capsule for controlled drug release at the targeted site for stipulated time. METHOD: The solubility of drug was determined in various vehicles like oils, surfactants and cosurfactants. Pseudo ternary phase diagrams were constructed to identify the efficient self emulsifying region. SMEDDS were tested for micro emulsifying properties. The resultant microemulsions were evaluated and were further selected for the floating drug delivery. Magnesium hydroxide was used as carrier to transform SMEDDS into Solid SMEDD (S-SMEDD). Non-effervescent floating capsule containing S-SMEDD were optimized using factorial design with independent variable HPMC K4M and ethyl cellulose. RESULTS: SMEDD consists of PCM, isopropyl myristate, tween 80 and PEG 400 as a drug, oil, surfactant and co-surfactant (1:1 ratio). Optimized formulation F5 showed 10 hrs floating time and percent drug release 91.56±2.7% with controlled drug delivery in stomach. F5 followed Korsmeyer Peppas release kinetics where the drug followed Fickian diffusion transport mechanism due to swelling of polymers in controlled manner. CONCLUSION: It can be concluded that SMEDD enhanced the solubility of drug and floating capsule gave site specific drug release of PCM with the advantages of reduced dosing frequency and better compliance.
Asunto(s)
Antipsicóticos/administración & dosificación , Proclorperazina/administración & dosificación , Antipsicóticos/farmacocinética , Disponibilidad Biológica , Preparaciones de Acción Retardada , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Estabilidad de Medicamentos , Emulsiones , Excipientes , Mucosa Gástrica/metabolismo , Patentes como Asunto , Proclorperazina/farmacocinética , SolubilidadRESUMEN
CONTEXT: Controlled release (CR) matrix tablet of Prochlorperazine maleate was developed to improve its patient compliance. METHODS: Tablet formulations F1, F2 and F3 based on different concentrations of Methocel(®) K100 LV-CR Premium, were compacted by direct compression method while tablet formulations F4, F5 and F6, based on distinct blends of Methocel(®) K100 LV-CR Premium and Ethocel(®) Standard 7FP Premium, were compressed by flow-bound dry granulation-slugging method. The prepared powder mixtures, granules and tablets were evaluated for their physicochemical performance. Bioequivalence study of the optimized test tablet versus reference-conventional Stemitil(®) tablet was conducted on rabbits, using HPLC-UV system at λ(max) 254 nm. RESULTS: The test tablet, containing 28% Methocel(®) and 58% Ethocel(®) (F6) exhibited desired zero order kinetics for 24 h and was found stable at accelerated storage conditions for 6 months. In vitro drug release rate decreased as the Ethocel(®) content in the blend was increased, perhaps due to slower penetrability of water. Hydrodynamic conditions and hardness of tablets could not affect drug release kinetics. The tablet displayed significantly (p < 0.05) optimized peak drug concentration-C(max) (45 ± 3.42 vs. 64.5 ± 4.03), extended half life-t(1/2) (16.071 ± 3.97 vs. 5.257 ± 1.314 h) and bioequivalence to the reference tablet taken three times a day (1409 ± 15 ng·h/mL vs. 1346 ± 23 ng h/mL). The tablet showed strong Level A correlation (R(2) = 0.8458) between drug absorbed in vivo and drug released in vitro. CONCLUSIONS: The developed tablet may be adopted by pharmaceutical industry to improve patient compliance of the Prochlorperazine maleate.
Asunto(s)
Antipsicóticos/farmacocinética , Celulosa/análogos & derivados , Metilcelulosa/farmacología , Proclorperazina/farmacocinética , Animales , Antipsicóticos/química , Disponibilidad Biológica , Celulosa/farmacología , Cromatografía Líquida de Alta Presión , Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos , Humanos , Masculino , Polímeros/química , Polímeros/farmacocinética , Proclorperazina/química , Conejos , Comprimidos , Equivalencia TerapéuticaRESUMEN
The indomethacin/prochlorperazine/caffeine fixed combination (Difmetré®) combines the NSAID indomethacin with the phenothiazine antiemetic prochlorperazine and caffeine. It is currently available as two oral (effervescent tablet and coated tablet) and two rectal (suppository and low-dose suppository) formulations. Oral and rectal formulations of indomethacin/prochlorperazine/caffeine were effective and generally well tolerated in the treatment of migraine and episodic tension-type headache (TTH) in adult patients participating in randomized, multicentre, active-comparator controlled studies. For the most part, the efficacy of oral indomethacin/prochlorperazine/caffeine did not significantly differ from that of oral sumatriptan in patients with migraine and oral nimesulide in patients with episodic TTH. With rectal administration, indomethacin/prochlorperazine/caffeine was, in general, significantly more effective than sumatriptan in patients with migraine. Thus, oral and rectal formulations of indomethacin/prochlorperazine/caffeine provide a further option in the acute treatment of migraine and in the treatment of episodic TTH in adult patients.
