RESUMEN
Reactive oxygen species (ROS) are aerobic products generated during cellular respiration, but in the case of oxidative stress, they become key factors in the development of inflammatory processes and chronic diseases such as diabetes and rheumatoid arthritis. In this work, Euterpe oleracea oil (EOO), as well as the complexes produced by slurry (S) and kneading (K), were analyzed for antioxidant capacity in vitro, while only the ß-cyclodextrin complex obtained by kneading (EOO-ßCD-K), which showed better complexation, was selected for anti-inflammatory assays in vivo. In the scavenging activity of OH·, the hydroxypropyl-ß-cyclodextrin complex obtained by kneading (EOO-HPßCD-K) exhibited an activity 437% higher than the pure oil. In the paw edema assay, EOO-ßCD-K reduced edema by 200% and myeloperoxidase (MPO) activity by 112%. In an air pouch model, this treatment showed a reduction in leukocyte, MPO, and Interleukin-1ß (IL-1ß) levels; meanwhile those of glutathione and IL-10 were increased, demonstrating its ability to potentiate the anti-inflammatory effect of EOO.
Asunto(s)
Euterpe/química , Aceites de Plantas/química , Aceites de Plantas/farmacología , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/administración & dosificación , Antioxidantes/química , Antioxidantes/farmacología , Edema/tratamiento farmacológico , Femenino , Técnicas In Vitro , Masculino , Ratones , Fitoquímicos/administración & dosificación , Fitoquímicos/química , Fitoquímicos/farmacología , Aceites de Plantas/administración & dosificación , Plantas Medicinales/química , beta-Ciclodextrinas/administración & dosificaciónRESUMEN
Niemann-Pick disease type C (NPC) is a recessive hereditary disease caused by mutation of the NPC1 or NPC2 gene. It is characterized by abnormality of cellular cholesterol trafficking with severe neuronal and hepatic injury. In this study, we investigated the potential of glycoprotein nonmetastatic melanoma protein B (GPNMB) to act as a biomarker reflecting the therapeutic effect of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) in an NPC mouse model. We measured serum, brain, and liver expression levels of GPNMB, and evaluated their therapeutic effects on NPC manifestations in the brain and liver after the intracerebroventricular administration of HP-ß-CD in Npc1 gene-deficient (Npc1-/-) mice. Intracerebroventricular HP-ß-CD inhibited cerebellar Purkinje cell damage in Npc1-/- mice and significantly reduced serum and cerebellar GPNMB levels. Interestingly, we also observed that the intracerebral administration significantly reduced hepatic GPNMB expression and elevated serum ALT in Npc1-/- mice. Repeated doses of intracerebroventricular HP-ß-CD (30 mg/kg, started at 4 weeks of age and repeated every 2 weeks) drastically extended the lifespan of Npc1-/- mice compared with saline treatment. In summary, our results suggest that GPNMB level in serum is a potential biomarker for evaluating the attenuation of NPC pathophysiology by intracerebroventricular HP-ß-CD treatment.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Cerebelo/efectos de los fármacos , Proteínas del Ojo/metabolismo , Hígado/efectos de los fármacos , Melanoma/metabolismo , Glicoproteínas de Membrana/metabolismo , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Enfermedad de Niemann-Pick Tipo C/metabolismo , Animales , Biomarcadores/metabolismo , Cerebelo/metabolismo , Colesterol/metabolismo , Modelos Animales de Enfermedad , Femenino , Glicoproteínas/metabolismo , Infusiones Intraventriculares , Hígado/metabolismo , Masculino , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Células de Purkinje/efectos de los fármacos , Células de Purkinje/metabolismoRESUMEN
The aim of present study was to evaluate the feasibility of a naringenin-hydroxypropyl-ß-cyclodextrin (naringenin-HPßCD) inhalation solution for pulmonary delivery. Naringenin, a flavanone derived from citrus fruits, has been proven to exhibit excellent peripheral antitussive effect. To address the limitation of its poor oral bioavailability and low local concentration in the lung, a naringenin-HPßCD inhalation solution was prepared for pulmonary delivery. The aerosolization performance of formulation was evaluated by next generation impactor (NGI). Both dose-dependent and time-dependent antitussive effects of naringenin-HPßCD inhalation solution on acute cough induced by citric acid in guinea pigs were investigated. In vitro toxicity of naringenin-HPßCD inhalation solution in pulmonary Calu-3 cells was evaluated by MTS assay, and in vivo local toxicity investigation was achieved by assessing bronchoalveolar lavage (BALF) and lung histology after a 7-day inhalation treatment in guinea pigs. Fine particle fraction (FPF) of the formulation was determined as 53.09%. After inhalation treatment of 15 min, naringenin-HPßCD inhalation solution within the studied range of 0.2-3.6 mg/kg could dose-dependently reduce the cough frequency with the antitussive rate of 29.42-39.42%. Naringenin-HPßCD inhalation solution in concentration range of 100-400 µM did not decrease cell viability of Calu-3 cells, and the maximum effective dose (3.6 mg/kg) was non-toxic during the short-term inhalation treatment for guinea pigs. In conclusion, naringenin-HPßCD inhalation solution was capable for nebulization and could provide rapid response with reduced dose for the treatment of cough.