RESUMO
Over the past few years, considerable attention has focused on cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the two major constituents of Cannabis sativa, mainly due to the promising potential medical uses they have shown. However, more information on the fate of these cannabinoids in human subjects is still needed and there is limited research on the pharmacokinetic drug-drug interactions that can occur in the clinical setting and their prevalence. As the use of cannabinoids is substantially increasing for many indications and they are not the first-line therapy in any treatment, health care professionals must be aware of drug-drug interactions during their use as serious adverse events can happen related with toxic or ineffective outcomes. The present chapter overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD and THC in humans and discusses relevant drug-drug interactions, giving a plausible explanation to facilitate further research in the area.
Assuntos
Canabinoides , Preparações Farmacêuticas , Canabidiol , Canabinoides/efeitos adversos , Dronabinol , Interações Medicamentosas , HumanosRESUMO
In a recently published investigation, the authors argued against the likelihood of sex-based subject-by-formulation interactions in bioequivalence studies, i.e. male and female subjects exhibiting different discriminatory potential to detect bioavailability differences between formulations. The researchers performed a strong methodological study showing the increased probability of false-positive findings in exploratory subgroup analysis, a well-known and documented statistical issue. Indeed, the main limitation of assessing a sex-by-formulation interaction in average bioequivalence studies lies in the fact that these clinical trials are not designed for this purpose. In this commentary, we further discuss on why the impact of sex differences in gastrointestinal physiology over in vivo drug dissolution and absorption rate cannot remain hidden behind statistical limitations, particularly when average bioequivalence conclusions could be affected. Regulatory agencies should encourage and support these important issues related to biopharmaceutical quality of drug products in both sexes. In addition, a sex-based analysis of bioequivalence results will enhance the representativeness of conclusions and provide important information regarding formulation performance, thereby promoting the efficacy and safety of generic drugs and reducing consumer risk. The extrapolation of study conclusions from one sex to another is far away from being scientifically proven.
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Benzoxazinas , Alcinos , Disponibilidade Biológica , Ciclopropanos , Feminino , Masculino , Comprimidos , Equivalência TerapêuticaRESUMO
Nevirapine (NVP) extensive data obtained after oral single dose administration of 200 mg in a crossover study involving 16 healthy subjects was used to develop a descriptive population pharmacokinetic model including drug recirculation, since secondary peaks were observed in plasma concentration-time profiles for all subjects. Through implementation of model event time feature in NONMEM 7.3.0, a simple mechanistic model physiologically consistent with the process of drug cycling was able to describe multiple peaks phenomena and quantify its pharmacokinetic parameters, achieving a better performance than its analogue conventional one. Absorption process, between subject and-between occasion variability of pharmacokinetic parameters was also assessed. Estimated mean fraction of NVP bioavailable dose undergoing recirculation process was 51.6 %, a magnitude which could hardly be explained by enterohepatic cycling. In this work we propose an alternative disposition process to explain NVP drug recirculation: gastric secretion with posterior intestinal reabsorption. Due to physicochemical and pharmacokinetic properties of the drug, this neglected phenomenon is more likely to explain the results obtained, and might be present in disposition of several basic drugs.
Assuntos
Fármacos Anti-HIV/farmacocinética , Nevirapina/farmacocinética , Administração Oral , Adolescente , Adulto , Algoritmos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/química , Estudos Cross-Over , Feminino , Humanos , Absorção Intestinal , Masculino , Modelos Estatísticos , Nevirapina/administração & dosagem , Nevirapina/química , População , Reprodutibilidade dos Testes , Processos Estocásticos , Adulto JovemRESUMO
Concomitant use of cannabinoids with other drugs may result in pharmacokinetic drug-drug interactions, mainly due to the mechanism involving Phase I and Phase II enzymes and/or efflux transporters. Cannabinoids are not only substrates but also inhibitors or inducers of some of these enzymes and/or transporters. This narrative review aims to provide the available information reported in the literature regarding human data on the pharmacokinetic interactions of cannabinoids with other medications. A search on Pubmed/Medline, Google Scholar, and Cochrane Library was performed. Some studies were identified with Google search. Additional articles of interest were obtained through cross-referencing of published literature. All original research papers discussing interactions between cannabinoids, used for medical or recreational/adult-use purposes, and other medications in humans were included. Thirty-two studies with medicinal or recreational/adult-use cannabis were identified (seventeen case reports/series, thirteen clinical trials, and two retrospective analyses). In three of these studies, a bidirectional pharmacokinetic drug-drug interaction was reported. In the rest of the studies, cannabinoids were the perpetrators, as in most of them, concentrations of cannabinoids were not measured. In light of the widespread use of prescribed and non-prescribed cannabinoids with other medications, pharmacokinetic interactions are likely to occur. Physicians should be aware of these potential interactions and closely monitor drug levels and/or responses. The existing literature regarding pharmacokinetic interactions is limited, and for some drugs, studies have relatively small cohorts or are only case reports. Therefore, there is a need for high-quality pharmacological studies on cannabinoid-drug interactions.
