RESUMO

This study aims to evaluate the impact of liver fibrosis stages of chronic infection with hepatitis C virus (HCV) on the in vivo activity of organic cation transporters (hepatic OCT1 and renal OCT2) using metformin (MET) as a probe drug. Participants allocated in Group 1 (n = 15, mild to moderate liver fibrosis) or 2 (n = 13, advanced liver fibrosis and cirrhosis) received a single MET 50 mg oral dose before direct-acting antiviral (DAA) drug treatment (Phase 1) and 30 days after achieving sustained virologic response (Phase 2). OCT1/2 activity (MET AUC0-24) was found to be reduced by 25% when comparing the two groups in Phase 2 (ratio 0.75 (0.61-0.93), p < 0.05) but not in Phase 1 (ratio 0.81 (0.66-0.98), p > 0.05). When Phases 1 and 2 were compared, no changes were detected in both Groups 1 (ratio 1.10 (0.97-1.24), p > 0.05) and 2 (ratio 1.03 (0.94-1.12), p > 0.05). So, this study shows a reduction of approximately 25% in the in vivo activity of OCT1/2 in participants with advanced liver fibrosis and cirrhosis after achieving sustained virologic response and highlights that OCT1/2 in vivo activity depends on the liver fibrosis stage of chronic HCV infection.

RESUMO

α-Bisabolol (α-BIS) is a sesquiterpene alcohol present in chamomile essential oil [Chamomilla recutita (L.) Rauschert]. Despite its numerous pharmacological effects, its pharmacokinetics remain understudied. An analytical method capable of quantifying α-BIS in plasma is crucial to enable pharmacokinetic analysis. Presently, only one study has quantified it using mass spectrometry. Administering α-BIS requires a nanoemulsion for intravenous injection. This study aimed to develop and validate a bioanalytical method using high-performance liquid chromatography with an ultraviolet detector to quantify α-BIS in rat plasma. The method employed acetonitrile and ultrapure water (80:20, v/v) as the mobile phase, with a flow rate of 1 ml/min and concentrations ranging from 465 to 29.625 µg/ml. All US Food and Drug Administration-designated assays were successful, indicating the method's precision, accuracy, sensitivity and linearity in determining α-BIS in rat plasma. The developed nanoemulsion, assessed through dynamic light scattering analysis, the ensemble collection of particles and polydispersity index evaluation, proved safe and effective for intravenous administration. The pharmacokinetic parameters such as volume of distribution, clearance and half-life indicated that α-BIS tends to persist in the body. This study provides a foundation for further research to explore α-BIS's potential pharmaceutical applications in the future.

Assuntos

Emulsões , Sesquiterpenos Monocíclicos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Ratos , Emulsões/química , Reprodutibilidade dos Testes , Sesquiterpenos Monocíclicos/farmacocinética , Sesquiterpenos Monocíclicos/sangue , Sesquiterpenos Monocíclicos/química , Masculino , Projetos Piloto , Modelos Lineares , Limite de Detecção , Sesquiterpenos/farmacocinética , Sesquiterpenos/sangue , Sesquiterpenos/química , Ratos Sprague-Dawley , Espectrofotometria Ultravioleta/métodos

RESUMO

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Assuntos

Acetilcisteína , Antioxidantes , Ácido Ascórbico , Desferroxamina , Traumatismo por Reperfusão Miocárdica , Estresse Oxidativo , Humanos , Antioxidantes/farmacocinética , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Masculino , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacocinética , Acetilcisteína/efeitos adversos , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/farmacocinética , Ácido Ascórbico/efeitos adversos , Adulto , Estresse Oxidativo/efeitos dos fármacos , Feminino , Desferroxamina/farmacocinética , Desferroxamina/administração & dosagem , Desferroxamina/efeitos adversos , Voluntários Saudáveis , Adulto Jovem , Infusões Intravenosas , Pessoa de Meia-Idade , Método Duplo-Cego , Quimioterapia Combinada , Biomarcadores/sangue

RESUMO

Patients with diabetes face a 2-4-fold greater cardiovascular risk compared to those without diabetes. Both metformin and acetylsalicylic acid (aspirin) treatment have demonstrated a significant reduction in this risk. This single-center, open-label, sequence randomized, 2 × 2 crossover, single-dose clinical trial evaluated the pharmacokinetics profile and comparative bioavailability of a novel oral fixed-dose combination (FDC) of metformin/acetylsalicylic acid (500/100 mg tablet) versus the reference mono-drugs administered concomitantly, metformin 500 mg tablet and acetylsalicylic acid 100 mg tablet, in 22 healthy Mexican adult volunteers under fasting conditions. Blood samples were collected predose and at specified intervals across a 24-hour period following administration and were analyzed for metformin and salicylic acid using high-performance liquid chromatography coupled with tandem mass spectrometry. Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC0 -t), and (area under the plasma drug concentration-time cruve from 0 up to infinity (AUC0 ∞) data were within the range of 80%-125%. The results obtained from the present clinical study demonstrate the comparative bioavailability of the FDC when compared with the coadministration of reference mono-drugs. There were no adverse events or adverse reactions reported throughout the study.