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Aerosoles/química , Antitusígenos/administración & dosificación , Flavanonas/administración & dosificación , 2-Hidroxipropil-beta-Ciclodextrina/química , Administración por Inhalación , Animales , Disponibilidad Biológica , Flavanonas/química , Cobayas , Pulmón , beta-Ciclodextrinas/administración & dosificaciónRESUMEN
Niemann-Pick disease type C (NPC) is a neurodegenerative disease in which mutation of NPC1 or NPC2 gene leads to lysosomal accumulation of unesterified cholesterol and sphingolipids. Diagnosis of NPC disease is challenging due to non-specific early symptoms. Biomarker and genetic tests are used as first-line diagnostic tests for NPC. In this study, we developed a plasma test based on N-(3ß,5α,6ß-trihydroxy-cholan-24-oyl)glycine (TCG) that was markedly increased in the plasma of human NPC1 subjects. The test showed sensitivity of 0.9945 and specificity of 0.9982 to differentiate individuals with NPC1 from NPC1 carriers and controls. Compared to other commonly used biomarkers, cholestane-3ß,5α,6ß-triol (C-triol) and N-palmitoyl-O-phosphocholine (PPCS, also referred to as lysoSM-509), TCG was equally sensitive for identifying NPC1 but more specific. Unlike C-triol and PPCS, TCG showed excellent stability and no spurious generation of marker in the sample preparation or aging of samples. TCG was also elevated in lysosomal acid lipase deficiency (LALD) and acid sphingomyelinase deficiency (ASMD). Plasma TCG was significantly reduced after intravenous (IV) 2-hydroxypropyl-ß-cyclodextrin (HPßCD) treatment. These results demonstrate that plasma TCG was superior to C-triol and PPCS as NPC1 diagnostic biomarker and was able to evaluate the peripheral treatment efficacy of IV HPßCD treatment.
Asunto(s)
Glicina/sangre , Péptidos y Proteínas de Señalización Intracelular/genética , Enfermedad de Niemann-Pick Tipo C/sangre , Enfermedad de Niemann-Pick Tipo C/genética , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Ácidos y Sales Biliares/sangre , Biomarcadores/sangre , Femenino , Glicina/análogos & derivados , Glicina/aislamiento & purificación , Humanos , Masculino , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Enfermedad de Niemann-Pick Tipo C/patología , Espectrometría de Masas en Tándem , Proteínas de Transporte Vesicular/genéticaRESUMEN
BACKGROUND: We investigated the protective effect of silibinin on rat liver and kidney after hepatic inschemia/reperfusion (I/R) injury. METHODS AND MATERIALS: Sixty three male Wistar-type rats (median age 13 weeks; average weight 314 g) were subjected to I/R injury of the liver. They were randomly divided into three groups: Sham (n = 7), Control (C, n = 28) and Silibinin (Si, n = 28). The last group received intravenously silibinin. The C and Si groups were each subdivided in four subgroups according to euthanasia times (i.e., 60, 120, 180, 240 min). We assessed expression of caspase-3 and TUNEL assay, and biochemical and histological parameters. RESULTS: At 240 min, expression of caspase-3 and TUNEL assay were statistically significantly lower in the Si compared to the C group for both liver and kidney. SGOT and SGPT were also statistically significantly lower in the Si than in the C group at all time points. Histological parameters of the liver were also improved in the Si group. CONCLUSION: Silibinin was found to exhibit a protective effect on liver and kidney after hepatic I/R injury. The present results are encouraging for further studies and future clinical application.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Riñón/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Silibina/administración & dosificación , 2-Hidroxipropil-beta-Ciclodextrina/química , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/genética , Caspasa 3/metabolismo , Humanos , Riñón/fisiopatología , Hígado/efectos de los fármacos , Hígado/fisiopatología , Masculino , Ratas , Ratas Wistar , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/fisiopatología , Silibina/químicaRESUMEN