Assuntos
Canabinoides , Interações Medicamentosas , Humanos , Canabinoides/farmacocinética , Canabinoides/farmacologiaRESUMO
BACKGROUND AND OBJECTIVE: Model-based bioequivalence (MBBE) encompasses the use of nonlinear mixed effect models supporting the estimation of pharmacokinetic endpoints to assess the relative bioavailability between multi-source drug products. This application emerges as a valuable alternative to the standard non-compartmental analysis (NCA) in bioequivalence (BE) studies in which dense sampling is not possible. In this work, we aimed to assess the application of MBBE compared to traditional methods in evaluating the relative bioavailability of two formulations with different drug release properties. Additionally, we sought to predict the performance of a modified-release formulation in a multiple-dose scenario, leveraging data from a single-dose study. METHODS: MBBE analysis was implemented to estimate the BE endpoints (90% CI for the Test/Reference geometric mean ratio, T/R GMR) in area under the concentration-time curve (AUC) and maximum concentration (Cmax) using data from a single-dose, 2-period, 2-sequence BE study performed in 14 healthy subjects between a locally developed valproic acid extended-release formulation (Test) and the brand-name delayed-release formulation (Reference). RESULTS: Results were compared with the standard approach, revealing that MBBE analysis achieved higher discrimination between formulations for Cmax, addressing limitations of the experimental sampling design and highlighting an advantage for this model-based analysis even when rich data are available. Additionally, the bioequivalence outcome under the multiple-dose scenario was predicted through a simulation-based study for both total and unbound valproic acid concentrations, considering the impact of valproic acid saturable binding on BE conclusions. CONCLUSIONS: The MBBE analysis was superior to the NCA approach in detecting product-related differences, overcoming limitations in the study experimental design. Predictions for the multiple-dose scenario preclude that the extended-release properties of the Test formulation would persist at steady state, resulting in lower peak-to-trough fluctuation and bioequivalent performance in terms of the extent of drug absorption. Overall, these results should discourage unnecessary experimentation in healthy subjects.
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Área Sob a Curva , Disponibilidade Biológica , Preparações de Ação Retardada , Modelos Biológicos , Equivalência Terapêutica , Ácido Valproico , Ácido Valproico/farmacocinética , Ácido Valproico/administração & dosagem , Humanos , Preparações de Ação Retardada/farmacocinética , Masculino , Adulto , Adulto Jovem , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/administração & dosagem , Feminino , Voluntários Saudáveis , Estudos Cross-OverRESUMO
BACKGROUND: Several oral ivermectin (IVM) formulations for use in sheep are available in the pharmaceutical veterinary market in different countries. All of them are indicated at the same dose rate to treat the gastrointestinal nematodes. However, there is a lack of information on the relative systemic exposure (plasma bioavailability) and clinical efficacy among oral formulations routinely used in sheep. The main goal of the work reported here was to perform a pharmaco-parasitological assessment of three different IVM oral formulations in lambs infected with multiple resistant gastrointestinal nematodes. The comparative drug systemic exposure (IVM plasma concentrations) and nematodicidal efficacies (clinical efficacy) in lambs were determined for a reference (RF) and two different test (T1, T2) IVM oral formulations. One hundred and fifty six (n= 156) healthy Corriedale lambs, naturally infected with multiple resistant gastrointestinal nematodes were allocated into four experimental groups (n=39). Animals in each group received treatment (200 µg/kg) with either the RF, one of the test IVM formulations or were kept as untreated control. Blood samples were collected over 15 days post-treatment (n=8). The IVM plasma concentrations were measured by high performance liquid chromatography with fluorescence detection. The faecal nematode egg count reduction test (FECRT) (n=39) and evaluation of the clinical efficacy were performed at day 14 post-treatment (n=6), where a predominance of IVM highly resistant nematodes was observed. RESULTS AND CONCLUSIONS: Neither the overall kinetic behaviour nor the IVM systemic exposure differed among all the tested oral formulations. Equivalent efficacy results were obtained for the different preparations, with an evident therapeutic failure to control Haemonchus spp. and Teladorsagia circumcincta, which correlates with a high degree of nematode resistance to IVM.
