RESUMEN
BACKGROUND: Infections with Clostridium difficile are a health threat, yet no products are currently licensed for prevention of primary C difficile infections. Intravenous ß-lactam antibiotics are considered to confer a high risk of C difficile infection because of their biliary excretion into the gastrointestinal tract and disruption of the gut microbiome. ribaxamase (SYN-004) is an orally administered ß-lactamase that was designed to be given with intravenous ß-lactam antibiotics to degrade excess antibiotics in the upper gastrointestinal tract before they disrupt the gut microbiome and lead to C difficile infection. We therefore aimed to determine whether administration of ribaxamase could prevent C difficile infection in patients being treated with intravenous ceftriaxone for a lower respiratory tract infection, thereby supporting continued clinical development. METHODS: In this parallel-group, double-blind, multicentre, phase 2b, randomised placebo-controlled trial, we recruited patients who had been admitted to a hospital with a lower respiratory tract infection with a pneumonia index score of 90-130 and who were expected to be treated with ceftriaxone for at least 5 days. Patients were recruited from 54 clinical sites in the USA, Canada, Bulgaria, Hungary, Poland, Romania, and Serbia. We randomly assigned patients older than 50 years to groups (1:1) in blocks of four by use of an interactive web portal; these groups were assigned to receive either 150 mg ribaxamase or placebo four times per day during, and for 72 h after, treatment with ceftriaxone. All patients, clinical investigators, study staff, and sponsor personnel were masked to the study drug assignments. The primary endpoint was the incidence of C difficile infection, as diagnosed by the local laboratory, in patients who received at least one treatment dose, and this outcome was assessed during treatment and for 4 weeks after treatment. This study is registered with ClinicalTrials.gov, number NCT02563106. FINDINGS: Between Nov 16, 2015, and Nov 10, 2016, we screened 433 patients for inclusion in the study. Of these patients, 20 (5%) patients were excluded from the study (16 [4%] patients did not meet inclusion criteria; four [1%] patients because of dosing restrictions). We enrolled and randomly assigned 413 patients to groups, of whom 207 patients were assigned to receive ceftriaxone plus ribaxamase and 206 patients were assigned to receive ceftriaxone plus placebo. However, one (<1%) patient in the ribaxamase group withdrew consent and was not treated with ribaxamase. During the study and within the 4 weeks after antibiotic treatment, two (1·0%) patients in the ribaxamase group and seven (3·4%) patients in the placebo group were diagnosed with an infection with C difficile (risk reduction 2·4%, 95% CI -0·6 to 5·9; one-sided p=0·045). Adverse events were similar between groups but more deaths were reported in the ribaxamase group (11 deaths vs five deaths in the placebo group). This disparity was due to the higher incidence of deaths attributed to cardiac-associated causes in the ribaxamase group (six deaths vs one death in the placebo group). INTERPRETATION: In patients treated with intravenous ceftriaxone for lower respiratory tract infections, oral ribaxamase reduced the incidence of C difficile infections compared with placebo. The imbalance in deaths between the groups appeared to be related to the underlying health of the patients. Ribaxamase has the potential to prevent C difficile infection in patients treated with intravenous ß-lactam antibiotics, and our findings support continued clinical development of ribaxamase to prevent C difficile infection. FUNDING: Synthetic Biologics.
Asunto(s)
Antibacterianos/administración & dosificación , Infecciones por Clostridium/prevención & control , Proteínas Recombinantes/administración & dosificación , beta-Lactamasas/administración & dosificación , beta-Lactamas/administración & dosificación , Administración Intravenosa , Administración Oral , Anciano , Anciano de 80 o más Años , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/epidemiología , Método Doble Ciego , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the safety and efficacy of methazolamide as a potential therapy for type 2 diabetes. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled study randomized 76 patients to oral methazolamide (40 mg b.i.d.) or placebo for 24 weeks. The primary efficacy end point for methazolamide treatment was a placebo-corrected reduction in HbA1c from baseline after 24 weeks (ΔHbA1c). RESULTS: Mean ± SD baseline HbA1c was 7.1 ± 0.7% (54 ± 5 mmol/mol; n = 37) and 7.4 ± 0.6% (57 ± 5 mmol/mol; n = 39) in the methazolamide and placebo groups, respectively. Methazolamide treatment was associated with a ΔHbA1c of -0.39% (95% CI -0.82, 0.04; P < 0.05) (-4.3 mmol/mol [-9.0, 0.4]), an increase in the proportion of patients achieving HbA1c ≤6.5% (48 mmol/mol) from 8 to 33%, a rapid reduction in alanine aminotransferase (â¼10 units/L), and weight loss (2%) in metformin-cotreated patients. CONCLUSIONS: Methazolamide is the archetype for a new intervention in type 2 diabetes with clinical benefits beyond glucose control.
