RESUMEN
OBJECTIVES: To compare the rate and extent of absorption of a launched generic calcium dobesilate capsule versus the branded reference formulation under fasting and fed conditions in healthy Chinese subjects, and to assess their bioequivalence and tolerability. METHODS: This single-dose, open-label, randomized-sequence, 2-period crossover bioequivalence study was conducted on healthy Chinese volunteers aged 18 to 45 years. Subjects received a single 0.5 g dose of calcium dobesilate capsule under fasting or fed conditions, with a 3-day washout period between doses of the test (T) and reference (R) formulations. Blood samples were collected before and up to 24 hours after administration. The plasma concentration of calcium dobesilate was determined by a validated Liquid chromatography-tandem mass spectrometry method. Non-compartmental analysis was applied to identify the pharmacokinetic (PK) properties. The primary PK parameters including the maximal plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC0-t), and the AUC extrapolated to infinity (AUC0-inf) were used for bioequivalence evaluation. RESULTS: The mean of PK parameters for T and R capsules under fasting (fed) condition were: Cmax, 13.57 (6.71) and 12.59 (7.25) µg/mL; AUC0-t, 97.32 (79.74) and 96.97 (80.71) h*µg/mL; AUC0-inf, 101.68 (88.01) and 101.64 (87.81) h*µg/mL. The 90% confidence intervals (CIs) of GMRs under fasting (fed) condition were: Cmax, 97.91%-116.62% (88.63%-96.53%); AUC0-t, 97.15%-104.00% (96.58%-101.39%); and AUC0-inf, 97.19%-102.89% (98.67%-103.99%). These 90% CIs were all within the bioequivalence range of 80%-125%. All adverse events were mild. CONCLUSION: In this study, the T calcium dobesilate 0.5 g capsule was bioequivalent to the reference product under both fasting and fed conditions. Taking food would slow down its rate and reduce its amount of absorption. Both formulations were generally well tolerated.
Asunto(s)
Dobesilato de Calcio , Medicamentos Genéricos , Pueblos del Este de Asia , Conducta Alimentaria , Medicamentos bajo Prescripción , Humanos , Área Bajo la Curva , Dobesilato de Calcio/sangre , Dobesilato de Calcio/farmacocinética , Cápsulas , Estudios Cruzados , Ayuno/sangre , Ayuno/fisiología , Conducta Alimentaria/fisiología , Voluntarios Sanos , Equivalencia Terapéutica , Medicamentos Genéricos/farmacocinética , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Absorción Gastrointestinal/fisiología , Medicamentos bajo Prescripción/farmacocinéticaRESUMEN
The incidence of diabetic retinopathy is still increasing in developed countries. Tight glycemic control and laser therapy reduce vision loss and blindness, but do not reverse existing ocular damage and only slow the progression of the disease. New pharmacologic agents that are currently under development and are specifically directed against clearly defined biochemical targets (i.e. aldose reductase inhibitors and protein kinase C-beta inhibitors) have failed to demonstrate significant efficacy in the treatment of diabetic retinopathy in clinical trials. In contrast, calcium dobesilate (2,5-dihydroxybenzenesulfonate), which was discovered more than 40 years ago and is registered for the treatment of diabetic retinopathy in more than 20 countries remains, to our knowledge, the only angioprotective agent that reduces the progression of this disease. An overall review of published studies involving calcium dobesilate (CLS 2210) depicts a rather 'non-specific' compound acting moderately, but significantly, on the various and complex disorders that contribute to diabetic retinopathy. Recent studies have shown that calcium dobesilate is a potent antioxidant, particularly against the highly damaging hydroxyl radical. In addition, it improves diabetic endothelial dysfunction, reduces apoptosis, and slows vascular cell proliferation.