Assuntos
Antinematódeos/farmacocinética , Ivermectina/farmacocinética , Administração Oral , Animais , Animais Recém-Nascidos , Antinematódeos/administração & dosagem , Antinematódeos/uso terapêutico , Disponibilidade Biológica , Fezes/parasitologia , Feminino , Ivermectina/administração & dosagem , Ivermectina/uso terapêutico , Masculino , Infecções por Nematoides/tratamento farmacológico , Infecções por Nematoides/parasitologia , Infecções por Nematoides/veterinária , Contagem de Ovos de Parasitas/veterinária , Ovinos , Doenças dos Ovinos/tratamento farmacológico , Doenças dos Ovinos/parasitologia , Resultado do TratamentoRESUMO
Plasma concentration-time data obtained after an oral single dose of 500-mg valproic acid (VPA) in a delayed release formulation was used to model enterohepatic cycling of the drug. Fourteen healthy subjects (seven women and seven men) were enrolled, food intake was standardized, blood samples were withdrawn up to 48 h post dosing and VPA plasma concentrations were analyzed by HPLC-UV method. Secondary peaks of VPA were observed in almost all subjects. A population pharmacokinetic analysis with sex, weight, age and contraceptive therapy as possible covariates was performed. Women without contraceptive therapy presented a longer lag time, a lower VPA hepatic output and a higher reabsorbed fraction than men. Weight affected both volume of the central compartment and the absorption rate constant. Women under contraceptive therapy showed similar disposition parameters to men. Reabsorbed fraction of bioavailable dose was 46.2 % in women and 21.8 % in men, revealing important sex differences in drug hepatobiliar output. These results showed that VPA displays sex-related pharmacokinetic differences due to different metabolic and transporter-mediated disposition.
Assuntos
Ácido Valproico/administração & dosagem , Ácido Valproico/farmacocinética , Absorção , Administração Oral , Adulto , Estudos Cross-Over , Feminino , Humanos , Masculino , Fatores Sexuais , Ácido Valproico/sangue , Adulto JovemRESUMO
Valproic acid (VPA) is a short-chain fatty acid widely prescribed in the treatment of seizure disorders and epilepsy syndromes, although its therapeutic value may be undermined by its toxicity. VPA serious adverse effects are reported to have a significant and dose-dependent incidence, many associated with VPA-induced hyperammonemia. This effect has been linked with reduced levels of carnitine; an endogenous compound involved in fatty acid's mitochondrial ß-oxidation by facilitation of its entrance via the carnitine shuttle. High exposure to VPA can lead to carnitine depletion causing a misbalance between the intra-mitochondrial ß-oxidation and the microsomal ω-oxidation, a pathway that produces toxic metabolites such as 4-en-VPA which inhibits ammonia elimination. Moreover, a reduction in carnitine levels might be also related to VPA-induced obesity and lipids disorder. In turn, L-carnitine supplementation (CS) has been recommended and empirically used to reduce VPA's hepatotoxicity. The aim of this work was to develop a Quantitative Systems Pharmacology (QSP) model to characterize VPA-induced hyperammonemia and evaluate the benefits of CS in preventing hyperammonemia under both chronic treatment and after VPA overdosing. The QSP model included a VPA population pharmacokinetics model that allowed the prediction of total and unbound concentrations after single and multiple oral doses considering its saturable binding to plasma proteins. Predictions of time courses for 2-en-VPA, 4-en-DPA, VPA-glucuronide, carnitine, ammonia and urea levels, and for the relative change in fatty acids, Acetyl-CoA, and glutamate reflected the VPA induced changes and the efficacy of the treatment with L-carnitine. The QSP model was implemented to give a rational basis for the L-carnitine dose selection to optimize CS depending on VPA dosage regime and to assess the currently recommended L-carnitine rescue therapy after VPA overdosing. Results show that a L-carnitine dose equal to the double of the VPA dose using the same interdose interval would maintain the ammonia levels at baseline. The QSP model may be expanded in the future to describe other adverse events linked to VPA-induced changes in endogenous compounds.