Lipids present in lipoproteins cleared from the circulation are processed sequentially by three major proteins within the late endosomal/lysosomal (E/L) compartment of all cells: lysosomal acid lipase (LAL), Niemann-Pick (NPC) C2 and NPC1. When all three of these proteins are functioning normally, unesterified cholesterol (UC) exits the E/L compartment and is used in plasma membrane maintenance and various pathways in the endoplasmic reticulum including esterification by sterol O-acyltransferase 2 (SOAT2) or SOAT1 depending partly on cell type. Mutations in either NPC2 or NPC1 result in continual entrapment of UC and glycosphingolipids leading to neurodegeneration, pulmonary dysfunction, splenomegaly and liver damage. To date, the most effective agent for promoting release of entrapped UC in nearly all organs of NPC1-deficient mice and cats is 2-hydroxypropyl-ß-cyclodextrin (2HPßCD). The cytotoxic nature of the liberated UC triggers various defenses including suppression of sterol synthesis and increased esterification. The present studies, using the Npc1-/-nih mouse model, measured the comparative quantitative importance of these two responses in the liver versus the spleen of Npc1-/-: Soat2+/+ and Npc1-/-: Soat2-/- mice in the 24 h following a single acute treatment with 2HPßCD. In the liver but not the spleen of both types of mice suppression of synthesis alone or in combination with increased esterification provided the major defense against the rise in unsequestered cellular UC content. These findings have implications for systemic 2HPßCD treatment in NPC1 patients in view of the purportedly low levels of SOAT2 activity in human liver.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/farmacología , Colesterol/metabolismo , Proteína Niemann-Pick C1/genética , Esterol O-Aciltransferasa/metabolismo , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Animales , Hígado/enzimología , Ratones , Ratones Endogámicos BALB C , Esterol O-Aciltransferasa/genética , Esterol O-Aciltransferasa 2RESUMEN
Cyclodextrins are widely used pharmaceutical excipients, particularly for insoluble compounds dosed orally, such as the oral solution of itraconazole, which is frequently used in clinical drug-drug interaction studies to inhibit cytochrome P450 3A. Since cyclodextrins act by forming inclusion complexes with their coformulated drug, they could have an unintended consequence of affecting absorption if they form a strong complex with the potential victim drug in an itraconazole drug-drug interaction study. This observation was made in a drug-drug interaction study with the Bruton's tyrosine kinase (BTK) inhibitor fenebrutinib and itraconazole, in which, relative to the control group, the expected increase in fenebrutinib maximum plasma concentration (Cmax ) was not observed in the itraconazole group, and a delay in time to reach maximum plasma concentration (Tmax ) was observed in the itraconazole group. The in vitro binding constant between fenebrutinib and hydroxypropyl-ß-cyclodextrin was determined to be 2 × 105 M-1 , and the apparent permeability of fenebrutinib across a Madin-Darby canine kidney cell monolayer decreased in a cyclodextrin concentration-dependent manner. This observation was confirmed in vivo, in a pentagastrin-pretreated dog model, in which fenebrutinib was administered with or without cyclodextrin; a reduction in Cmax , a prolonged Tmax , and increased fenebrutinib recovery in feces replicated the previous observation in healthy volunteers and supported the hypothesis that complexation with cyclodextrin decreased rate and extent of fenebrutinib absorption. Physiologically-based pharmacokinetic modeling was used to translate the in vitro effect of cyclodextrin on fenebrutinib apparent permeability to the in vivo effect on absorption, which was then confirmed using the in vivo dog pharmacokinetic data.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/efectos adversos , Excipientes/administración & dosificación , Absorción Intestinal/efectos de los fármacos , Itraconazol/efectos adversos , Piperazinas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Piridonas/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Administración Oral , Adolescente , Adulto , Animales , Perros , Esquema de Medicación , Interacciones Farmacológicas , Excipientes/toxicidad , Heces/química , Femenino , Humanos , Itraconazol/administración & dosificación , Células de Riñón Canino Madin Darby , Masculino , Persona de Mediana Edad , Modelos Animales , Permeabilidad , Piperazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridonas/administración & dosificación , Adulto JovenRESUMEN
