RESUMEN
An echogenic, intravenous drug delivery platform is proposed in which an encapsulated chemotherapeutic can travel to a desired location and drug delivery can be triggered using external, focused ultrasound at the area of interest. Three methods of loading poly(lactic acid) (PLA) shelled ultrasound contrast agents (UCA) with doxorubicin are presented. Effects on encapsulation efficiency, in vitro enhancement, stability, particle size, morphology and release during UCA rupture are compared by loading method and drug concentration. An agent containing doxorubicin within the shell was selected as an ideal candidate for future hepatocellular carcinoma studies. The agent achieved a maximal drug load of 6.2 mg Dox/g PLA with an encapsulation efficiency of 20.5%, showed a smooth surface morphology and tight size distribution (poly dispersity index=0.309) with a peak size of 1865 nm. Acoustically, the agent provided 19 dB of enhancement in vitro at a dosage of 10 microg/ml, with a half life of over 15 min. In vivo, the agent provided ultrasound enhancement of 13.4+/-1.6 dB within the ascending aorta of New Zealand rabbits at a dose of 0.15 ml/kg. While the drug-incorporated agent is thought to be well suited for future drug delivery experiments, this study has shown that agent properties can be tailored for specific applications based on choice of drug loading method.
Asunto(s)
Antineoplásicos/administración & dosificación , Medios de Contraste/administración & dosificación , Doxorrubicina/administración & dosificación , Portadores de Fármacos , Ácido Láctico/química , Polímeros/química , Ultrasonido , Ultrasonografía Doppler de Pulso , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Aorta/diagnóstico por imagen , Aorta/metabolismo , Química Farmacéutica , Medios de Contraste/química , Medios de Contraste/metabolismo , Doxorrubicina/química , Doxorrubicina/metabolismo , Composición de Medicamentos , Semivida , Inyecciones Intravenosas , Riñón/diagnóstico por imagen , Riñón/metabolismo , Cinética , Microscopía Confocal , Tamaño de la Partícula , Poliésteres , Conejos , Ratas , Ratas Sprague-Dawley , Solubilidad , Propiedades de Superficie , Tecnología FarmacéuticaRESUMEN
BACKGROUND: Patients with depressive disorders smoke tobacco more often than the population at large and find quitting more difficult. Furthermore, when they quit smoking, they are more likely to suffer a relapse of depression. We evaluated the addition of bupropion sustained release (SR) for smoking cessation among patients with a history of depressive disorders being maintained in a euthymic state with selective serotonin reuptake inhibitor (SSRI) antidepressants. METHOD: Twenty-five adults with DSM-IV major depressive disorder or depressive disorder NOS currently receiving SSRI maintenance treatment and smoking > or = 15 cigarettes per day participated in the 9-week study. Bupropion SR, 150 mg/day, was added to SSRI treatment and increased to 300 mg/day. Subjects were counseled on smoking cessation measures and chose a target quit date 2 or 4 weeks after the initiation of bupropion SR. Self-reported smoking status, expired carbon monoxide (CO) measurements, Hamilton Rating Scales for Depression and Anxiety scores, and weight were measured at each visit. Subjects were abstinent if they reported not smoking during the prior 7 days, confirmed with an expired-air CO value of < or = 10 ppm. RESULTS: Eight (32%) of 25 subjects were abstinent after 9 weeks. At 3-month follow-up, 3 subjects remained abstinent, 3 relapsed, and 2 were lost to follow-up. Eleven subjects (44%) were nonresponders, and 6 (24%) dropped out prior to 3 weeks of treatment due to side effects (N = 3) or were lost to follow-up (N = 3). Mean weight gain was approximately 0.5 lb (0.2 kg) for those completing 9 weeks of bupropion SR treatment. During the 9-week study and the 3-month follow-up, there was no evidence of emergent depression in any subject. Four subjects (16%) spontaneously reported an improvement in SSRI-associated sexual dysfunction. CONCLUSION: These open data suggest modest effectiveness for and the safety of bupropion SR as a smoking cessation agent in individuals with depression maintained on treatment with SSRIs. Minimal weight gain, lack of emergent depressive episodes, and improvement of SSRI-associated sexual dysfunction are added advantages.