Assuntos
Overdose de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hiperamonemia , Humanos , Ácido Valproico , Carnitina/uso terapêutico , Hiperamonemia/induzido quimicamente , Hiperamonemia/tratamento farmacológico , Amônia/efeitos adversos , Farmacologia em Rede , Suplementos Nutricionais , Anticonvulsivantes/uso terapêuticoRESUMO
The serious widespread development of nematode resistance has motivated the use of combined anthelmintic formulations. However, the advantages/disadvantages of the combined use of anthelmintics require further scientific characterization. The goals of the current trial were a) to characterize the pharmacokinetics of closantel (CLO) and moxidectin (MXD) administered both subcutaneously (sc) and orally either separately or co-administered (CLO + MXD) to lambs; b) to compare the nematodicidal activity of both molecules given individually or co-administered to lambs infected with resistant nematodes. Seventy (70) Corriedale lambs naturally infected with multiple resistant gastrointestinal nematodes were involved in the pharmacokinetic and efficacy trials. The animals were allocated into six groups (n = 10) and treated with either CLO, MXD, or with the CLO + MXD combined formulation by both the oral and sc routes. Additionally, an untreated control group (n = 10) was included for the efficacy trial. The efficacy was estimated by the faecal egg count reduction test (FECRT). Higher systemic exposure of both CLO and MXD was observed after the sc compared to the oral administration in lambs. The combined administration of CLO + MXD did not markedly alter their disposition kinetics. At 13 days post-treatment, the administration of both molecules as a single active principle reached efficacy levels ranging between 80% (MXDoral), 84% (CLOoral), 85% (CLOsc), and 92% (MXDsc). The combined oral and sc treatments reached 99% efficacy. No adverse effects were observed after the combined treatment of CLO + MXD, and their co-administration did not show any adverse pharmacokinetic interaction. The combined effect of CLO + MXD successfully restored the maximum efficacy levels, which were not reached by the individual active ingredients.
Assuntos
Anti-Helmínticos , Nematoides , Infecções por Nematoides , Doenças dos Ovinos , Animais , Fezes , Ivermectina/uso terapêutico , Infecções por Nematoides/tratamento farmacológico , Infecções por Nematoides/veterinária , Contagem de Ovos de Parasitas/veterinária , Ovinos , Doenças dos Ovinos/tratamento farmacológicoRESUMO
Drug-resistant epilepsy has been explained by different mechanisms. The most accepted one involves overexpression of multidrug transporters proteins at the blood brain barrier and brain metabolizing enzymes. This hypothesis is one of the main pharmacokinetic reasons that lead to the lack of response of some antiseizure drug substrates of these transporters and enzymes due to their limited entrance into the brain and limited stay at the sites of actions. Although uncontrolled seizures can be the cause of the overexpression, some antiseizure medications themselves can cause such overexpression leading to treatment failure and thus refractoriness. However, it has to be taken into account that the inductive effect of some drugs such as carbamazepine or phenytoin not only impacts on the brain but also on the rest of the body with different intensity, influencing the amount of drug available for the central nervous system. Such induction is not only local drug concentration but also time dependent. In the case of valproic acid, the deficient disposition of ammonia due to a malfunction of the urea cycle, which would have its origin in an intrinsic deficiency of L-carnitine levels in the patient or by its depletion caused by the action of this antiseizure drug, could lead to drug-resistant epilepsy. Many efforts have been made to change this situation. In order to name some, the administration of once-daily dosing of phenytoin or the coadministration of carnitine with valproic acid would be preferable to avoid iatrogenic refractoriness. Another could be the use of an adjuvant drug that down-regulates the expression of transporters. In this case, the use of cannabidiol with antiseizure properties itself and able to diminish the overexpression of these transporters in the brain could be a novel therapy in order to allow penetration of other antiseizure medications into the brain.