Asunto(s)
Inhibidores de Anhidrasa Carbónica/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metazolamida/uso terapéutico , Anciano , Inhibidores de Anhidrasa Carbónica/efectos adversos , Método Doble Ciego , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/uso terapéutico , Metazolamida/efectos adversos , Persona de Mediana Edad , Pérdida de Peso/efectos de los fármacosRESUMEN
Tocopheryl Polyethylene Glycol Succinate 1000 (TPGS 1000) can inhibit P-glycoprotein (P-gp); TPGS 1000 was not originally designed to inhibit an efflux pump. Recent work from our laboratories demonstrated that TPGS activity has a rational PEG chain length dependency. In other recent work, inhibition mechanism was investigated and appears to be specific to the ATPase providing P-gp energy. Based on these observations, we commenced rational surface-active design. The current work summarizes new materials tested in a validated Caco-2 cell monolayer model; rhodamine 123 (10microM) was used as the P-gp substrate. These results demonstrate that one may logically construct non-ionic surfactants with enhanced propensity to inhibit in vitro efflux. One new surfactant based inhibitor, Tocopheryl Polypropylene Glycol Succinate 1000 (TPPG 1000), approached cyclosporine (CsA) in its in vitro efflux inhibitory potency. Subsequently, TPPG 1000 was tested for its ability to enhance the bioavailability of raloxifene - an established P-gp substrate -in fasted male rats. Animals dosed with raloxifene and TPPG 1000 experienced an increase in raloxifene oral bioavailability versus a control group which received no inhibitor. These preliminary results demonstrate that one may prepare TPGS analogs that possess enhanced inhibitory potency in vitro and in vivo.
Asunto(s)
Tensoactivos/química , Tensoactivos/farmacología , Vitamina E/análogos & derivados , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Disponibilidad Biológica , Transporte Biológico/efectos de los fármacos , Células CACO-2 , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Portadores de Fármacos , Humanos , Masculino , Espectrometría de Masas , Polietilenglicoles/química , Polietilenglicoles/farmacología , Clorhidrato de Raloxifeno/administración & dosificación , Clorhidrato de Raloxifeno/farmacocinética , Ratas , Ratas Endogámicas , Rodamina 123/farmacocinética , Vitamina E/química , Vitamina E/farmacologíaRESUMEN
Raloxifene is a highly insoluble, highly metabolized serum estrogen receptor modulator approved for use in the treatment of osteoporosis. Hydroxybutenyl-beta-cyclodextrin (HBenBCD) is a novel solubility enhancer previously demonstrated to increase the oral bioavailability of tamoxifen, letrozole, and itraconazole. The current study evaluated the pharmacokinetics of raloxifene in oral and intravenous formulations with HBenBCD in male Wistar-Hannover rats. Analytical methodology to measure raloxifene and its metabolites was developed by measuring raloxifene metabolism in vitro. Formulation with HBenBCD significantly increased raloxifene oral bioavailability. Mean+/-S.D. oral bioavailabilities were 2.6+/-0.4% for raloxifene formulated with microcrystalline cellulose, 7.7+/-2.1% for a solid capsule formulation of raloxifene:HBenBCD complex, and 5.7+/-1.3% for a liquid-filled capsule formulation containing raloxifene:HBenBCD/PEG400/H(2)O. Relative to raloxifene/microcrystalline filled capsules, the presence of HBenBCD in the solid capsule formulation afforded: (i) a decrease in raloxifene T(max) (2.5+/-0.5h versus 4.0+/-0.5h); (ii) a two-fold increase in raloxifene C(max) and a three-fold increase in raloxifene AUC; and (iii) a 12-fold increase in raloxifene glucuronide C(max) and a 6.5-fold increase in raloxifene glucuronide AUC. Hence, these studies demonstrate that raloxifene formulations containing HBenBCD significantly increased the oral bioavailability in rats relative to formulations that did not contain HBenBCD.