Asunto(s)
Cafeína/uso terapéutico , Indometacina/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Proclorperazina/uso terapéutico , Cefalea de Tipo Tensional/tratamiento farmacológico , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/uso terapéutico , Antieméticos/administración & dosificación , Antieméticos/efectos adversos , Antieméticos/farmacocinética , Antieméticos/uso terapéutico , Cafeína/administración & dosificación , Cafeína/efectos adversos , Cafeína/farmacocinética , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/efectos adversos , Estimulantes del Sistema Nervioso Central/farmacocinética , Estimulantes del Sistema Nervioso Central/uso terapéutico , Combinación de Medicamentos , Femenino , Humanos , Indometacina/administración & dosificación , Indometacina/efectos adversos , Indometacina/farmacocinética , Masculino , Persona de Mediana Edad , Proclorperazina/administración & dosificación , Proclorperazina/efectos adversos , Proclorperazina/farmacocinética , Adulto JovenRESUMEN
Prochlorperazine (PCPZ) is used as a drug of first choice to treat opioid-induced nausea and vomiting. To examine the feasibility of the development of a transdermal drug delivery system for PCPZ, we performed an in vitro skin permeation study with hairless mouse skin. When the concentration of L-menthol in the hydrogel was 0-0.5%, the PCPZ flux was small; on the other hand, the flux was increased remarkably when the L-menthol concentration was higher than 1%. The optimal formulation of hydrogel would be contained 20% isopropanol (IPA), 10% N-methyl-2-pyrrolidone (NMP), 2% L-menthol and 1% PCPZ. The strong inhibitory effects to stereotyped behavior were observed at 4 h after administration of PCPZ hydrogel, and the efficacy was sustained for at least 8 h after the administration in mice in vivo. Thus, it was considered that PCPZ was delivered to brain via systemic circulation by the administration of PCPZ hydrogel.
Asunto(s)
Antieméticos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Proclorperazina/administración & dosificación , Absorción Cutánea , Piel/metabolismo , Administración Cutánea , Animales , Antieméticos/farmacocinética , Antieméticos/farmacología , Apomorfina/farmacología , Cromatografía Líquida de Alta Presión , Estudios de Factibilidad , Hidrogeles , Técnicas In Vitro , Masculino , Ratones , Ratones Pelados , Permeabilidad , Proclorperazina/farmacocinética , Proclorperazina/farmacología , Absorción Cutánea/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacosRESUMEN
A sensitive and specific method using a one-step liquid-liquid extraction with dichloromethane followed by liquid chromatographic-electrospray ionization-mass spectrometric was developed and validated to determine prochlorperazine maleate in human plasma using amitriptyline hydrochloride as an internal standard. The samples were separated using a Thermo Hypersil-Hypurity C18 reversed-phase column (150mmx2.1mm i.d., 5mum). A mobile phase containing 10mM ammonium acetate (pH 3.6)-methanol-acetonitrile (27:68:5, v/v/v) was used isocratically eluting at a flow rate of 0.22ml/min. The average extraction recovery of prochlorperazine and internal standard were 81.8+/-2.2% and 79.5+/-3.7%, respectively. Prochlorperazine maleate and internal standard were measured by electrospray ion source in positive selective ion monitoring mode. The method demonstrated that good linearity ranged from 0.20 to 6.40ng/ml with r(2)=0.9989. The limit of quantification for prochlorperazine maleate in the plasma was 0.20ng/ml. The established method has been successfully applied to a bioequivalence study of two prochlorperazine maleate formulations in 18 healthy male Chinese volunteers.