Assuntos
Epilepsia Resistente a Medicamentos , Fenitoína , Encéfalo/metabolismo , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Fenitoína/metabolismo , Ácido Valproico/metabolismoRESUMO
Blood flow enables the delivery of oxygen and nutrients to the different tissues of the human body. Drugs follow the same route as oxygen and nutrients; thus, drug concentrations in tissues are highly dependent on the blood flow fraction delivered. Although the free drug concentration in blood correlates with pharmacodynamics, the pharmacodynamics of a drug is primarily commanded by the drug concentrations in the aqueous spaces of bodily tissues. However, the concentrations of the drug are not homogeneous throughout the tissues, and they rarely reflect the free drug concentration in the blood. This heterogeneity is due to differences in the blood flow fraction delivered to the tissues and membrane transporters, efflux pumps, and metabolic enzymes. The rate of drug elimination from the body (systemic elimination) depends more on the driving force of drug elimination than on the free concentration of the drug at the site from which the drug is being eliminated. In fact, the actual free drug concentration in the tissues results from the balance between the input and output rates. In the present paper, we develop a theoretical concept regarding solute partition between intravascular and extravascular spaces; discuss experimental research on aqueous/non-aqueous solute partitioning and clinical research on microdialysis; present hypotheses to predict in-vivo elimination using parameters of in-vitro metabolism.
Assuntos
Proteínas de Membrana Transportadoras , Oxigênio , Transporte Biológico , Humanos , Soluções , Distribuição TecidualRESUMO
The aim of the present study was to evaluate the suitability of saliva as a biological fluid in relative bioavailability (RBA) studies, with the focus on the statistical design and data variability. A randomized, open-label, four periods and two sequences (4 × 2) crossover RBA study in saliva of two phenytoin (PHT) 100 mg immediate-release capsules was performed. PHT is a narrow therapeutic index drug that has been widely used for epilepsy treatment for many years. Published information regarding its bioavailability is available, but plasma assessed. This study was designed and performed using saliva as the biological fluid and the simplest conditions that produce coherent results with previously published plasma studies. Pharmacokinetic parameters (C (max), T (max), AUC(0-t ), AUC(0-inf), C (max)/AUC(0-t ), K (e), and t (1/2)) for each volunteer at each period were calculated. Four different BE calculations were performed: individual bioequivalence, by the method of moments, and three average bioequivalence with data averaged over the two administrations and with data of periods 1-2 and 3-4. ANOVA calculation showed no significant subject-by-formulation interaction, period and sequence effects. The intra-subject variabilities were at least 20-fold lower than the inter-subject ones for C (max), AUC(0-t ) and AUC(0-inf). In all four BE calculations, the 90% CIs for the T/R ratios of studied pharmacokinetics parameters fell within the 80-125% range proposed by most regulatory agencies.
Assuntos
Fenitoína/farmacocinética , Saliva/metabolismo , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Humanos , Masculino , Equivalência TerapêuticaRESUMO
Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation. This distribution process is evidenced by multiple peaks in pharmacokinetic profiles. Commonly, hepatobiliary drug secretion is assumed to be the underlying mechanism (enterohepatic reabsorption, EHR), neglecting other possible mechanisms such as gastric secretion (enterogastric reabsorption, EGR). In addition, the impact of drug reabsorption on systemic clearance, volume of distribution and bioavailability has been a subject of long-standing discussions. In this work, we propose semi-mechanistic pharmacokinetic models to reflect EHR and EGR and compare their respective impact on primary pharmacokinetic parameters. A simulation-based analysis was carried out considering three drug types with the potential for reabsorption, classified according to their primary route of elimination and their hepatic extraction: (A) hepatic metabolism-low extraction; (B) hepatic metabolism-intermediate/high extraction; (C) renal excretion. Results show that an increase in EHR can significantly reduce the clearance of drugs A and B, increase bioavailability of B drugs, and increase the volume of distribution for all drugs. Conversely, EGR had negligible impact in all pharmacokinetic parameters. Findings provide background to explain and forecast the role that this process can play in pharmacokinetic variability, including drug-drug interactions and disease states.