Asunto(s)
Clorhidrato de Raloxifeno/farmacocinética , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinética , beta-Ciclodextrinas/farmacología , Animales , Disponibilidad Biológica , Perros , Femenino , Humanos , Mucosa Intestinal/metabolismo , Hígado/metabolismo , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos , Microsomas/metabolismo , Microsomas Hepáticos/metabolismo , Clorhidrato de Raloxifeno/administración & dosificación , Clorhidrato de Raloxifeno/sangre , Clorhidrato de Raloxifeno/química , Ratas , Ratas Endogámicas , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Moduladores Selectivos de los Receptores de Estrógeno/sangre , Moduladores Selectivos de los Receptores de Estrógeno/química , Solubilidad , beta-Ciclodextrinas/administración & dosificaciónRESUMEN
The current research evaluated the ability of hydroxybutenyl-beta-cyclodextrin (HBenBCD) to enhance saquinavir in vitro solubility and in vivo oral bioavailability; both the base and mesylate salt forms of saquinavir were investigated. HBenBCD was effective and significantly improved saquinavir solubility in aqueous media. In the presence of 10 wt % HBenBCD, saquinavir base solubility in water was increased to ca. 5.5 +/- 0.4 mg/mL and represents a 27-fold increase from that observed in water (207 +/- 5 microg/mL) in the absence of HBenBCD. Saquinavir-HBenBCD formulations were found to have rapid dissolution over a wide pH range (1.2-6.8), and saquinavir solubility in these media was maintained throughout the experiments. When saquinavir-HBenBCD formulations were administered to Wistar-Hannover rats, saquinavir was rapidly absorbed and rapidly eliminated. Rapid saquinavir elimination was particularly pronounced when saquinavir-HBenBCD formulations were given as an oral aqueous gavage. Saquinavir oral bioavailability in rats obtained from saquinavir mesylate capsules (2.0% +/- 0.7%) was increased (9 +/- 4)-fold (18.6% +/- 7.3%) when dosed with saquinavir base-HBenBCD capsules. Clearly, HBenBCD can significantly improve the solubility and oral bioavailability of saquinavir; however, further formulation studies are required to optimize saquinavir oral delivery using this technology.
Asunto(s)
Saquinavir/farmacocinética , beta-Ciclodextrinas/administración & dosificación , Administración Oral , Animales , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/farmacocinética , Inyecciones Intravenosas , Ratas , Ratas Wistar , Saquinavir/administración & dosificaciónRESUMEN
The current research evaluated and compared the efficacy of hydroxybutenyl-beta-cyclodextrin (HBenBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) as enhancers of itraconazole solubility and oral bioavailability. At 10 wt% cyclodextrin, 17-fold and 3.8-fold increases in itraconazole aqueous solubility were observed in the presence of HBenBCD and HPBCD, respectively. Significant differences in the dissolution of itraconazole in the presence of these two cyclodextrins were also observed. Itraconazole pharmacokinetics is known to exhibit a significant food effect. However, testing in biorelevant media indicated that no food effects should be observed after oral administration of itraconazole:HBenBCD complexes. Formulations of itraconazole with HBenBCD were prepared and these complexes, along with the commercial forms of itraconazole with and without HPBCD (Sporanox) were administered to male Sprague-Dawley rats by oral and intravenous routes. Intravenous administration of itraconazole formulated with HBenBCD resulted in a higher AUC relative to Sporanox. When administered as oral solutions, the itraconazole:HBenBCD formulation provided higher oral bioavailability than the Sporanox oral solution. When administered as solid formulations, the itraconazole:HBenBCD solid formulation provided a 2x increase in oral bioavailability relative to the Sporanox solid formulation. No food effects were observed with the itraconazole:HBenBCD solid dosage forms. Drug/metabolite ratios were dependent upon the dosage form.