Asunto(s)
Cromatografía Liquida/métodos , Proclorperazina/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Estabilidad de Medicamentos , Humanos , Modelos Lineales , Masculino , Proclorperazina/farmacocinética , Sensibilidad y Especificidad , Equivalencia TerapéuticaRESUMEN
A thermally generated aerosol (TGA) system can effect reliable delivery of excipient-free drug to alveoli, resulting in rapid systemic drug absorption. We developed a pharmacokinetic model of prochlorperazine, administered by inhalation and as a rapid intravenous infusion, and we determined absolute TGA bioavailability in eight healthy volunteers in this institutional review board-approved, two-period crossover study. After the drug was administered as either a 5-s intravenous infusion or a TGA single-breath inhalation, blood was collected at various times for up to 24 h. Plasma prochlorperazine concentrations were measured using liquid chromatography-tandem mass spectrometry. Inhalation and rapid intravenous administration produced similar plasma prochlorperazine concentration profiles. Intravenous and inhalation pharmacokinetics were well characterized by a simultaneous two-compartment model with multiple absorption delays. Prochlorperazine pharmacokinetic parameters were similar to those reported for single intravenous doses. The geometric mean bioavailability after TGA delivery was 1.10. The administration of prochlorperazine by inhalation resulted in pharmacokinetics similar to that seen after intravenous administration, in terms of speed, extent, and consistency of absorption.
Asunto(s)
Proclorperazina/administración & dosificación , Proclorperazina/farmacocinética , Adolescente , Adulto , Aerosoles , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Modelos Biológicos , Proclorperazina/sangre , Adulto JovenRESUMEN
Oral disintegrating film containing prochlorperazine, a dopamine D(2) receptor antagonist with anti-emetic property, was newly developed using microcrystalline cellulose, polyethlene glycol and hydroxypropylmethyl cellulose as the base materials. The uniformity of dosage units of the preparation was acceptable according to the criteria of JP15 or USP27. The film showed an excellent stability at least for 8 weeks when stored at 40 degrees C and 75% in humidity. The dissolution test revealed a rapid disintegration property, in which most of prochlorperazine dissolved within 2 min after insertion into the medium. Subsequently, rats were used to compare pharmacokinetic properties of the film preparation applied topically into the oral cavity with those of oral administration of prochlorperazine solution. None of the parameters, including T(max), C(max), area under curves, clearance and steady-state distribution volume was significantly different between oral disintegrating film and oral solution. These findings suggest that the present prochlorperazine-containing oral film is potentially useful to control emesis induced by anti-cancer agents or opioid analgesics in patients who limit the oral intake.
Asunto(s)
Antieméticos/administración & dosificación , Antieméticos/farmacocinética , Sistemas de Liberación de Medicamentos , Proclorperazina/administración & dosificación , Proclorperazina/farmacocinética , Administración Bucal , Animales , Antieméticos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Celulosa/química , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Formas de Dosificación , Composición de Medicamentos , Estabilidad de Medicamentos , Excipientes/química , Derivados de la Hipromelosa , Masculino , Espectrometría de Masas , Metilcelulosa/análogos & derivados , Metilcelulosa/química , Polietilenglicoles/química , Proclorperazina/sangre , Ratas , Ratas Sprague-Dawley , Solubilidad , Factores de TiempoRESUMEN
A thermal aerosol generation process is capable of delivering pure drug reliably to the alveoli where it is absorbed systemically. Although deep lung absorption of drugs administered as an aerosol has been shown to be rapid, detailed characterization of their absorption and distribution has not been reported. The present study describes the pharmacokinetics of prochlorperazine from the moment of administration as either a rapid intravenous infusion or a thermally generated aerosol and determines the bioavailability of the aerosol by two independent methods. Prochlorperazine disposition was determined in four anesthetized dogs after a 5-s intravenous infusion and after thermally generated aerosol administration in one breath. Venous blood samples were collected frequently from the time of drug administration to 24 h and left ventricular blood samples were drawn more often until 10 min after drug administration. Prochlorperazine disposition after intravenous and aerosol administration was characterized by fitting a recirculatory model to left ventricular and venous drug concentration data simultaneously. Prochlorperazine aerosol administration produced plasma drug concentrations similar to those after rapid intravenous administration of the same nominal dose, with peak left ventricular concentrations achieved in less than 30 s. Plasma concentration profiles of prochlorperazine administered by both routes were well described by the recirculatory model. Bioavailability of the thermally generated aerosol was consistent and averaged more than 80% of emitted dose. Pulmonary administration of a thermally generated drug aerosol in one breath may be a viable alternative to rapid intravenous administration of drugs requiring rapid and predictable production of effective plasma concentrations.