Assuntos
Absorção Intestinal , Preparações Farmacêuticas/metabolismo , Farmacocinética , Administração Intravenosa , Disponibilidade Biológica , Simulação por Computador , Cinética , Modelos Biológicos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/sangueRESUMO
AIM: To develop a population pharmacokinetic model for Uruguayan patients under treatment with cyclosporine (CsA) that can be applied to TDM. Patients and Methods. A total of 53 patients under treatment with CsA were included. 37 patients with at least one pharmacokinetic profile described with four samples were considered for model building, while the remaining 16 were considered for the assessments of predictive performances. Pharmacokinetic parameter estimation was performed using a nonlinear mixed effect modelling implemented in the Monolix® software (version 2019R1, Lixoft, France); meanwhile, simulations were performed in R v.3.6.0 with the mlxR package. RESULTS: A two-compartment model with a first-order disposition model including lag time was used as a structural model. The final model was internally validated using prediction corrected visual predictive check (pcVPC) and other graphical diagnostics. A total of 621 CsA steady-state concentrations were analyzed for model development. Population estimates for the absorption constant (ka) and lag time were 0.523 h-1 and 0.512 h, respectively; apparent clearance (CL/F) was 30.3 L/h (relative standard error [RSE] ± 8.25%) with an interindividual variability of 39.8% and interoccasion variability of 38.0%; meanwhile, apparent clearance of distribution (Q/F) was 17.0 L/h (RSE ± 12.1%) with and interindividual variability of 53.2%. The covariate analysis identified creatinine clearance (ClCrea) as an individual factor influencing the Cl of CsA. The predictive capacity of the population model was demonstrated to be effective since predictions made for new patients were accurate for C1 and C2 (MPPEs below 50%). Bayesian forecasting improved significantly in the second and third occasions. CONCLUSION: A population pharmacokinetic model was developed to reasonably estimate the individual cyclosporine clearance for patients. Hence, it can be utilized to individualize CsA doses for prompt and adequate achievement of target blood concentrations of CsA.
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Ciclosporina/farmacocinética , Monitoramento de Medicamentos , Modelos Biológicos , Adulto , Ciclosporina/sangue , Feminino , Humanos , MasculinoRESUMO
Background: Seizure control is challenging in the palliative care setting. Subcutaneous (SC) levetiracetam (LEV) is currently an off-label route of administration and effectiveness, tolerability, and pharmacokinetics studies for this route are scarce. Objectives: This prospective study aimed at evaluating effectiveness and tolerability of SC LEV as well as characterizing its pharmacokinetics. Subjects: Patients (n = 7) who attended the palliative care clinic between September 2018 and January 2019 with diagnosis of seizures, ≥18 years, and in need of SC route of administration were included in the study. Measurements: LEV plasma levels were determined using high-performance liquid chromatography and pharmacokinetic analysis were performed using Monolix 2018R2 (France). pH and osmolality of the three SC infusion solutions were also determined. Results: Seven patients took part in the study. Seizures were controlled in six out of seven patients with doses of 1000 and 3000 mg/day. Adverse effects were mild. pH and osmolality of the SC infusion solutions were within the accepted values reported in the literature. Mean plasma LEV concentrations were 14.4 mg/L (1000 mg/day) and 27.7 mg/L (2000 mg/day). The population clearance (2.5 L/h) and the elimination half-life (10.4 hours) were successfully estimated. Conclusions: Based on this data, SC LEV was effective and well tolerated. Pharmacokinetic parameters for the SC route were successfully determined.
Assuntos
Epilepsia , Cuidados Paliativos , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , França , Humanos , Levetiracetam/uso terapêutico , Estudos Prospectivos , Resultado do TratamentoRESUMO
The aim of the present study was to present new evidence supporting the use of saliva as a biological fluid in relative bioavailability studies. Carbamazepine was chosen as a model drug because of its suitability for salivary therapeutic drug monitoring and its well-documented plasma bioavailability. A relative bioavailability study of four different immediate release carbamazepine products was performed. Stimulated saliva samples were collected by chewing on parafilm wax and by the spitting method. In vitro dissolution testing of formulations, using 900 ml of 1% sodium lauryl sulphate in water, was also carried out. The in vitro-in vivo correlations obtained in this salivary study were consistent with previous correlations assessed using plasma. These results support the suitability of saliva as the biological fluid in relative bioavailability studies.