Vaccine adjuvants are traditionally used to augment and modulate the immunogenicity of vaccines, although in many cases it is unclear which specific molecules contribute to their stimulatory activity. We previously reported that both subcutaneous and intranasal administration of hydroxypropyl-ß-cyclodextrin (HP-ß-CD), a pharmaceutical excipient widely used to improve solubility, can act as an effective adjuvant for an influenza vaccine. However, the mechanisms by which mucosal immune pathway is critical for the intranasal adjuvant activity of HP-ß-CD have not been fully delineated. Here, we show that intranasally administered HP-ß-CD elicits a temporary release of IL-33 from alveolar epithelial type 2 cells in the lung; notably, IL-33 expression in these cells is not stimulated following the use of other vaccine adjuvants. The experiments using gene deficient mice suggested that IL-33/ST2 signaling is solely responsible for the adjuvant effect of HP-ß-CD when it is administered intranasally. In contrast, the subcutaneous injection of HP-ß-CD and the intranasal administration of alum, as a damage-associated molecular patterns (DAMPs)-inducing adjuvant, or cholera toxin, as a mucosal adjuvant, enhanced humoral immunity in an IL-33-independent manner, suggesting that the IL-33/ST2 pathway is unique to the adjuvanticity of intranasally administered HP-ß-CD. Furthermore, the release of IL-33 was involved in the protective immunity against influenza virus infection which is induced by the intranasal administration of HP-ß-CD-adjuvanted influenza split vaccine. In conclusion, our results suggest that an understanding of administration route- and tissue-specific immune responses is crucial for the design of unique vaccine adjuvants.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/farmacología , Adyuvantes Inmunológicos/farmacología , Vacunas contra la Influenza/inmunología , Interleucina-33/fisiología , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Administración Intranasal , Animales , Vacunas contra la Influenza/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , Proteínas Serina-Treonina Quinasas/fisiología , Células Th2/inmunologíaRESUMEN
Pulmonary fibrosis (PF) is a kind of interstitial lung disease with the features of progressive and often fatal dyspnea. Tetrandrine (TET) is the major active constituent of Chinese herbal Stephania tetrandra S. Moore, which has already applied clinically to treat rheumatism, lung cancer, and silicosis. In this work, a tetrandrine-hydroxypropyl-ß-cyclodextrin inclusion compound (TET-HP-ß-CD) was developed for the treatment of pulmonary fibrosis via inhalation administration. TET-HP-ß-CD was prepared by the freeze-drying method and identified using the cascade impactor, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectrum (FT-IR). A bleomycin-induced pulmonary fibrosis rat model was used to assess the effects of inhaled TET and TET-HP-ß-CD. Animal survival, hydroxyproline content in the lungs, and lung histology were detected. The results showed that inhalation of TET-HP-ß-CD alleviated inflammation and fibrosis, limited the accumulation of hydroxyproline in the lungs, regulated protein expression in PF development, and improved postoperative survival. Moreover, nebulized delivery of TET-HP-ß-CD accumulated chiefly in the lungs and limited systemic distribution compared with intravenous administration. The present results indicated that inhalation of TET-HP-ß-CD is an attractive candidate for the treatment of pulmonary fibrosis.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/química , Bencilisoquinolinas/química , Fibrosis Pulmonar/tratamiento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , 2-Hidroxipropil-beta-Ciclodextrina/farmacocinética , Administración por Inhalación , Animales , Bencilisoquinolinas/administración & dosificación , Bencilisoquinolinas/farmacocinética , Modelos Animales de Enfermedad , Pulmón/metabolismo , Pulmón/patología , Masculino , Fibrosis Pulmonar/mortalidad , Fibrosis Pulmonar/patología , Ratas , Ratas Sprague-Dawley , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Factor de Necrosis Tumoral alfa/análisisRESUMEN
The chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-ß-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-ß-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-ß-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i.âp. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i.âv., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i.âp. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-ß-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Benzopiranos/administración & dosificación , 2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/farmacocinética , Animales , Benzopiranos/química , Benzopiranos/farmacocinética , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Espectroscopía de Resonancia Magnética , Ratas , SolubilidadRESUMEN