Asunto(s)
Proclorperazina/farmacocinética , Aerosoles , Animales , Disponibilidad Biológica , Perros , Femenino , Modelos Biológicos , Proclorperazina/administración & dosificación , Distribución TisularRESUMEN
A deficiency of most current drug products for treatment of acute conditions is slow onset of action. A promising means of accelerating drug action is through rapid systemic drug administration via deep lung inhalation. The speed of pulmonary drug absorption depends on the site of aerosol deposition within the lung and the dissolution rate and drug content of the deposited particles. Alveolar delivery of fast-dissolving, pure drug particles should in theory enable very rapid absorption. We have previously shown that heating of thin drug films generates vapor-phase drug that subsequently cools and condenses into pure drug particles of optimal size for alveolar delivery. Here we present a hand held, disposable, breath-actuated device incorporating this thermal aerosol technology, and its application to the delivery of alprazolam, an anti-panic agent, and prochlorperazine, an anti-emetic with recently discovered anti-migraine properties. Thermal aerosol particles of these drugs exist in an amorphous state, which results in remarkably rapid drug absorption from the lung into the systemic circulation, with peak left ventricular concentrations achieved within 20 s, even quicker than following rapid (5 s) intravenous infusion. Absorption of the thermal aerosol is nearly complete, with >80% absolute bioavailability found in both dogs and human normal volunteers.
Asunto(s)
Pulmón/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Absorción , Administración por Inhalación , Adulto , Aerosoles , Alprazolam/administración & dosificación , Alprazolam/farmacocinética , Animales , Área Bajo la Curva , Rastreo Diferencial de Calorimetría , Cromatografía Líquida de Alta Presión , Perros , Antagonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/farmacocinética , Método Doble Ciego , Femenino , Moduladores del GABA/administración & dosificación , Moduladores del GABA/farmacocinética , Ventrículos Cardíacos/metabolismo , Humanos , Pulmón/fisiología , Masculino , Microscopía Electrónica de Rastreo , Persona de Mediana Edad , Miocardio/metabolismo , Tamaño de la Partícula , Preparaciones Farmacéuticas/química , Proclorperazina/administración & dosificación , Proclorperazina/farmacocinética , Difracción de Rayos XRESUMEN
BACKGROUND: The combination of indomethacin, prochlorperazine and caffeine (IPC) is one of the most utilized formulations for the treatment of migraine attacks in Italy. Several patients suffering from chronic headache overuse this symptomatic medication in the attempt to control their headache. OBJECTIVE: To verify whether overuse of IPC combination by chronic headache patients is associated with modified disposition of its components. METHODS: We studied indomethacin, prochlorperazine, and caffeine disposition in 34 female subjects suffering from primary headaches, subdivided into four groups: eight migraine patients occasionally using IPC combination suppositories-group 1; nine patients with chronic headache and probable medication-overuse headache, daily taking one or more suppositories of the IPC combination-group 2; 11 migraine patients occasionally using "mild" suppositories of the IPC combination-group 3; six migraine patients occasionally taking tablets of the IPC combination-group 4. The IPC combination habitually used was administered to each patient. Blood samples were taken at baseline and at fixed intervals up to 6h after administration. Plasma levels of indomethacin and prochlorperazine were assayed by high-pressure liquid chromatographic (HPLC) method; caffeine levels were assayed by enzyme multiplied immunoassay test (EMIT). Pharmacokinetic parameters were calculated by means of a computer software (P K Solutions 2.0. Summit Research Services, Montrose, CO, USA). RESULTS: Half-life of indomethacin was longer, and clearance lower, in group 2 than in the other groups; AUC of indomethacin in group 2 was twice that in group 1 (P<0.05, Newman-Keuls' test). Peak concentrations and AUC(0-->infinity) of caffeine were significantly higher in group 2 than in the other groups (P<0.05, Newman-Keuls' test). We could not define prochlorperazine disposition because it was not detectable in the majority of blood samples. CONCLUSION: Overuse of IPC combination in chronic headache patients is associated with increased plasma levels of indomethacin and caffeine, and with delayed elimination of indomethacin; the high and sustained concentrations of these drugs may cause rebound headache, organ damages, and perpetuate medication-overuse headache.