RESUMO

In this chapter we explored the growing interest in cannabinoids, particularly cannabidiol (CBD), over the last two decades due to their potential therapeutic applications in neurodegenerative and psychiatric disorders. CBD, a major non-psychotomimetic compound derived from Cannabis sativa, is highlighted as a safer alternative to other cannabinoids like Δ9-tetrahydrocannabinol (THC). Clinical trials have been investigating CBD formulations for conditions such as schizophrenia, multiple sclerosis, Alzheimer's, Parkinson's diseases, and stress-related disorders. However, limited access to CBD-approved formulations primarily due to their high-cost and concerns about the quality of market-available products, challenges regulatory agencies globally. The pharmacokinetics of CBD, especially after oral administration, present challenges with erratic absorption and low bioavailability. CBD's "promiscuous" pharmacodynamics involve interactions with various targets beyond the endocannabinoid system, complicating precise dosing in therapeutic interventions. This chapter delves into CBD's dose-response curves, revealing complexities that pose challenges in clinical practice. Nanobiotechnology emerges as a promising solution, with recent developments showing improved bioavailability, stability, and reduced toxicity through nanoencapsulation of CBD. While this phytocannabinoid holds immense promise in neuropsychopharmacology, we provided a comprehensive overview of the current state of CBD research and suggests potential future directions regarding the pharmacology of CBD, harnessing the benefits of this intriguing compound.

Assuntos

Canabidiol , Transtornos Mentais , Canabidiol/farmacocinética , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Humanos , Transtornos Mentais/tratamento farmacológico , Animais

RESUMO

Multimodal analgesia is defined as using several drugs or techniques simultaneously to target different pain pathways or receptors to avoid pain propagation. This study evaluated the pharmacokinetic profile and comparative bioavailability of etoricoxib 90 mg and tramadol 50 mg dosing alone (reference drugs) or in a novel fixed-dose combination (test drug) under fasting conditions in Mexican healthy volunteers. This was a randomized, open-label, 3-way, crossover, single-dose, prospective, and longitudinal study with a 14-day washout period. Eligible subjects were healthy Mexican adult volunteers. The drugs were dosing orally, according to the randomization sequence, after 10 hours of fasting and 4 hours before breakfast with 250 mL of water at room temperature. Serial blood samples were collected before and after dosing, both drugs were quantified using high-performance liquid chromatography coupled with tandem mass spectrometry. Forty-two subjects were enrolled and 38 completed the study (28 men and 14 women, mean age 25.2 years, mean weight 66.6 kg). Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed for (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC0-t), and (area under the plasma drug concentration-time curve from 0 up to infinity (AUC0-∞) data were within the range of 80%-125%. Non-serious adverse events were observed. The results demonstrate that the pharmacokinetic profile and bioavailability of the etoricoxib/tramadol fixed-dose combination are comparable to those of the reference products.

RESUMO

Aim: Compare two vancomycin dosing strategies in critical patients with methicillin-resistant Staphylococcus aureus (MRSA) infections, considering the heterogeneity of the dosing regimens administered and their implications for toxicity and efficacy. Materials & methods: Longitudinal retrospective observational study in two patient cohorts (standard dosing vs dosing via Bayesian algorithms). Results: The group of Bayesian algorithms received substantially higher and significantly heterogeneous doses, with an absence of nephrotoxicity. The speed of decrease observed in CRP and PCT was greater for the Bayesian strategy (p = 0.045 and 0.0009, respectively). Conclusion: Applying Bayesian algorithms to vancomycin dosage individualization allows for administering much higher doses than with standard regimens, facilitating a quicker clinical response in the absence of nephrotoxicity.

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[Box: see text].

Assuntos

Algoritmos , Antibacterianos , Teorema de Bayes , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Vancomicina , Humanos , Vancomicina/administração & dosagem , Estudos Retrospectivos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Longitudinais , Idoso , Medicina de Precisão/métodos , Estado Terminal , Adulto

RESUMO

OBJECTIVES: This study aimed to determine the oxygenator impact on alterations of remdesivir (RDV) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane -oxygenation (ECMO) circuit including the Quadrox-i oxygenator. METHODS: One-quarter-inch and a 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A 1-time dose of RDV was administered into the circuits and serial preoxygenator and postoxygenator concentrations were obtained at 0 to 5 minutes, and 1-, 2-, 3-, 4-, 5-, 6-, 8-, 12-, and 24-hour time points. The RDV was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. RESULTS: For the 1/4-inch circuits with an oxygenator, there was a 35% to 60% RDV loss during the study period. For the 1/4-inch circuits without an oxygenator, there was a 5% to 20% RDV loss during the study period. For the 3/8-inch circuit with and without an oxygenator, there was a 60% to 70% RDV loss during the study period. CONCLUSIONS: There was RDV loss within the circuit during the study period and the RDV loss was more pronounced with the larger 3/8-inch circuit when compared with the 1/4-inch circuit. The impact of the -oxygenator on RDV loss appears to be variable and possibly dependent on the size of the circuit and -oxygenator. These preliminary data suggest RDV dosing may need to be adjusted for concern of drug loss via the ECMO circuit. Additional single- and multiple-dose studies are needed to validate these findings.