Cardiac hypertrophy often causes impairment of cardiac function. Xenon (Xe), a naturally occurring noble gas, is known to provide neurological and myocardial protection without side effects. The conventional method of Xe delivery by inhalation is not feasible on a chronic basis. We have developed an orally deliverable, effective Xe formulation for long-term administration. We employed 2-hydroxypropyl)-ß-cyclodextrin (HPCD), which was dissolved in water to increase the Xe concentration in solution. The beneficial effects of long-term oral administration of Xe-enriched solutions on cardiovascular function were evaluated in vivo. HPCD increased Xe solubility from 0.22 mM to 0.67 mM (3.8-fold). Aged ApoE knockout mice fed high-fat diet for 6 weeks developed hypertension, and myocardial hypertrophy with impaired cardiac function. Oral Xe prevented this ischemic damage, preserving normal blood pressure, while maintaining normal left ventricular mass and wall thickness. This novel formulation allows for gastrointestinal delivery and cardiovascular stabilization.
Asunto(s)
Cardiotónicos/administración & dosificación , Sistema Cardiovascular/efectos de los fármacos , Xenón/administración & dosificación , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Administración Oral , Animales , Apolipoproteínas E/genética , Presión Sanguínea/efectos de los fármacos , Corazón/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Solubilidad , Soluciones/administración & dosificaciónRESUMEN
BACKGROUND: Niemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPßPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPßCD has been administered to NPC patients with approved INDs globally since 2009. RESULTS: Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPßCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPßCD following on average 13 months of IV HPßCD. Several patients transitioned to an alternate HPßCD. Moderately affected NPC patients treated with HPßCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer. CONCLUSIONS: These expanded access data support the safety and potential benefit of systemic IV administration of HPßCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPßCD in NPC patients.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/uso terapéutico , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
2-Hydroxypropyl-beta-cyclodextrin (HPBCD) is utilized in the formulation of pharmaceutical products and recently orphan designation was granted for the treatment of Niemann-Pick disease, type C. The exact mechanism of HPBCD action and side effects are not completely explained. We used fluorescently labelled hydroxypropyl-beta-cyclodextrin (FITC-HPBCD) to study its pharmacokinetic parameters in mice and compare with native HPBCD data. We found that FITC-HPBCD has fast distribution and elimination, similar to HPBCD. Interestingly animals could be divided into two groups, where the pharmacokinetic parameters followed or did not follow the two-compartment, first-order kinetic model. Tissue distribution studies revealed, that a significant amount of FITC-HPBCD could be detected in kidneys after 60 min treatment, due to its renal excretion. Ex vivo fluorescent imaging showed that fluorescence could be measured in lung, liver, brain and spleen after 30 min of treatment. To model the interaction and cellular distribution of FITC-HPBCD in the wall of blood vessels, we treated human umbilical vein endothelial cells (HUVECs) with FITC-HPBCD and demonstrated for the first time that this compound could be detected in the cytoplasm in small vesicles after 30 min of treatment. FITC-HPBCD has similar pharmacokinetic to HPBCD and can provide new information to the detailed mechanism of action of HPBCD.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/farmacocinética , Citoplasma/química , Fluoresceína-5-Isotiocianato/química , Riñón/química , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , 2-Hidroxipropil-beta-Ciclodextrina/química , Animales , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Modelos Biológicos , Eliminación Renal , Distribución TisularRESUMEN