Asunto(s)
Cafeína/uso terapéutico , Cefaleas Secundarias/tratamiento farmacológico , Trastornos de Cefalalgia/tratamiento farmacológico , Indometacina/uso terapéutico , Proclorperazina/uso terapéutico , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/uso terapéutico , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapéutico , Área Bajo la Curva , Cafeína/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacocinética , Estimulantes del Sistema Nervioso Central/uso terapéutico , Enfermedad Crónica , Combinación de Medicamentos , Femenino , Semivida , Trastornos de Cefalalgia/sangre , Trastornos de Cefalalgia/inducido químicamente , Trastornos de Cefalalgia/fisiopatología , Cefaleas Secundarias/sangre , Cefaleas Secundarias/inducido químicamente , Cefaleas Secundarias/fisiopatología , Humanos , Indometacina/farmacocinética , Persona de Mediana Edad , Proclorperazina/farmacocinética , Factores de TiempoRESUMEN
Prochlorperazine has been accepted as an effective antiemetic for more than 50 years; however, its therapeutic success has been limited by its low and variable absorption and high first-pass metabolism. A buccal dosage form of prochlorperazine has been developed. This article discusses 2 clinical studies conducted to characterize the single-dose and multiple-dose pharmacokinetics of prochlorperazine and its metabolites after buccal administration. The results of these studies demonstrate that buccal administration of prochlorperazine produces plasma concentrations more than twice as high as an oral tablet, with less than half the variability. In addition to the metabolites, N-desmethyl prochlorperazine and prochlorperazine sulfoxide, 2 new metabolites, prochlorperazine 7-hydroxide and prochlorperazine sulfoxide 4'-N-oxide, were identified and quantitated. Exposure to metabolites after the buccal prochlorperazine formulation was approximately half that observed after the oral tablet. Buccal administration of prochlorperazine, twice daily, should enhance the therapeutic role of prochlorperazine in preventing and treating nausea and vomiting.
Asunto(s)
Antieméticos/farmacocinética , Proclorperazina/farmacocinética , Administración Bucal , Administración Oral , Adulto , Antieméticos/administración & dosificación , Antieméticos/efectos adversos , Disponibilidad Biológica , Femenino , Humanos , Masculino , Proclorperazina/administración & dosificación , Proclorperazina/efectos adversosRESUMEN
The field of drug metabolism has been revolutionized by liquid chromatography/mass spectrometry (LC/MS) applications with new technologies such as triple quadrupoles, ion traps and time-of-flight (ToF) instrumentation. Over the years, these developments have often relied on the improvements to the mass spectrometer hardware and software, which has allowed users to benefit from lower levels of detection and ease-of-use. One area in which the development pace has been slower is in high-performance liquid chromatography (HPLC). In the case of metabolite identification, where there are many challenges due to the complex nature of the biological matrices and the diversity of the metabolites produced, there is a need to obtain the most accurate data possible. Reactive or toxic metabolites need to be detected and identified as early as possible in the drug discovery process, in order to reduce the very costly attrition of compounds in late-phase development. High-resolution, exact mass measurement plays a very important role in metabolite identification because it allows the elimination of false positives and the determination of non-trivial metabolites in a much faster throughput environment than any other standard current methodology available to this field. By improving the chromatographic resolution, increased peak capacity can be achieved with a reduction in the number of co-eluting species leading to superior separations. The overall enhancement in the chromatographic resolution and peak capacity is transferred into a net reduction in ion suppression leading to an improvement in the MS sensitivity. To investigate this, a number of in vitro samples were analyzed using an ultra-performance liquid chromatography (UPLC) system, with columns packed with porous 1.7 mum particles, coupled to a hybrid quadrupole time-of-flight (ToF) mass spectrometer. This technique showed very clear examples for fundamental gains in sensitivity, chromatographic resolution and speed of analysis, which are all important factors for the demands of today's HTS in discovery.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Dextrometorfano/farmacocinética , Microsomas Hepáticos/metabolismo , Proclorperazina/farmacocinética , Espectrometría de Masa por Ionización de Electrospray/métodos , Células Cultivadas , Evaluación Preclínica de Medicamentos/métodos , Humanos , Tasa de Depuración Metabólica , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