Assuntos
Carbamazepina/sangue , Carbamazepina/farmacocinética , Monitoramento de Medicamentos , Saliva/metabolismo , Área Sob a Curva , Disponibilidade Biológica , Formas de Dosagem , Medicamentos Genéricos/economia , Feminino , Humanos , Modelos Lineares , Masculino , Solubilidade , Comprimidos/análise , Equivalência TerapêuticaRESUMO
BACKGROUND: Current therapy of neurological disorders has several limitations. Although a high number of drugs are clinically available, several subjects do not achieve full symptomatic remission. In recent years, there has been an increasing interest in the therapeutic potential of L-carnitine (LCAR) and acetyl-L-carnitine (ALCAR) because of the multiplicity of actions they exert in energy metabolism, as antioxidants, neuromodulators and neuroprotectors. They also show excellent safety and tolerability profile. OBJECTIVE: To assess the role of LCAR and ALCAR in neurological disorders. METHODS: A meticulous review of the literature was conducted in order to establish the linkage between LCAR and ALCAR and neurological diseases. RESULTS: LCAR and ALCAR mechanisms and effects were studied for Alzheimer's disease, depression, neuropathic pain, bipolar disorder, Parkinson's disease and epilepsy in the elderly. Both substances exert their actions mainly on primary metabolism, enhancing energy production, through ß-oxidation, and the ammonia elimination via urea cycle promotion. These systemic actions impact positively on the Central Nervous System state, as Ammonia and energy depletion seem to underlie most of the neurotoxic events, such as inflammation, oxidative stress, membrane degeneration, and neurotransmitters disbalances, present in neurological disorders, mainly in the elderly. The impact on bipolar disorder is controversial. LCAR absorption seems to be impaired in the elderly due to the decrease of active transportation; therefore, ALCAR seems to be the more effective option to administer. CONCLUSION: ALCAR emerges as a simple, economical and safe adjuvant option in order to impair the progression of most neurological disorders.
Assuntos
Acetilcarnitina/farmacologia , Doença de Alzheimer , Carnitina , Idoso , Metabolismo Energético , Humanos , Estresse OxidativoRESUMO
Clozapine (CZP) is an atypical antipsychotic agent commonly used in the treatment of schizophrenia. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active metabolite, norclozapine (NCZP). Significant intra- and interindividual pharmacokinetic (PK) variability for CZP and NCZP has been observed in routine therapeutic drug monitoring. So the goal of this study was to evaluate the magnitude and variability of concentration exposure to CZP and its active metabolite NCZP on pharmacokinetic parameters in Uruguayan patients with schizophrenia with a focus on covariates such as cigarette smoking, age, sex, caffeine consumption, brands available of CZP, and comedication using population PK (PPK) modeling methodologies. Patients with a diagnosis of schizophrenia treated with brand-name CZP (Leponex®) for more than a year were included in the study. Then these patients were switched to the similar brand of CZP (Luverina®). Morning predose blood samples for determination of CZP and NCZP using a HPLC system equipped with a UV detector were withdrawn on both occasions at steady state and under the same comedication. Ninety-eight patients, 22 women and 76 men, took part in the study. Mean ± standard deviation for CZP and NCZP concentration was 421 ± 262 ng/mL and 275 ± 180 ng/mL, respectively. After covariate evaluation, only smoking status remained significant in CZP apparent clearance, inducing a mean increment of 32% but with no clinical impact. The results obtained with the two brands of CZP should ensure comparable efficacy and tolerability with the clinical use of either product. Smoking was significantly associated with a lower exposure to CZP due to higher clearance. The results obtained with the two brands commercialized in our country hint a bioequivalence scenario in the clinical setting.
Assuntos
Clozapina/análogos & derivados , Modelos Biológicos , Esquizofrenia , Adulto , Idoso , Clozapina/administração & dosagem , Clozapina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , UruguaiRESUMO
A simple isocratic reverse-phase HPLC method for the determination of six antichagasic phenylethenylbenzofuroxans and its major synthetic secondary products, the corresponding geometric isomers and the benzofurazans, was developed and validated for use in the analysis of pre-clinical studies. Separation was achieved on a reverse-phase Supelco LC-18 column using either methanol-acetonitrile-water or acetonitrile-water, in different proportions, as mobile phase. The compounds were eluted isocratically at a flow rate of either 0.8 or 1.0 mLmin(-1). The compounds were analyzed with UV detection at 210 and 300 nm. The validation characteristics included linearity, accuracy, precision, specificity, limit of detection and quantification and robustness. Validation acceptance criteria were met in all cases. This method was used successfully for the quality assessment of the drugs production in the scale-up procedures.