Topical application of aluminum-chloride phthalocyanine (AlClPc) is a challenge because of the drug's extremely low solubility, which prevents its absorption into deeper skin layers and causes molecule aggregation, reducing the photophysical effect. The goal of this study was to obtain a formulation applied in a certain condition that would allow homogeneous accumulation of AlClPc in cutaneous tissues, meaning a safer and non-invasive topical treatment for skin tumors based on photodynamic therapy. We first prepared and characterized AlClPc complexes with cyclodextrin to increase the photosensitizing agent solubility. The inclusion complex of AlClPc with hydroxypropyl-ß-cyclodextrin (HP-ßCD) amplified its loading dose in aqueous medium and maintained its photosensitizing properties in terms of reactive oxygen species production. Assays to determine the complex's in vitro cytotoxicity against murine melanoma skin cancer cells showed that when irradiated, the complex significantly reduced cell viability, whereas the absence of irradiation did not affect cell viability. Three physical techniques for permeation enhancement (i.e., tape-stripping abrasion, microneedle pretreatment and iontophoresis) were then evaluated. When applied in impaired skin, the complex could not increase drug penetration. The skin penetration of AlClPc, however, increased 2.3-fold following iontophoresis application in a shorter period compared to passive permeation. Therefore, these results suggest the administration of complexed AlClPc mediated by iontophoresis, followed by application of photodynamic therapy, might be an effective and non-invasive alternative for topical treatment of cutaneous tumors.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Cloruro de Aluminio/administración & dosificación , Indoles/administración & dosificación , Melanoma Experimental/tratamiento farmacológico , Compuestos Organometálicos/administración & dosificación , Fármacos Fotosensibilizantes/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina/química , Administración Cutánea , Cloruro de Aluminio/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Indoles/química , Iontoforesis , Ratones , Compuestos Organometálicos/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Especies Reactivas de Oxígeno/química , Piel/metabolismo , Absorción Cutánea , PorcinosRESUMEN
BACKGROUND: A 1-mL aqueous solution for parenteral injection containing diclofenac sodium and hydroxypropyl-ß-cyclodextrin, presently on the market for intramuscular and subcutaneous administration (Akis®/Dicloin®), was further developed for intravenous (i.v.) bolus administration. OBJECTIVES: The study objective was to compare the tolerability and diclofenac pharmacokinetics after a single i.v. bolus of the investigational solution to those of other parenteral diclofenac products. METHODS: The study comprised three parts: (i) Part 1: an exploratory dose-escalation study to evaluate the tolerability of 25 mg/1 mL, 50 mg/1 mL and 75 mg/1 mL diclofenac sodium formulations administered as a single 5-s i.v. bolus; (ii) Part 2: an exploratory, randomised, crossover study to evaluate the pharmacokinetics of diclofenac following 5-, 15-, and 30-s i.v. bolus injections of diclofenac sodium 75 mg/1 mL; (iii) Part 3: a randomised crossover study to compare the pharmacokinetics of diclofenac following a 5-s i.v. bolus of the 75 mg/1 mL solution to the pharmacokinetics of diclofenac following a 30-min i.v. infusion or intramuscular administration of a 75 mg/3 mL reference formulation. RESULTS: The extent of exposure to diclofenac sodium afforded by the 5-s i.v. bolus of 75 mg/1 mL was equivalent to that provided by the 30-min i.v. infusion of 75 mg/3 mL, since the 90% confidence interval of the geometric mean ratio (GMR) of the area under the curve (AUC) from time 0 to the last plasma concentration time t (AUC0-t) was within the limits 80.00-125.00%, as was the 90% confidence interval of the GMR of the AUC from time 0 extrapolated to infinity (AUC0-∞). The maximum observed plasma concentration (Cmax) was approximately 2.7-fold higher and was achieved earlier (0.05 vs. 0.50 h) with the 1 mL than with the 3 mL formulation, and was similar to data published for a 75 mg/2 mL formulation given as a 15-s i.v. bolus. CONCLUSIONS: Diclofenac sodium 75 mg/1 mL solution administered as a 5-s i.v. bolus was well tolerated. The pharmacokinetic profile, which showed a faster onset and a higher concentration peak than seen for other products and administration routes, suggests a superior analgesic effect.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacocinética , Diclofenaco/efectos adversos , Diclofenaco/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , 2-Hidroxipropil-beta-Ciclodextrina/efectos adversos , 2-Hidroxipropil-beta-Ciclodextrina/farmacocinética , Adolescente , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Diclofenaco/administración & dosificación , Femenino , Humanos , Inyecciones Intramusculares , Inyecciones Intravenosas/métodos , Persona de Mediana Edad , Adulto JovenRESUMEN