Asunto(s)
Ciclodextrinas/administración & dosificación , Ciclodextrinas/farmacocinética , Itraconazol/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina , Administración Oral , Animales , Antifúngicos/administración & dosificación , Antifúngicos/sangre , Antifúngicos/química , Antifúngicos/farmacocinética , Disponibilidad Biológica , Ciclodextrinas/sangre , Ciclodextrinas/química , Interacciones Alimento-Droga , Inyecciones Intravenosas , Itraconazol/administración & dosificación , Itraconazol/sangre , Itraconazol/química , Masculino , Ratas , Ratas Sprague-Dawley , Solubilidad , beta-Ciclodextrinas/administración & dosificación , beta-Ciclodextrinas/sangre , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinéticaRESUMEN
Oral and intravenous administration of tamoxifen base and tamoxifen citrate formulated with hydroxybutenyl-beta-cyclodextrin (HBenBCD) to Sprague-Dawley rats significantly increased the oral bioavailability of tamoxifen relative to that of parent drug (no HBenBCD). When formulated with HBenBCD, the form of tamoxifen (base vs. salt) made no difference in the oral bioavailability of tamoxifen. Liquid formulations (PG:PEG400:H2O) provided higher oral bioavailability than solid formulations dissolved and dosed as aqueous oral solutions. The oral bioavailability of tamoxifen was significantly influenced by both dietary status and time of dosing of the animals. Tamoxifen metabolite plasma concentrations were not affected by complexation of tamoxifen with HBenBCD. Collectively, the data indicated that dosing of fasted animals in the morning with tamoxifen:HBenBCD formulations provided a very significant increase in tamoxifen oral bioavailability (up to 10- to 14-fold).
Asunto(s)
Tamoxifeno/farmacocinética , beta-Ciclodextrinas/administración & dosificación , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Química Farmacéutica , Inyecciones Intravenosas , Masculino , Ratas , Ratas Sprague-Dawley , Tamoxifeno/administración & dosificaciónRESUMEN
Cyclosporine (CyA) is an immunosuppressant metabolized primarily by the liver and small intestine. The pharmacokinetics (PK) of CyA-were studied in 6 patients prior to and 1 to 3 months after liver transplantation (tx). Sixteen blood samples were collected over 24 hours following a 2-3 mg/kg intravenous dose of CyA. PK parameters, presented as mean +/- SD, were estimated using noncompartmental techniques. Pre-tx AUCs (14,540 +/- 5200 micrograms.h/L) were found to be significantly higher than during the post-tx phase (8120 +/- 2870 micrograms.h/L, p = 0.04). CyA clearance values were lower pre-tx as compared to post-tx (0.21 +/- 0.06 L/h/kg vs. 0.38 +/- 0.14 L/h/kg, respectively). There was no change in volume of distribution. End-stage liver disease can markedly decrease hepatic clearance of CyA relative to patients with stable hepatic function post-liver tx. The degree of impairment in clearance is not consistent or predictable based on liver function tests.
Asunto(s)
Ciclosporina/farmacocinética , Inmunosupresores/farmacocinética , Hepatopatías/metabolismo , Trasplante de Hígado , Adulto , Alcoholismo/complicaciones , Colangitis Esclerosante/metabolismo , Ciclosporina/administración & dosificación , Femenino , Hepatitis B/metabolismo , Hepatitis C/metabolismo , Humanos , Inmunosupresores/administración & dosificación , Infusiones Intravenosas , Hígado/metabolismo , Hepatopatías/etiología , Masculino , Persona de Mediana Edad , Periodo PosoperatorioRESUMEN
The contributions of cytochrome P450 3A (CYP3A) and P-glycoprotein to sirolimus oral bioavailability in rats were evaluated by coadministration of sirolimus (Rapamune) with the CYP3A inhibitor ketoconazole or the P-glycoprotein inhibitor D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS). Groups of six male Sprague-Dawley rats (250-300 g) were administered Rapamune (1 mg/kg) by oral gavage, alone and with ketoconazole (30 mg/kg) or TPGS (50 mg/kg). Sirolimus levels were measured in whole blood over a 6-h time course. Sirolimus C(max) (6.6 +/- 1.6 versus 26 +/- 7 ng/ml) and area under the concentration versus time curve from 0 to 6 h (AUC(0-6)) (22 +/- 7 versus 105 +/- 27 ng. h/ml) were increased 3- to 5-fold by ketoconazole. Median T(max) (1.5-2 h) was unchanged. TPGS had no effect on sirolimus absorption. The interaction of sirolimus with P-glycoprotein was also evaluated in vitro using HCT-8 and Caco-2 cell monolayers. Consistent with published reports, sirolimus was a good inhibitor of P-glycoprotein, inhibiting polarized basolateral-to-apical flux of rhodamine 123 with an IC(50) of 0.625 to 1.25 microM (cyclosporine caused >80% inhibition at 5 microM). Sirolimus did not demonstrate significant polarized flux in either direction using the same monolayers (basolateral-to-apical flux was <2 times the apical-to-basolateral). Moreover, sirolimus flux was not impacted by cyclosporine, suggesting that it does not undergo P-glycoprotein-mediated transport in this system. The lack of significant sirolimus transport by P-glycoprotein may, in part, explain the lack of a TPGS effect on sirolimus absorption in rats.
