Improving the drug-likeness of inspiring natural products - evaluation of the antiparasitic activity against Trypanosoma cruzi through semi-synthetic and simplified analogues of licarin A.

Neolignan licarin A (1) was isolated from leaves of Nectandra oppositifolia (Lauraceae) and displayed activity against trypomastigote forms of the etiologic agent of American trypanosomiasis, Trypanosoma cruzi. Aiming for the establishment of SAR, five different compounds (1a - 1e) were prepared and tested against T. cruzi. The 2-allyl derivative of licarin A (1d) exhibited higher activity against trypomastigotes of T. cruzi (IC50 = 5.0 µM and SI = 9.0), while its heterocyclic derivative 1e displayed IC50 of 10.5 µM and reduced toxicity against NCTC cells (SI > 19.0). However, these compounds presented limited oral bioavailability estimation (<85%, Papp <1.0 × 10-6 cm/s) in parallel artificial membrane permeability assays (PAMPA) due to excessive lipophilicity. Based on these results, different simplified structures of licarin A were designed: vanillin (2), vanillyl alcohol (3), isoeugenol (4), and eugenol (5), as well as its corresponding methyl (a), acetyl (b), O-allyl (c), and C-allyl (d) analogues. Vanillin (2) and its acetyl derivative (2b) displayed expressive activity against intracellular amastigotes of T. cruzi with IC50 values of 5.5 and 5.6 µM, respectively, and reduced toxicity against NCTC cells (CC50 > 200 µM). In addition, these simplified analogues showed a better permeability profile (Papp > 1.0 × 10-6 cm/s) on PAMPA models, resulting in improved drug-likeness. Vanillyl alcohol acetyl derivative (3b) and isoeugenol methyl derivative (4a) displayed activity against the extracellular forms of T. cruzi (trypomastigotes) with IC50 values of 5.1 and 8.8 µM respectively. Based on these results, compounds with higher selectivity index against extracellular forms of the parasite (1d, 1e, 3d, and 4a) were selected for a mechanism of action study. After a short incubation period (1 h) all compounds increased the reactive oxygen species (ROS) levels of trypomastigotes, suggesting cellular oxidative stress. The ATP levels were increased after two hours of incubation, possibly involving a high energy expenditure of the parasite to control the homeostasis. Except for compound 4a, all compounds induced hyperpolarization of mitochondrial membrane potential, demonstrating a mitochondrial imbalance. Considering the unique mitochondria apparatus of T. cruzi and the lethal alterations induced by structurally based on licarin A, these compounds are interesting hits for future drug discovery studies in Chagas disease.

Efficacy and safety of eslicarbazepine acetate as adjunctive therapy for refractory focal-onset seizures in children: A double-blind, randomized, placebo-controlled, parallel-group, multicenter, phase-III clinical trial.

PURPOSE: This was a phase-III, randomized, double-blind, placebo-controlled study aimed to evaluate efficacy and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy in pediatric patients with refractory focal-onset seizures (FOS). METHODS: Children (2-18 years old) with FOS, receiving 1-2 antiepileptic drugs, were randomized to ESL or placebo. Treatment was started at 10 mg/kg/day, up-titrated up to 20-30 mg/kg/day, and maintained for 12 weeks, followed by one-year open-label follow-up. Primary efficacy endpoints were relative reduction in standardized seizure frequency (SSF) and proportion of responders (≥50% SSF reduction) from baseline. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs). RESULTS: The intention-to-treat (ITT) set included 134 patients randomized to ESL and 129 to placebo; 89.6% and 91.5%, respectively, completed the trial. An unbalanced number of seizures at baseline were observed between groups. Least square (LS) mean relative change in SSF from baseline was higher in the ESL group (-18.1%) than in placebo (-8.6%). Proportion of responders between ESL and placebo groups was not statistically different. A post hoc analysis showed greater relative reduction in SSF in patients above 6 years old treated with ESL 20 or 30 mg/kg/day compared with placebo; this was significant in patients above 6 years old treated with ESL 30 mg/kg/day (LS mean difference: 31.9%; p = 0.0478). The observed safety profile in children was consistent with that established in adult studies. CONCLUSIONS: Adjunctive ESL treatment was well-tolerated, but this trial failed to demonstrate that ESL was more effective than placebo in the predefined efficacy endpoints; factors that may have contributed to this outcome, affecting particularly the young age group, include etiological heterogeneity, difficulty in recognizing simple partial seizures, high seizure frequency with risk of imbalance, and underestimation of the efficacious dose range.