Preexposure prophylaxis (PrEP) with antiretrovirals (ARV) can prevent human immunodeficiency virus (HIV) transmission, but its efficacy is highly dependent on strict patient adherence to daily dosing regimen. Long-acting (LA) ARV formulations or delivery systems that reduce dosing frequency may increase adherence and thus PrEP efficacy. While cabotegravir (CAB) long-acting injectable (CAB LA), an integrase strand transfer inhibitor (INSTI), reduces dosing frequency to bimonthly injections, variable pharmacokinetics (PK) between patients and various adverse reactions necessitate improvement in delivery methods. Here we developed a subcutaneously implantable nanofluidic device for the sustained delivery of CAB formulated with 2-hydroxypropyl-ß-cyclodextrin (ßCAB) and examined the pharmacokinetics (PK) in Sprague-Dawley rats for 3â¯months in comparison to CAB. Our study demonstrated ßCAB treatment group maintained clinically-relevant plasma CAB concentrations 2 times above the protein-adjusted concentration that inhibits viral replication by 90% (2â¯×â¯PA-IC90) and drug penetration into tissues relevant to HIV-1 transmission. Further, we successfully fitted plasma CAB concentrations into a PK model (R2â¯=â¯0.9999) and determined CAB apparent elimination half-life of 47â¯days. Overall, our data shows the potential of sustained release of ßCAB via a nanofluidic implant for long-term PrEP delivery, warranting further investigation for efficacy against HIV infections.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Sistemas de Liberación de Medicamentos/instrumentación , Infecciones por VIH/prevención & control , Profilaxis Pre-Exposición , Piridonas/farmacocinética , Animales , Sistemas de Liberación de Medicamentos/efectos adversos , Masculino , Piridonas/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
Thymoquinone is an effective phytochemical compound in the treatment of various diseases. However, its practical administration has been limited due to poor aqueous solubility and bioavailability. In this work, we developed a novel inclusion complex of thymoquinone and hydroxypropyl-ß-cyclodextrin that features improved solubility and bioactivity. The drug solubility was markedly accelerated in the increasing ratio of hydroxypropyl-ß-cyclodextrin to thymoquinone amount. The formation of the thymoquinone/hydroxypropyl-ß-cyclodextrin inclusion complex was evidenced using X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, Fourier transform infrared, scanning electron microscopy and nuclear magnetic resonance. The release behavior of the complex, as well as of their mixtures, was examined in artificial gastric (pHâ¯1.2) and intestinal (pHâ¯6.8) dissolution media. The formulated complex released the drug rapidly at the initial stage, followed by a slow release. Thermodynamic parameters ΔH, ΔS and ΔG were calculated with temperatures ranging from 20 to 45⯰C to evaluate the complexation process. The activity of the inclusion complex was evaluated on IgE-mediated allergic response in rat basophilic leukemia (RBL-2H3) cells by monitoring key allergic mediators. The results revealed that compared with free thymoquinone, the inclusion complex more strongly inhibited the release of histamine, tumor necrosis factor-α, and interleukin-4, and was not cytotoxic at the tested thymoquinone concentrations (0.125-4⯵g/mL) indicating the inclusion complex possibly had better antiallergic effects. Our finding suggested that the inclusion complex achieved prolonged action and reduced side-effect of thymoquinone.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Antialérgicos/administración & dosificación , Benzoquinonas/administración & dosificación , Sistemas de Liberación de Medicamentos , Animales , Antialérgicos/química , Benzoquinonas/química , Línea Celular Tumoral , Liberación de Fármacos , Jugo Gástrico/química , Histamina/metabolismo , Interleucina-4/metabolismo , Secreciones Intestinales/química , Ratas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We previously reported the altered pulmonary function and pathology found in the mouse model of infantile Niemann-Pick C1 disease, the Npc1-/- mouse. Despite its salutary properties on brain and liver parameters, we did not find efficacious effects of hydroxypropyl-ß-cyclodextrin (HPBCD) on pulmonary pathology. Since we had previously shown the beneficial effects of probucol on the somatic phenotype in the Npc1-/- mice, we have now studied the effects of combined therapy with HPBCD and probucol on the lung with mostly negative results. Body weight and lung weight for body weight were increased in parallel while inspiratory capacity for body weight was markedly decreased. Other physical, biochemical, and pulmonary function parameters were not much changed. There were trends towards improved lung elastance (p = 0.09) and compliance (p = 0.07).