Asunto(s)
Bupropión/uso terapéutico , Trastorno Depresivo/prevención & control , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Cese del Hábito de Fumar/métodos , Adolescente , Adulto , Anciano , Índice de Masa Corporal , Peso Corporal , Bupropión/administración & dosificación , Comorbilidad , Preparaciones de Acción Retardada , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/epidemiología , Esquema de Medicación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Disfunciones Sexuales Psicológicas/tratamiento farmacológico , Disfunciones Sexuales Psicológicas/epidemiología , Disfunciones Sexuales Psicológicas/psicología , Fumar/tratamiento farmacológico , Prevención del Hábito de Fumar , Resultado del TratamientoRESUMEN
We describe a patient with marked elevations of creatine kinase following institution of clozapine treatment. The enzyme levels promptly subsided with discontinuation of clozapine. The clinical features did not meet any of the published criteria for neuroleptic malignant syndrome.
Asunto(s)
Clozapina/efectos adversos , Creatina Quinasa/sangre , Esquizofrenia Paranoide/tratamiento farmacológico , Adulto , Clozapina/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Masculino , Síndrome Neuroléptico Maligno/diagnóstico , Síndrome Neuroléptico Maligno/enzimología , Esquizofrenia Paranoide/diagnóstico , Esquizofrenia Paranoide/enzimología , Esquizofrenia Paranoide/psicologíaRESUMEN
It is important to remember that while a new class of therapeutic agents like oligonucleotides may introduce novel concerns, the basic regulatory issues regarding the chemistry, manufacturing, and controls of drug substances and drug products must be addressed. This article focuses on information that should be included in an Investigational New Drug Application (IND), a request to use an investigational drug in clinical studies. The regulatory challenge presented with oligonucleotide therapeutics is to prove the identity of the oligonucleotide, and demonstrate its quality, purity, and strength/potency using both those characteristics that are the same as all other drugs, as well as those that are unique. Most of the discussion will concern issues that are unique to oligonucleotides, or those topics that deserve more detailed attention than would be needed for more typical small molecule drugs. Regulatory issues will need to be evaluated so that safety concerns are addressed while not imposing undue burden on the sponsors of investigational drugs.
Asunto(s)
Aplicación de Nuevas Drogas en Investigación , Oligonucleótidos Antisentido/uso terapéutico , Ensayos Clínicos como Asunto , Estabilidad de Medicamentos , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/normas , Control de Calidad , Estados Unidos , United States Food and Drug AdministrationRESUMEN
BACKGROUND: Clozapine, an atypical neuroleptic, is an effective medication in a subgroup of schizophrenic patients who have either failed to respond to the typical neuroleptics or experienced intolerable side effects such as neuroleptic malignant syndrome and disabling tardive dyskinesia. Its efficacy for persistent and disabling akathisia is less clear. Akathisia, especially the chronic and disabling form, can be a treatment dilemma for the clinician and the patient. METHOD: We describe three representative case illustrations of schizophrenic patients who had severe, persistent treatment-resistant akathisia. Two of them had refractory psychoses and the third had multiple disabling side effects during treatment with typical neuroleptics. Two had tardive dyskinesia. These patients were treated with clozapine while other neuroleptics were discontinued. RESULTS: During a 2-year follow-up, these patients made impressive social and vocational strides coinciding with a fairly rapid remission of akathisia (under 3 months) and a lesser though notable improvement in the psychoses. Tardive dyskinesia also remitted, though over a period of 6 to 12 months. CONCLUSION: Our experience leads us to suggest a trial of clozapine in a subgroup of schizophrenic patients, who in addition to refractory psychoses have persistent disabling akathisia. However, given the risk of agranulocytosis with clozapine, we suggest that the usual treatment strategies for akathisia be tried before clozapine is initiated in the approved manner. Future controlled trials of clozapine that specifically investigate persistent akathisia may answer this question more conclusively.