RESUMEN
Use of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against bulky and solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, we utilized a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase-9-based safety switch (iRC9) was developed to allow in vivo elimination of CAR-T cells. iMC costimulation induced by systemic rimiducid administration enhanced CAR-T cell proliferation, cytokine secretion, and antitumor efficacy in both in vitro assays and xenograft tumor models. Conversely, rapamycin-mediated iRC9 dimerization rapidly induced apoptosis in a dose-dependent fashion as an approach to mitigate therapy-related toxicity. This novel, regulatable dual-switch system may promote greater CAR-T cell expansion and prolonged persistence in a drug-dependent manner while providing a safety switch to mitigate toxicity concerns.
RESUMEN
Chloroquine is used in the treatment of malaria, a disease caused by infection with the parasite Plasmodium. Although chloroquine appears to possess diverse pharmacological activity, its plasmodicidal activity results from augmentation of parasite oxidative stress. Chloroquine also appears to augment oxidative stress in metabolically active mammalian cells, including human astroglial cells. The authors propose that chloroquine may augment oxidative stress induced by radiotherapy in the treatment of glioblastoma multiforme, enhancing therapeutic efficacy. Such an effect would be consistent with the known pharmacological effects of chloroquine observed in Plasmodium. Other selective redox agents, such as tempol and artemisinin, should be investigated clinically for therapeutic benefit when coadministered with combined radio- and chemotherapy for cancer.
Asunto(s)
Neoplasias Encefálicas/radioterapia , Cloroquina/farmacología , Glioblastoma/tratamiento farmacológico , Oxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Artemisininas/farmacología , Artemisininas/uso terapéutico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirugía , Cloroquina/metabolismo , Cloroquina/uso terapéutico , Óxidos N-Cíclicos/farmacología , Óxidos N-Cíclicos/uso terapéutico , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Glioblastoma/cirugía , Hemina/metabolismo , Humanos , Membranas Intracelulares/efectos de los fármacos , Hierro/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Lisosomas/efectos de los fármacos , Lípidos de la Membrana/química , Oxidantes/uso terapéutico , Oxidación-Reducción , Plasmodium/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Sesquiterpenos/farmacología , Sesquiterpenos/uso terapéutico , Marcadores de SpinRESUMEN
OBJECTIVES: This trial was conducted to test the effects of an alpha7 nicotinic receptor full agonist, TC-5619, on negative and cognitive symptoms in subjects with schizophrenia. METHODS: In 64 sites in the United States, Russia, Ukraine, Hungary, Romania, and Serbia, 477 outpatients (18-65 years; male 62%; 55% tobacco users) with schizophrenia, treated with a new-generation antipsychotic, were randomized to 24 weeks of placebo (n = 235), TC-5619, 5mg (n = 121), or TC-5619, 50 mg (n = 121), administered orally once daily. The primary efficacy measure was the Scale for the Assessment of Negative Symptoms (SANS) composite score. Key secondary measures were the Cogstate Schizophrenia Battery (CSB) composite score and the University of California San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) total score. Secondary measures included: Positive and Negative Syndrome Scale in Schizophrenia (PANSS) total and subscale scores, SANS domain scores, CSB item scores, Clinical Global Impression-Global Improvement (CGI-I) score, CGI-Severity (CGI-S) score, and Subject Global Impression-Cognition (SGI-Cog) total score. RESULTS: SANS score showed no statistical benefit for TC-5619 vs placebo at week 24 (5 mg, 2-tailed P = .159; 50 mg, P = .689). Likewise, no scores of CSB, UPSA-B, PANSS, CGI-I, CGI-S, or SGI-Cog favored TC-5619 (P > .05). Sporadic statistical benefit favoring TC-5619 in some of these outcome measures were observed in tobacco users, but these benefits did not show concordance by dose, country, gender, or other relevant measures. TC-5619 was generally well tolerated. CONCLUSION: These results do not support a benefit of TC-5619 for negative or cognitive symptoms in schizophrenia.
Asunto(s)
Benzofuranos/farmacología , Agonistas Nicotínicos/farmacología , Evaluación de Resultado en la Atención de Salud , Quinuclidinas/farmacología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Índice de Severidad de la Enfermedad , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Adulto , Benzofuranos/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agonistas Nicotínicos/administración & dosificación , Quinuclidinas/administración & dosificación , Adulto JovenRESUMEN
Recently, fluphenazine, a phenothiazine neuroleptic, has been associated with idiosyncratic retinopathy. Neuroleptic-induced retinopathy appears to be isolated to only a few structurally related phenothiazines, suggesting that the causality is not the result of dopamine antagonism. The chemical structure of fluphenazine is very similar to that of chlorpromazine and thioridazine, agents known to produce retinopathy. Like chlorpromazine and thioridazine, fluphenazine may be oxidized by retinal cytochrome P450 and/or myeloperoxidase to an electrophile, producing injury in susceptible patients.
