Fabián Buontempo

Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats

Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic–pharmacodynamic (PK–PD) modeling. Male Sprague–Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1–3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK–PD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis. A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PK–PD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats. Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.

Enantioselective pharmacokinetic–pharmacodynamic modelling of carvedilol in a NG-nitro-l-arginine methyl ester rat model of secondary hypertension

Objectives  The role of vascular sympatholytic activity of carvedilol in its antihypertensive effect in NG‐nitro‐l‐arginine methyl ester (L‐NAME) hypertensive rats was assessed by means of enantioselective pharmacokinetic–pharmacodynamic (PK‐PD) modelling.

Carvedilol stability in paediatric oral liquid formulations

OBJECTIVE Two carvedilol aqueous solutions and one carvedilol aqueous suspension for paediatric oral use (1mg/ml) were studied to determine their stability. METHOD All samples were stored at 4, 25 and 40°C. Carvedilol content of each of the three formulations was tested using high performance liquid chromatography (HPLC). Each sample was analysed in triplicate at 0, 3, 7, 14, 28 and 56 days. RESULTS Carvedilol stayed stable in the acidic aqueous solution at the three different temperatures during the 56 days of the study. In the alkaline solution, carvedilol was stable during 56 days at 25°C, but only 28 days at 4 and 40°C. In the aqueous suspension, carvedilol was stable during 56 days at 4 and 25°C, but only 28 days at 40°C. CONCLUSIONS All the formulations that were tested can be stored at 25°C for at least 56 days.OBJECTIVE Lenalidomide (LDM) is an immunomodulatory and anti-angiogenic drug which has been shown to be effective in several haematological disorders (multiple myeloma [MM], myeloid metaplasia with myelofibrosis [MF] and myelodysplastic syndrome [MDS]). The objective of this study is to evaluate the effectiveness and tolerability of LDM in our patients. METHOD Retrospective observational study which included patients at our hospital who were monitored by the haematology unit, diagnosed with MM, MF and MDS and candidates for LDM treatment. Treatment effectiveness was assessed after approximately 4 cycles of treatment. RESULTS Between February 2007 and March 2008, 16 patients were listed as candidates for receiving treatment with LDM (50% female/50% male, with a mean age of 69.6 years); of these candidates, 3 never initiated treatment. Five of the six patients with MM treated at our hospital obtained some sort of response (83.3%). Of the 4 patients with MF, 2 (66.6%) experienced some sort of response to treatment. Of the 6 patients diagnosed with MDS, treatment was initiated in 3, and it had to be suspended in 2 cases due to different reasons. Treatment only had to be suspended in two of the 13 patients who began it (15.4%) due to adverse effects (AE). CONCLUSION LDM is well-tolerated and produces sustained clinical benefits, especially in MM and MF. More studies are needed for in-depth examination of treatment duration, new indications and the use of treatments combined with other drugs.

Pharmaceutical optimization of lipid-based dosage forms for the improvement of taste-masking, chemical stability and solubilizing capacity of phenobarbital

Abstract Microemulsions (MEs) and self-emulsifying drug delivery systems (SEEDS) containing phenobarbital (Phe) were developed to improve its chemical stability, solubilizing capacity and taste-masking in oral liquid dosage forms. Cremophor® RH40 and Labrasol® were used as surfactants for the screening of ME regions, Capmul® MCM L, Captex® 355, Imwitor® 408, Myglyol® 840 and Isopropyl myristate were the oil phases assayed; Transcutol® P, Polyethylene-glycol 400, glycerol, Propylene-glycol and ethanol the cosurfactants. Phe stability assay was carried out (20:4:20:56% and 20:4:35:41% (w/w); surfactant:oily phase:cosurfactant:water) for both surfactants; only one containing ethanol showed significant dismissing in its drug content. Solubility capacity for these selected formulations were also evaluated, an amount between 17 and 58 mg/mL of Phe could be loaded. At last, an optimized ME formulation with Cremophor® RH40 20%, Capmul® MCM L 4%, PEG 400 35% and sucralose 2% (w/w) was chosen in order to optimize taste-masking using an electronic tongue. Strawberry along with banana and tutti-frutti flavors plus mint flavor proved to be the best ones. Labrasol-based pre-concentrates were tested for (micro)emulsifying properties; all of them resulted to behave as SEDDS. In summary, a rationale experimental design conducted to an optimized ME for Phe oral pediatric administration which was able to load 5-fold times the currently used dose (4 mg/mL), with no sign of physical or chemical instability and with improved taste; SEDDS for capsule filling were also obtained. The biopharmaceutical advantages described for these dosage forms encourage furthering in vivo evaluation.