Asunto(s)
Dobesilato de Calcio/uso terapéutico , Retinopatía Diabética/tratamiento farmacológico , Animales , Antioxidantes , Barrera Hematorretinal , Dobesilato de Calcio/efectos adversos , Dobesilato de Calcio/farmacocinética , Retinopatía Diabética/prevención & control , Retinopatía Diabética/cirugía , Medicina Basada en la Evidencia , Humanos , Estrés Oxidativo , RatasRESUMEN
A sensitive method for the determination of dobesilate in pharmaceutical preparations and human urine is described by using controlled-reagent-release technology. The method entailed the use of luminol and periodate, which are immobilized on anion exchange resin and react in alkaline medium, giving chemiluminescence (CL) at 425 nm. Dobesilate was detected by measuring the decrease of CL intensity, and which was observed linear over the dobesilate concentration range of 10-600 pg ml(-1), and the limit of detection was 3.5 pg ml(-1) (3sigma) and a relative standard deviation of less than 3.0%. At a flow rate of 2.0 ml min(-1), the determination of dobesilate, including sampling and washing, could be performed in 0.5 min, giving a throughput of about 120 times per hour. The proposed method has an extremely low limit of detection down to 3.5 pg ml(-1), thus it can be applied directly in the assay of human urine without any pre-treatment. It was also found that the dobesilate concentration reached its maximum after orally administrated for 3.5h, and the excretion ratio in 24h was 58.8% in the body of volunteers.
Asunto(s)
Dobesilato de Calcio/análisis , Mediciones Luminiscentes , Dobesilato de Calcio/farmacocinética , Dobesilato de Calcio/orina , Análisis de Inyección de Flujo , Humanos , Concentración de Iones de Hidrógeno , Hidróxido de Sodio , Factores de TiempoRESUMEN
1 We have evaluated the participation of endothelium-derived hyperpolarizing factor (EDHF) in the endothelium-dependent relaxation of isolated human penile resistance arteries (HPRA) and human corpus cavernosum (HCC) strips. In addition, the effect of the angioprotective agent, calcium dobesilate (DOBE), on the endothelium-dependent relaxation of these tissues was investigated. 2 Combined inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) nearly abolished the endothelium-dependent relaxation to acetylcholine (ACh) in HCC, while 60% relaxation of HPRA was observed under these conditions. Endothelium-dependent relaxation of HPRA resistant to NOS and COX inhibition was prevented by raising the extracellular concentration of K(+) (35 mM) or by blocking Ca(2)(+)-activated K(+) channels, with apamin (APA; 100 nM) and charybdotoxin (CTX; 100 nM), suggesting the involvement of EDHF in these responses. 3 Endothelium-dependent relaxation to ACh was markedly enhanced by DOBE (10 micro M) in HPRA but not in HCC. The potentiating effects of DOBE on ACh-induced responses in HPRA, remained after NOS and COX inhibition, were reduced by inhibition of cytochrome P450 oxygenase with miconazole (0.3 mM) and were abolished by high K(+) or a combination of APA and CTX. 4 In vivo, DOBE (10 mg kg(-1) i.v.) significantly potentiated the erectile responses to cavernosal nerve stimulation in male rats. 5 EDHF plays an important role in the endothelium-dependent relaxation of HPRA but not in HCC. DOBE significantly improves endothelium-dependent relaxation of HPRA mediated by EDHF and potentiates erectile responses in vivo. Thus, EDHF becomes a new therapeutic target for the treatment of erectile dysfunction (ED) and DOBE could be considered a candidate for oral therapy for ED.