PURPOSE: The purpose of these sequential phase I studies was to evaluate the antiemetic efficacy and pharmacokinetics of high-dose continuous infusion prochlorperazine. METHODS: A total of 52 patients with advanced cancer were treated in two sequential phase I studies utilizing high-dose prochlorperazine. In study 1, designed to investigate the antiemetic effects of dose-intensive prochlorperazine, various cisplatin-based multiagent chemotherapeutic regimens were administered in combination with escalating doses of prochlorperazine. In study 2, a fixed dose of cisplatin (60 mg/m2) was administered over 24 h as a continuous intravenous infusion in combination with infusional high-dose prochlorperazine. Antiemetic efficacy in the first trial was assessed in terms of the number of episodes of nausea, retching, and/or emesis during the 24 h following cisplatin administration. The pharmacokinetics of high-dose prochlorperazine were evaluated in eight patients treated in study 2 at the two dose levels below those at which dose-limiting toxicity was noted. RESULTS: The maximally tolerated dose of prochlorperazine in combination with cisplatin (60 mg/m2 administered as a continuous infusion over 24 h) was 24 mg/h. The dose-limiting toxicity was grade 4 agitation and confusion noted in one patient treated at 26 mg/h. This patient died 3 days following cessation of chemotherapy due to the toxicity of the regimen in combination with the debilitating pulmonary effects of the disease. The mean end of infusion prochlorperazine level at the 24 mg/h dose level was 1.1 microM, a concentration previously reported to be consistent with the reversal of the multidrug resistance phenotype. Two partial responses were observed in study 2. CONCLUSIONS: We conclude that the antiemetic efficacy of high-dose infusional prochlorperazine does not appear to be improved over more convenient bolus administration. However, prochlorperazine levels consistent with those required in vitro for drug resistance reversal are attainable within the dose range having a tolerable toxicity profile.
Asunto(s)
Antieméticos/farmacocinética , Antieméticos/uso terapéutico , Proclorperazina/farmacocinética , Proclorperazina/uso terapéutico , Vómitos/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Antieméticos/administración & dosificación , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/inducido químicamente , Proclorperazina/administración & dosificación , Vómitos/inducido químicamenteRESUMEN
Incubation of drug-resistant human tumor cells with a combination of prochlorperazine and dipyridamole has additive/synergistic effect on the cellular retention and cytotoxicity of doxorubicin. In patients administered a fixed dose of doxorubicin and prochlorperazine with escalating doses of dipyridamole, mean plasma levels of dipyridamole and prochlorperazine achieved were as high as 3.01 +/- 0.41 microm and 0.94 +/- 0.09 microm, respectively. Plasma samples from patients were analyzed in an in vitro assay to monitor the effect on the cellular retention of tritium-labeled daunorubicin in MDR1-transfected P388 cells. In 22 of 49 of the plasma samples analyzed, the daunorubicin in efflux blocking activity was one-half or greater than that of cells incubated with 12.5 microM verapamil, a well-known efflux blocker. These observations suggest that a combination of prochlorperazine and dipyridamole may enhance cellular doxorubicin retention by blocking efflux while reducing normal tissue toxicity and unwanted side effects in vivo.
Asunto(s)
Antineoplásicos/farmacocinética , Dipiridamol/farmacología , Doxorrubicina/farmacocinética , Proclorperazina/farmacología , Animales , Antineoplásicos/metabolismo , Área Bajo la Curva , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Medios de Cultivo/química , Medios de Cultivo/farmacología , Daunorrubicina/metabolismo , Daunorrubicina/farmacocinética , Dipiridamol/farmacocinética , Relación Dosis-Respuesta a Droga , Doxorrubicina/sangre , Doxorrubicina/metabolismo , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Humanos , Infusiones Intravenosas , Tasa de Depuración Metabólica , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Plasma/química , Proclorperazina/farmacocinética , Células Tumorales CultivadasRESUMEN
The dizziness associated with vertiginous disorders is often accompanied with nausea and/or vomiting. Antiemetic effect of prochlorperazine (PCZ) is diminished by its low bioavailability owing to a significant gastric and hepatic first pass effect. This effect could be further diminished by likelihood of regurgitation of nauseating patients further limiting the therapeutic effect of oral PCZ. A buccal preparation achieves higher plasma concentrations through direct systemic absorption. In this study buccal prochlorperazine (Bukatel) was compared for its efficacy and tolerability with commonly used metoclopramide. Bukatel was well tolerated and well rated by both patients and investigators with no adverse effects on buccal mucosa and causing less drowsiness and sedation. Results indicate that Bukatel is safe and effective for the treatment of nausea and/or vomiting in patients suffering from vertiginous disorders and could be safely and strongly recommended as an alternative to less bioavailable and indiscriminately used oral metoclopramide tablets.