Relationship between P-glycoprotein activity measured in peripheral blood mononuclear cells and indinavir bioavailability in healthy volunteers

Indinavir, a HIV-1 protease inhibitor, showed large inter-individual pharmacokinetic variability. It has been proposed as a substrate of P-glycoprotein (P-gp), an efflux transporter, that may contribute to limit indinavir bioavailability. A liquid formulation of indinavir was developed from indinavir capsules in order to study indinavir pharmacokinetics in healthy volunteers. Compartmental and noncompartmental analysis of indinavir plasma concentrations showed high inter-individual variability in terms of area under the curve (AUC) and maximal plasma concentration (C(max)). A significant negative association between AUC normalized to body weight (AUC x weight) and lymphocyte P-gp activity, using Rh123 efflux assay, was observed (p = 0.008; r = -0.75). AUC normalized to elimination rate constant (AUC x beta) also showed a significant negative relationship with lymphocyte P-gp activity (p = 0.03, r = -0.64). Apparent clearance (CL/[F x weight]) and volume of distribution (VD/[F x weight]) showed a positive correlation with P-gp activity. Conversely, elimination rate constant did not correlate with P-gp activity. Although there is not enough evidence of a correlation between lymphocitary and intestinal function of P-gp, our results suggest a relationship between a P-gp phenotype marker, Rh123 efflux assay in lymphocytes, and indinavir bioavailability.

Novel carvedilol paediatric nanomicelle formulation: in-vitro characterization and in-vivo evaluation.

Carvedilol (CAR) is a poorly water‐soluble beta‐blocker. Its encapsulation within nanomicelles (NMs) could improve drug solubility and its oral bioavailability, allowing the development of a paediatric liquid CAR formulation with commercially available copolymers: D‐α‐tocopheryl polyethylene glycol 1000 succinate (TPGS) and poly(vinyl caprolactam)‐poly(vinyl acetate)‐poly(ethylene glycol) (Soluplus®).

Extemporaneous clobazam suspensions for paediatric use prepared from commercially available tablets and pure drug

OBJECTIVE Two clobazam aqueous suspensions for paediatric oral usage (5 mg/ml) were investigated to determinate its physicochemical stability under different storage conditions. METHOD Formulations were stored at 4 and 25 °C and the clobazam content was determined by High Performance Liquid Chromatography. Each sample was analyzed by triplicate at different time points (0, 7, 14, 28 and 56 days). RESULTS Liquid suspensions were successfully formulated from pure drug and commercially available tablets. In both cases, samples showed suitable physical stability. Clobazam was chemically stable in aqueous suspension during the 56 days of the study at the two storage temperatures. CONCLUSIONS All the tried oral liquid formulations can be conserved at 4 and 25 °C at least 56-day period.

Coenzyme Q10 stability in pediatric liquid oral dosage formulations

OBJECTIVE, To study the stability of Coenzyme Q10 (CoQ10), used as therapeutic agent in treatment of cardiovascular and mitochondrial diseases, in three liquid formulations: two soybean oil solutions (50 mg/ml), one of them with the addition of vitamin E and an O/W emulsion (20 mg/ml) for pediatric use. Furthermore, optimize and validate a stabilityindicating HPLC method for the analysis of CoQ10 in the studied formulations. METHOD, All samples were stored at 25°C. CoQ10 content of each formulation was analyzed in duplicate using fast microbore high performance liquid chromatography (Micro HPLC) at 0, 3, 6, 15, 30, 60 and 110 days. RESULTS, All formulations stayed stable at 25°C during the 110 days of the study. However, the oil solutions presented greater content variations through all the study period. CONCLUSIONS, The CoQ10 emulsion can be stored for at least 110 days at 25 °C and it has proven to be safer when narrow dose adjustment is required. The proposed analytical method was suitable for the study of stability of different formulations meeting the validation parameters according to international guidelines.

Relative bioavailability of coenzyme Q10 formulation for paediatric individualized therapy

Conduct a preliminary comparison of the bioavailability between two formulations: commercial grade coenzyme Q10 (CoQ10) powder (solid formulation) and a new oil‐in‐water liquid emulsion and their effect on other antioxidants.

Ocular topotecan pharmacokinetics following topical administration to rabbits for diffused anterior retinoblastoma.

We characterized and compared the in‐vivo absorption of topotecan into the aqueous humor after instillation of aqueous and ointment formulations.