RESUMO

Follicle-stimulating hormone (FSH) is an important protein used for bovine ovarian hyperstimulation in multiple ovulation and embryo transfer technology (MOET). Several attempts to produce bovine FSH (bFSH) in recombinant systems have been reported, nonetheless, up to date, the most commonly used products are partially purified preparations derived from porcine or ovine (pFSH or oFSH) pituitaries. Here we describe the development of a biotechnology process to produce a novel, hyperglycosylated, long-acting recombinant bFSH (LA-rbFSH) by fusing copies of a highly O-glycosylated peptide. LA-rbFSH and a nonmodified version (rbFSH) were produced in suspension CHO cell cultures and purified by IMAC with high purity levels (>99%). LA-rbFSH presented a higher glycosylation degree and sialic acid content than rbFSH. It also demonstrated a notable improvement in pharmacokinetic properties after administration to rats, including a higher concentration in plasma and a significant (seven-fold) reduction in apparent clearance (CLapp). In addition, the in vivo specific bioactivity of LA-rbFSH in rats was 2.4-fold higher compared to rbFSH. These results postulate this new molecule as an attractive substitute for commercially available porcine pituitary-derived products.

Assuntos

Cricetulus , Hormônio Foliculoestimulante , Proteínas Recombinantes , Animais , Hormônio Foliculoestimulante/metabolismo , Células CHO , Glicosilação , Bovinos , Ratos , Feminino , Biotecnologia/métodos

RESUMO

In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine, dog culling is one of the main strategies used to control disease, making the development of new therapeutic interventions mandatory. We previously showed that Tanespimycin (17-AAG), a Hsp90 inhibitor, demonstrated potential for use in leishmaniasis treatment. The present study aimed to test the safety of 17-AAG in dogs by evaluating plasma pharmacokinetics, dose-proportionality, and the tolerability of 17-AAG in response to a dose-escalation protocol and multiple administrations at a single dose in healthy dogs. Two protocols were used: Study A: four dogs received variable intravenous (IV) doses (50, 100, 150, 200, or 250 mg/m2) of 17-AAG or a placebo (n = 4/dose level), using a cross-over design with a 7-day "wash-out" period; Study B: nine dogs received three IV doses of 150 mg/m2 of 17-AAG administered at 48 h intervals. 17-AAG concentrations were determined by a validated high-performance liquid chromatographic (HPLC) method: linearity (R2 = 0.9964), intra-day precision with a coefficient of variation (CV) ≤ 8%, inter-day precision (CV ≤ 20%), and detection and quantification limits of 12.5 and 25 ng/mL, respectively. In Study A, 17-AAG was generally well tolerated. However, increased levels of liver enzymes-alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)-and bloody diarrhea were observed in all four dogs receiving the highest dosage of 250 mg/m2. After single doses of 17-AAG (50-250 mg/m2), maximum plasma concentrations (Cmax) ranged between 1405 ± 686 and 9439 ± 991 ng/mL, and the area under the curve (AUC) plotting plasma concentration against time ranged between 1483 ± 694 and 11,902 ± 1962 AUC 0-8 h µg/mL × h, respectively. Cmax and AUC parameters were dose-proportionate between the 50 and 200 mg/m2 doses. Regarding Study B, 17-AAG was found to be well tolerated at multiple doses of 150 mg/m2. Increased levels of liver enzymes-ALT (28.57 ± 4.29 to 173.33 ± 49.56 U/L), AST (27.85 ± 3.80 to 248.20 ± 85.80 U/L), and GGT (1.60 ± 0.06 to 12.70 ± 0.50 U/L)-and bloody diarrhea were observed in only 3/9 of these dogs. After the administration of multiple doses, Cmax and AUC 0-48 h were 5254 ± 2784 µg/mL and 6850 ± 469 µg/mL × h in plasma and 736 ± 294 µg/mL and 7382 ± 1357 µg/mL × h in tissue transudate, respectively. In conclusion, our results demonstrate the potential of 17-AAG in the treatment of CVL, using a regimen of three doses at 150 mg/m2, since it presents the maintenance of high concentrations in subcutaneous interstitial fluid, low toxicity, and reversible hepatotoxicity.