Asunto(s)
Antieméticos/administración & dosificación , Metoclopramida/administración & dosificación , Náusea y Vómito Posoperatorios/tratamiento farmacológico , Proclorperazina/administración & dosificación , Administración Bucal , Administración Oral , Adolescente , Adulto , Anciano , Antieméticos/efectos adversos , Antieméticos/farmacocinética , Colecistectomía , Femenino , Humanos , Masculino , Metoclopramida/efectos adversos , Metoclopramida/farmacocinética , Persona de Mediana Edad , Náusea y Vómito Posoperatorios/prevención & control , Proclorperazina/efectos adversos , Proclorperazina/farmacocinética , Calidad de Vida , Recurrencia , Retratamiento , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
A high-performance liquid chromatographic method has been developed and tested for simultaneous extraction, elution and determination of doxorubicin and prochlorperazine content in human plasma samples. The procedure consists of extraction through a conditioned C18 solid-phase extraction cartridge, elution from a Spherisorb C8 reversed-phase column by an isocratic mobile phase (60% acetonitrile, 15% methanol and 25% buffer) followed by detection with electrochemical and fluorescence detectors. Recovery of doxorubicin and prochlorperazine from pooled human plasma samples (n=3) containing 100 ng/ml of the two drugs was 77.8+/-3.5% and 89.1+/-6.0%, respectively. The lower limits of quantitation for doxorubicin and prochlorperazine in plasma samples were 6.25 ng/ml and 10 ng/ml, respectively. A linear calibration curve was obtained for up to 2 microg/ml of doxorubicin and prochlorperazine. This combination method may be of particular value in clinical studies where phenothiazines such as prochlorperazine are used to enhance retention of doxorubicin in drug resistant tumor cells.
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Antibióticos Antineoplásicos/sangre , Cromatografía Líquida de Alta Presión/métodos , Doxorrubicina/sangre , Proclorperazina/sangre , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Clorpromazina/sangre , Ritmo Circadiano , Daunorrubicina/sangre , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Humanos , Infusiones Intravenosas , Modelos Lineales , Valor Predictivo de las Pruebas , Proclorperazina/administración & dosificación , Proclorperazina/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Fluorescencia , Factores de TiempoRESUMEN
The therapeutic activity of a wide variety of drugs is significantly improved when their longevity in the circulation is extended by encapsulation in liposomes. To improve the retention of cationic drugs in liposomes, we have investigated the effect of the cationic lipid stearylamine on the permeability of the calcium channel blocker verapamil and the antipsychotic drug prochlorperazine, both of which are also multidrug resistance modulators. Both drugs were efficiently incorporated into liposomes composed of DSPC/cholesterol that possessed a transmembrane pH gradient (inside acidic). However, the efflux of the loaded drugs was relatively rapid (i.e., 50% of the encapsulated verapamil was released after 4 h at 37 degrees C), despite the presence of a 3 unit pH gradient (pHi = 4.0, pHo = 7.5). Drug retention within the liposomes was improved by increasing the magnitude of the transmembrane pH gradient to approx. 5 units (pHi = 2.0, pHo = 7.5). Further improvements in drug retention were achieved by the addition of 10 mol% of the cationic lipid stearylamine in the DSPC/cholesterol liposomes. The combination of the 5 unit pH gradient and stearylamine resulted in increases of the retention of verapamil and prochlorperazine by approx. 20- and 5-fold, respectively. Calculation of the permeability coefficients for the charged (cationic) and neutral forms of the drugs indicated that the neutral forms of both drugs were approx. 10(4)-fold more permeable than were the cationic forms of the drugs. Further, the presence of stearylamine reduced the permeability coefficient for the cationic species of the drugs by approximately an order of magnitude, but had no effect on the neutral species of the drugs. The efflux curves observed for both verapamil and prochlorperazine could be mathematically modeled by assuming that the primary influence of stearylamine was on the development of a positive surface charge density on the inner monolayer of the liposome. Taken in sum, these results indicate that stearylamine is effective at decreasing the leakage of cationic drugs from liposomes, and may prove to be a valuable component of liposomal drug formulations.