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Antipsicóticos/efectos adversos , Flufenazina/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Retina/efectos de los fármacos , Animales , Glutatión/metabolismo , Humanos , Retina/metabolismoRESUMEN
PURPOSE: To assess the effects of a single 100-mg dose of sildenafil citrate on visual function in men with early-stage age-related macular degeneration. DESIGN: Randomized double-blind placebo-controlled clinical trial. METHODS: Nine men (mean age 71 years, range 59-85 years) with early-stage (minimal visual impairment and large drusen in the macula) age-related macular degeneration and 20/40 or better-corrected visual acuity in at least one eye were prospectively randomized to receive either placebo or sildenafil citrate (Viagra; Pfizer Inc, New York, New York) 100 mg as a single oral dose. After 7-14 days, they received the alternate treatment. Subjects underwent visual acuity, Amsler grid, color discrimination (D15), traffic light, Humphrey perimetry, and photo-stress testing in each eye before and at specific intervals within 8 hours after dosing. RESULTS: Compared with placebo, no pattern of errors were evident in any visual function test following sildenafil administration. No statistically or clinically relevant changes from baseline were observed in visual acuity, Humphrey perimetry (corrected pattern standard deviation), D15 color discrimination, or photo-stress tests. No clinically relevant changes were observed in the Amsler grid or traffic light tests. Sildenafil treatment was associated with transient mild or moderate headache, flushing, and rhinitis. There were no visual adverse events spontaneously reported to the investigator. CONCLUSION: A single 100-mg dose of sildenafil was well tolerated and produced no acute visual effects or exacerbation of preexisting visual impairment in nine men with early-stage age-related macular degeneration.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Percepción de Color/fisiología , Degeneración Macular/fisiopatología , Inhibidores de Fosfodiesterasa/administración & dosificación , Piperazinas/administración & dosificación , Agudeza Visual/fisiología , Campos Visuales/fisiología , Anciano , Anciano de 80 o más Años , Percepción de Color/efectos de los fármacos , Pruebas de Percepción de Colores , Estudios Cruzados , Método Doble Ciego , Evaluación de Medicamentos , Humanos , Degeneración Macular/complicaciones , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa/efectos adversos , Inhibidores de Fosfodiesterasa/farmacocinética , Piperazinas/efectos adversos , Piperazinas/farmacocinética , Estudios Prospectivos , Purinas , Seguridad , Citrato de Sildenafil , Sulfonas , Agudeza Visual/efectos de los fármacos , Pruebas del Campo Visual , Campos Visuales/efectos de los fármacosRESUMEN
Several pharmaceutical agents have been associated with rare but serious retinopathies, some resulting in blindness. Little is known of the mechanism(s) that produce these injuries. Mechanisms proposed thus far have not been embraced by the medical and scientific communities. However, preclinical and clinical data indicate that oxidative stress may contribute substantially to iatrogenic retinal disease. Retinal oxidative stress may be precipitated by the interaction of putative retinal toxins with the ocular redox system. The retina, replete with cytochromes P450 and myeloperoxidase, may serve to activate xenobiotics to oxidants, resulting in ocular injury. These activated agents may directly form retinal adducts or may diminish ocular reduced glutathione concentrations. Data are reviewed that suggest that indomethacin, tamoxifen, thioridazine, and chloroquine all produce retinopathies via a common mechanism-they produce ocular oxidative stress.
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Estrés Oxidativo/fisiología , Retina/fisiología , Enfermedades de la Retina/inducido químicamente , Animales , Ceguera/inducido químicamente , Cloroquina/efectos adversos , Humanos , Indometacina/efectos adversos , Retina/efectos de los fármacos , Retina/fisiopatología , Tamoxifeno/efectos adversos , Tioridazina/efectos adversosRESUMEN
Until recently the treatment of Overactive Bladder (OAB) has primarily been aimed at mitigating hypercholinergic activity in the bladder via antagonism of muscarinic acetylcholine receptors. However, antimuscarinic therapies have limited efficacy and significant side effects. It is now known that nicotinic acetylcholine receptor (nAChR) subtypes are expressed in the urothelium and on afferent nerve fibers in the bladder, and it is believed that these receptors serve to communicate urgency and facilitate voiding function. This presents the opportunity for an alternative to the antimuscarinic approach, one which involves inhibition of nAChRs in the bladder that are chronically overstimulated by acetylcholine. Specifically, we hypothesize that an orally administered nAChR-selective inhibitor with extensive renal elimination will result in higher local concentrations in the bladder and lower systemic exposure than current therapies, representing a novel targeted approach to the treatment of OAB with a more favorable side effect profile.