Asunto(s)
Absorción Intestinal/efectos de los fármacos , Cetoconazol/farmacología , Sirolimus/farmacocinética , Vitamina E/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Administración Oral , Animales , Línea Celular , Humanos , Cinética , Masculino , Tasa de Depuración Metabólica , Ratas , Ratas Sprague-Dawley , Sirolimus/administración & dosificación , Sirolimus/sangre , Células Tumorales CultivadasRESUMEN
The current work evaluated the effect of the CYP3A inhibitor ketoconazole on the oral absorption and first-pass metabolism of cyclosporine administered as the SangCyA formulation. Groups of 6 male Sprague-Dawley rats were administered SangCyA (5 and 15 mg/kg) by oral gavage alone and with ketoconazole (30 mg/kg). Blood cyclosporine levels were measured over 6 h, encompassing the cyclosporine absorption window. A significant vehicle effect on SangCyA absorption was observed. Comparing a 15 mg/kg dose, cyclosporine C(max) (mean+/-SD 1.12+/-0.16 microg/ml) and AUC(0-6) (5.34+/-0.71 microg h/ml) were 50% lower when propylene glycol was used as gavage vehicle instead of saline (2.19+/-0.94 microg/ml and 9.52+/-2.52 microg h/ml, respectively). Coefficients-of-variation for these parameters were halved in the propylene glycol vehicle however T(max) was unaffected. Ketoconazole increased cyclosporine C(max) and AUC(0-6) by 50-60%, regardless of the vehicle or the cyclosporine dose, without altering T(max) (2-3 h). The small effect of ketoconazole suggests that CYP3A-mediated intestinal and first-pass hepatic metabolism are minor determinants of cyclosporine oral bioavailability in rats.
Asunto(s)
Antifúngicos/farmacología , Ciclosporina/farmacocinética , Inmunosupresores/farmacocinética , Absorción Intestinal/efectos de los fármacos , Cetoconazol/farmacología , Animales , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Interacciones Farmacológicas , Masculino , Vehículos Farmacéuticos , Ratas , Espectrofotometría UltravioletaRESUMEN
Peppermint oil inhibits cyclosporine metabolism in vitro. The current work compared the effects of peppermint oil, ketoconazole, and D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS) on cyclosporine oral bioavailability. Male Sprague-Dawley rats were administered cyclosporine (25 mg/kg) as the Sandimmune formulation. Peppermint oil (100 mg/kg) tripled the mean cyclosporine maximum concentration (C(max)) from 0.60 to 1.6 microg/mL and increased the area under the concentration versus time curve (AUC(0-infinity)) from 8.3 to 24.3 microg x h/mL. The median time to reach C(max) (t(max)) was increased from 2 to 6 h. Terminal half-life (10 h) and mean residence time (MRT; 15 h) were unaffected. Coadministration of TPGS (50 mg/kg) with cyclosporine in a saline vehicle doubled cyclosporine C(max) from 1.3 to 2.9 microg/mL and increased AUC(0-infinity) from 28.5 to 59.7 microg x h/mL. The t(max) was unchanged (3 h). Terminal half-life and MRT were increased by 44% (15.4 versus 10.7 h) and 24% (19.9 versus 16.0 h), respectively. Cyclosporine pharmacokinetics were not altered when corn oil was used instead of saline as a gavage vehicle, however the TPGS effect was abolished. Ketoconazole (10 and 20 mg/kg) had no effect on cyclosporine absorption. The lack of a significant ketoconazole effect may reflect poor metabolism of cyclosporine in rat intestinal tissue and suggests that inhibition of cytochrome P450 3A is not the only means by which peppermint oil enhances cyclosporine oral bioavailability.