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Probucol/administración & dosificación , Proteínas/genética , Animales , Colesterol/genética , Modelos Animales de Enfermedad , Combinación de Medicamentos , Humanos , Péptidos y Proteínas de Señalización Intracelular , Pulmón/efectos de los fármacos , Pulmón/patología , Ratones , Ratones Noqueados , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/genética , Enfermedad de Niemann-Pick Tipo C/patologíaRESUMEN
PURPOSE: A major challenge in ocular therapeutics is poor bioavailability of drug, 1% or even less of the instilled dose is absorbed and frequent administration of conventional products leads to poor adherence to therapy. Hence, the present study is to synthesize N-trimethyl chitosan (TMC), a water-soluble chitosan derivative and to prepare flurbiprofen (FLU):hydroxyl propyl-ß-cyclodextrin (HP-ß-CD) complex-loaded nanoparticles for treatment of bacterial conjunctivitis which aims to increase the residence time in ocular tissue, thus enhancing patient compliance and improved efficacy. METHODS: TMC was synthesized and characterized by 1H NMR and FT-IR. TMC and chitosan (CS) nanoparticles containing inclusion complex were prepared by ionic gelation using sodium tripolyphosphate (TPP). The nanoparticles thus obtained were evaluated for particle size, zeta potential, drug entrapment, in-vitro release, in-vitro mucoadhesion, and TEM for morphology and irritation potential was evaluated by the HET-CAM technique. RESULTS: N-methyl quaternization of CS was confirmed by 1H NMR. The particle size and zeta potential of the TMC nanoparticles were found to be 201 ± 1.55 nm and +13.9 ± 1.697 mV and that of CS nanoparticles were 361.2 ± 1.55 nm and +10.9 ± 0.424 mV, respectively. The entrapment of FLU- HP-ß-CD inclusion complex in polymeric nanoparticles was found to be 10.91 ± 1.541%. The observed in-vitro release profile of TMC nanoparticles indicated characteristic burst release followed by delayed release. HET-CAM studies demonstrated the ocular safety of TMC nanoparticles. CONCLUSION: The developed TMC nanoparticles offered prolonged release potential for transmucosal ocular delivery of hydrophobic flurbiprofen.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Quitosano/química , Portadores de Fármacos , Flurbiprofeno/administración & dosificación , Nanopartículas/química , 2-Hidroxipropil-beta-Ciclodextrina/química , Animales , Antiinflamatorios no Esteroideos/química , Conjuntivitis Bacteriana/tratamiento farmacológico , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Flurbiprofeno/química , Espectroscopía de Resonancia Magnética , Microscopía Electrónica de Transmisión , Tamaño de la Partícula , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Solubilization of new chemical entities for toxicity assessment must use excipients that do not negatively impact drug pharmacokinetics and toxicology. In this study, we investigated the tolerability of a model freebase compound, GDC-0152, solubilized by pH adjustment with succinic acid and complexation with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) to enable intravenous use. Solubility, critical micelle concentration, and association constant with HP-ß-CD were determined. Blood compatibility and potential for hemolysis were assessed in vitro. Local tolerability was assessed after intravenous and subcutaneous injections in rats. A pharmacokinetic study was conducted in rats after intravenous bolus administration. GDC-0152 exhibited pH-dependent solubility that was influenced by self-association. The presence of succinic acid increased solubility in a concentration-dependent manner. HP-ß-CD alone also increased solubility, but the extent of solubility enhancement was significantly lower than succinic acid alone. Inclusion of HP-ß-CD in the solution of GDC-0152 improved blood compatibility, reduced hemolytic potential by â¼20-fold in vitro, and increased the maximum tolerated dose to 80 mg/kg.