Bioelectrical impedance analysis of body composition for the anesthetic induction dose of propofol in older patients.

BACKGROUND: Older people are currently the fastest growing segment of the worldwide population. The present study aimed to estimate propofol dose in older patients based on size descriptors measured by bioelectrical impedance analysis (BIA). METHODS: A cross sectional study in adult and older patients with body mass index equal to or lower than 35 kg/m2 was carried out. BIA and Clinical Frail Scale scoring were performed during pre-operative evaluation. Propofol infusion was started at 2000 mg/h until loss of consciousness (LOC) which was defined by "loss of eye-lash reflex" and "loss of response to name calling". Total dose of propofol at LOC was recorded. Propofol plasma concentration was measured using gas chromatography/ion trap-mass spectrometry. RESULTS: Forty patients were enrolled in the study. Total propofol dose required to LOC was lower in Age ≥ 65 group and a higher plasma propofol concentration was measured in this group. 60% of old patients were classified as "apparently vulnerable" or "frail" and narrow phase angle values were associated with increasing vulnerability scores. In the Age ≥ 65 group, the correlation analysis showed that the relationship between propofol dose and total body weight (TBW) scaled by the corresponding phase angle value is stronger than the correlation between propofol dose and TBW or fat free mass (FFM). CONCLUSIONS: This study demonstrates that weight-based reduction of propofol is suitable in older patients; however FFM was not seen to be more effective than TBW to predict the propofol induction dose in these patients. Guiding propofol induction dose according to baseline frailty score should also be considered to estimate individualized dosage profiles. Determination of phase angle value appears to be an easy and reliable tool to assess frailty in older patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02713698 . Registered on 23 February 2016.

Cyclodextrin multicomponent complexation and controlled release delivery strategies to optimize the oral bioavailability of vinpocetine.

In the present work, to maintain a suitable blood level of vinpocetine (VP) for a long period of time, VP-cyclodextrin-tartaric acid multicomponent complexes were prepared and formulated in hydroxypropylmethylcellulose matrix tablets. In vitro and in vivo performances of these formulations were investigated over a VP immediate release dosage form. Solubility studies were performed to evaluate the drug pH solubilization profile and to assess the effect of multicomponent complexation on VP solubility. The drug release process was investigated using United States Pharmacopeia apparatus 3 and a comparative oral pharmacokinetic study was subsequently undertaken in rabbits. Solubility studies denoted the pH-solubility dependence of VP and solubility improvement attained by complexation. Dissolution results showed controlled and almost complete release behavior of VP over a 12-h period from complex hydroxypropylmethylcellulose-based formulations. A clear difference between the pharmacokinetic patterns of VP immediate release and VP complex-based formulations was revealed. The area under the plasma concentration-time curve after oral administration of complex-based formulations was 2.1-2.9 times higher than that for VP immediate release formulation. Furthermore, significant differences found for mean residence time, elimination half-life, and elimination rate constant values corroborated prolonged release of VP from complex-based formulations. These results suggest that the oral bioavailability of VP was significantly improved by both multicomponent complexation and controlled release delivery strategies.

Performance of gentamicin population kinetic parameters in Portuguese neonates.

AIM: To evaluate the performance of eight different sets of gentamicin populational pharmacokinetic parameters, regarding potential implementation in clinical pharmacokinetic software as prior information. METHODS: The study involved 49 patients of 31.3+/-4.1 weeks of gestational age (GA), receiving gentamicin, and for whom peak and trough concentrations were obtained. Accuracy and precision were assessed by mean prediction error (ME), mean squared prediction error (MSE) and root mean squared prediction error (RMSE). Weighted prediction-error analysis was carried out in order to evaluate peak and trough concentrations together (ME(w), MSE(w) and RMSE(w)). RESULTS: The analysis showed CL=0.036 l/h/kg (< 34 weeks GA) or CL=0.051 l/h/kg (> or = 34 weeks GA), and V ( d )=0.5 l/kg (< or = 37 weeks GA) or Vd = 0.4 l/kg (>37 weeks of GA) as the most accurate and precise set of pharmacokinetic parameters (Set 4), presenting the highest percentage of clinically acceptable estimates (Error(Peak)<1 microg/ml, and Error(Trough) <0.375 microg/ml). CONCLUSION: The adoption of the previously mentioned set of parameters as population estimates seems to be the best option, bearing in mind the obtained results. However, we strongly believe that pharmacokinetic parameter determination of gentamicin should be carried out whenever possible in order to improve the rationale and cost-effectiveness of therapy.