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Aminas/farmacología , Antipsicóticos/farmacología , Bloqueadores de los Canales de Calcio/farmacocinética , Permeabilidad de la Membrana Celular/efectos de los fármacos , Proclorperazina/farmacocinética , Verapamilo/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antipsicóticos/administración & dosificación , Antipsicóticos/uso terapéutico , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/uso terapéutico , Cationes , Portadores de Fármacos , Sinergismo Farmacológico , Concentración de Iones de Hidrógeno , Membrana Dobles de Lípidos , Modelos Químicos , Proclorperazina/administración & dosificación , Proclorperazina/uso terapéutico , Verapamilo/administración & dosificación , Verapamilo/uso terapéuticoRESUMEN
Since gamma-hydroxybutyrate receptor agonists exhibit dopaminergic regulatory properties and neuroleptic-like effects in neuropharmacological tests, the common neuroleptics were tested for [3H] gamma-hydroxybutyrate binding activity on rat brain membranes. (-)-Sulpiride, sultopride, amisulpride and prochlorperazine possess affinity for the gamma-hydroxybutyrate site(s), consistent with their therapeutic dosage. This study has revealed that gamma-hydroxybutyrate receptors represent an additional target for antipsychotics.
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Antipsicóticos/farmacocinética , Benzamidas/farmacocinética , Proclorperazina/farmacocinética , Receptores de Superficie Celular/metabolismo , Oxibato de Sodio/farmacocinética , Animales , Unión Competitiva , Técnicas In Vitro , Masculino , Ratas , Ratas WistarRESUMEN
In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m2. The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m2 DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m2 PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m2. Large interpatient variation in peak PCZ plasma levels (91-3215 ng/ml) was seen, with the plasma half-life (t1/2 alpha) being approximately 57 min in patients given 135-180 mg/m2 PCZ. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) were 350.1 +/- 183.8 1/m2, 260.7 +/- 142.7 l m2 h-1 and 1539 +/- 922 ng ml h-1, respectively, in patients given 180 mg/m2 PCZ and the respective values for patients receiving 135 mg/m2 were 48.9 +/- 23.76 l/m2, 33.2 +/- 2.62 l m2 h-1, and 4117 +/- 302 ng ml h-1. High PCZ plasma levels (> 600 ng/ml) were sustained in all patients treated with 135 mg/m2 PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m2 PCZ, and a > 10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m2 with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Doxorrubicina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Proclorperazina/farmacocinética , Adulto , Anciano , Cromatografía Líquida de Alta Presión , Terapia Combinada , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Esquema de Medicación , Femenino , Semivida , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Proclorperazina/administración & dosificación , Proclorperazina/efectos adversosRESUMEN
Doxorubicin (DOX) efflux in drug-resistant cells is blocked by phenothiazines such as trifluoperazine (TFP) and prochlorperazine (PCZ) in vitro. The present phase I study was conducted in 13 patients with advanced, incurable, nonhematologic tumors to determine whether PCZ plasma levels high enough to block DOX efflux could be achieved in vivo. The treatment schedule consisted of prehydration and i.v. administration of 15, 30, 50, and 75 mg/m2 PCZ followed by a standard dose of 60 mg/m2 DOX. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose used. Toxicities attributable to PCZ were sedation, dryness of the mouth, cramps, chills, and restlessness. The maximal tolerated dose (MTD) of PCZ in this schedule was 75 mg/m2. Pharmacokinetic analysis indicated a large interpatient variation in peak plasma PCZ levels that ranged from 95 to 1100 ng/ml. The three plasma half-lives of PCZ were: t1/2 alpha (+/- SE), 20.9 +/- 5.3 min; t1/2 beta, 1.8 +/- 0.3 h; and t1/2 gamma, 21.9 +/- 5.3 h. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) for PCZ were 2254 +/- 886 l/m2, 60.2 +/- 13.5 l m-2 h-1, and 1624 +/- 686 ng ml-1 h, respectively. DOX retention in tumor cells retrieved from patients during the course of therapy indicated the appearance of cells with enhanced DOX retention. The combination of DOX and high-dose i.v. PCZ appeared to be safe, well tolerated, and active in non-small-cell lung carcinoma.