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Antagonistas Colinérgicos/farmacología , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vías Aferentes/efectos de los fármacos , Humanos , Modelos Biológicos , Urotelio/metabolismoRESUMEN
PURPOSE: We evaluated the efficacy and safety of sildenafil citrate in spontaneously or surgically postmenopausal women with female sexual arousal disorder (FSAD). MATERIALS AND METHODS: Sildenafil (a 50 mg dose adjustable to 100 or 25 mg) was evaluated in a 12-week, double-blind, placebo controlled study in 202 postmenopausal women with FSAD who had protocol specified estradiol and free testosterone concentrations, and/or were receiving estrogen and/or androgen replacement therapy. Patients were excluded if emotional, relationship or historical abuse issues contributed significantly to sexual dysfunction. Primary end points were questions 2 (increased genital sensation during intercourse or stimulation) and 4 (increased satisfaction with intercourse and/or foreplay) from the Female Intervention Efficacy Index (FIEI). Secondary end points were the remaining questions from this index, the Sexual Function Questionnaire and sexual activity event log questions. RESULTS: Significant improvements in FIEI questions 2 (p = 0.017) and 4 (p = 0.015) were noted with sildenafil compared with placebo. For women with FSAD without concomitant hypoactive sexual desire disorder (HSDD) sildenafil was associated with significantly greater improvement in 5 of 6 FIEI items compared with placebo (p <0.02). No significant improvements were shown for women with concomitant HSDD. Most adverse events were mild to moderate with headache, flushing, rhinitis, nausea and visual symptoms reported most frequently. CONCLUSIONS: Sildenafil was effective and well tolerated in postmenopausal women with FSAD without concomitant HSDD or contributory emotional, relationship or historical abuse issues. All patients had protocol specified estradiol and free testosterone concentrations or were receiving estrogen and/or androgen replacement therapy.
Asunto(s)
Inhibidores de Fosfodiesterasa/uso terapéutico , Piperazinas/uso terapéutico , Disfunciones Sexuales Psicológicas/tratamiento farmacológico , Adulto , Anciano , Método Doble Ciego , Estradiol/sangre , Femenino , Humanos , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa/efectos adversos , Piperazinas/efectos adversos , Posmenopausia , Purinas , Conducta Sexual , Disfunciones Sexuales Psicológicas/sangre , Citrato de Sildenafil , Sulfonas , Testosterona/sangreRESUMEN
Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K(i)=7 nM, rat pituicyte EC(50)=3 nM) and the des-methyl analogue 5c (hGHS-R1a K(i)=17 nM, rat pituicyte EC(50)=3 nM), increased plasma GH levels in an anesthesized rat model, with ED(50) values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat)=65%, F(dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.
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Dipéptidos/síntesis química , Dipéptidos/farmacología , Hormona del Crecimiento/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Animales , Células Cultivadas , Fenómenos Químicos , Química Física , ADN Complementario/metabolismo , Dipéptidos/farmacocinética , Perros , Diseño de Fármacos , Femenino , Semivida , Humanos , Indicadores y Reactivos , Indoles/farmacología , Espectroscopía de Resonancia Magnética , Piperidinas/farmacocinética , Hipófisis/citología , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Pirazoles/farmacocinética , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Solubilidad , Compuestos de Espiro/farmacologíaRESUMEN
New tert-butyl, picolyl and fluorinated analogues of capromorelin (3), a short-acting growth hormone secretagogue (GHS), were prepared as part of a program to identify long-acting GHSs that increase 24-h plasma IGF-1 levels. Compounds 4c and 4d (ACD LogD values >or=2.9) displayed extended plasma elimination half-lives in dogs, primarily due to high volumes of distribution, but showed weak GH secretagogue activities in rats (ED(50)s>10 mg/kg). A less lipophilic derivative 4 (ACD LogD=1.6) exhibited a shorter canine half-life, but stimulated GH secretion in two animal species. Repeat oral dosing of 4 in dogs for 29 days (6 mg/kg) resulted in a significant down-regulation of the post dose GH response and a 60 and 40% increase in IGF-1 levels relative to pre-dose levels at the 8- and 24-h post dose time points. Compound 4 (CP-464709-18) has been selected as a development candidate for the treatment of frailty.