Asunto(s)
Factores Biológicos/fisiología , Dobesilato de Calcio/farmacocinética , Relajación Muscular/efectos de los fármacos , Erección Peniana/efectos de los fármacos , Pene/irrigación sanguínea , Pene/efectos de los fármacos , Animales , Dobesilato de Calcio/administración & dosificación , Sinergismo Farmacológico , Estimulación Eléctrica , Endotelio/efectos de los fármacos , Endotelio/fisiopatología , Humanos , Inyecciones Intravenosas , Masculino , Relajación Muscular/fisiología , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico Sintasa/fisiología , Erección Peniana/fisiología , Pene/fisiopatología , Ratas , Ratas Sprague-Dawley , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
A rapid, simple reversed-phase high-performance liquid chromatographic method with ultraviolet absorbance detection has been developed for the determination of calcium dobesilate in human plasma. Sample processing is based on an ion-pairing extraction with tetra-n-butylammonium hydroxide as cationic pairing ion and dichloromethane. Separation of the investigated calcium dobesilate and 2,4-dihydroxybenzoic acid as internal standard was achieved on a Discovery RP-Amide C16 analytical column with 50 mM, pH 2.5, potassium dihydrogenphosphate buffer-acetonitrile (75:25, v/v) mobile phase. The wavelength was set at 305 nm. The limit of quantitation is 100 ng/ml and the calibration curve is linear up to 50 microg/ml. Within-day and between-day precision expressed as the relative standard deviation is about 10% and the accuracy of the determination did not deviate from 100% by more than +/-10%. The developed method was found to be suitable for application in human bioequivalence studies.
Asunto(s)
Dobesilato de Calcio/sangre , Dobesilato de Calcio/química , Dobesilato de Calcio/aislamiento & purificación , Dobesilato de Calcio/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Líquida de Alta Presión/normas , Estabilidad de Medicamentos , Humanos , Hidroxibenzoatos/normas , Estructura Molecular , Reproducibilidad de los Resultados , Equivalencia TerapéuticaRESUMEN
1. Calcium dobesilate (2,5-dihydroxybenzene sulfonate) is a drug commonly used in the treatment of diabetic retinopathy and chronic venous insufficiency. 2. The pharmacology of calcium dobesilate reveals its ability to decrease capillary permeability, as well as platelet aggregation and blood viscosity. 3. Furthermore, recent data show that calcium dobesilate increases endothelium-dependent relaxation owing to an increase in nitric oxide synthesis.
Asunto(s)
Dobesilato de Calcio/farmacología , Animales , Viscosidad Sanguínea/efectos de los fármacos , Dobesilato de Calcio/efectos adversos , Dobesilato de Calcio/farmacocinética , Permeabilidad Capilar/efectos de los fármacos , Humanos , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
The effect of calcium dobesilate on the alteration of the blood-retinal barrier was studied in 41 adult-onset, non-insulin dependent diabetic patients with minimal or no retinopathy, randomly assigned to receive either oral calcium dobesilate (1000 mg twice daily) or a placebo for 12 months. The posterior vitreous value and the penetration ratio, determined by vitreous fluorophotometry, reflected stabilisation of blood-retinal barrier permeability in the calcium dobesilate patients and deterioration of blood retinal barrier in those given placebo. During the relatively short period of the study, one year, no significant change in microaneurysm and capillary closure gradings was observed. No side effects were associated with calcium dobesilate.
Asunto(s)
Bencenosulfonatos/farmacología , Barrera Hematorretinal/efectos de los fármacos , Dobesilato de Calcio/farmacología , Retinopatía Diabética/tratamiento farmacológico , Análisis de Varianza , Dobesilato de Calcio/farmacocinética , Retinopatía Diabética/metabolismo , Método Doble Ciego , Femenino , Fluorofotometría , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Permeabilidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Cuerpo Vítreo/metabolismoRESUMEN
In clinical practice, the co-administration of antiplatelet drugs, such as acetylsalicylic acid (ASA) and dipyridamole (DP) and calcium dobesilate, is often recommended in order to obtain secondary prophylaxis against certain ischaemic diseases. Therefore the possible pharmacokinetic interactions between these three drugs were studied after a single-dose in beagle dogs. The plasma concentrations of ASA, DP and CaDb were measured by HPLC. It was found that the DP and CaDb kinetics were unaffected by concurrent intake of ASA, DP or CaDb. However, concurrent DP or CaDb improved the bioavailability of ASA, particularly the increased Cmax and (AUC).