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The widespread use of the oral poliovaccine from Sabin strains (tOPV) radically reduced poliomyelitis incidence worldwide. However, OPV became a source of neurovirulent vaccine-derived polioviruses (VDPVs). Currently, circulating type 2 VDPVs (cVDPV2) are the leading cause of poliomyelitis. The novel OPV type 2 vaccine (nOPV2), based on genetically modified Sabin strain with increased genetic stability and reduced risk of cVDPV formation, has been used to combat cVDPV2 outbreaks, including one in Tajikistan in 2021. In order to identify the importation of cVDPV2 and nOPV2-derivates, stool samples from 12,127 healthy migrant children under 5 years of age arriving from Tajikistan were examined in Russia (March 2021-April 2022). Viruses were isolated in cell culture and identified via intratype differentiation RT-PCR, VP1 and whole-genome sequencing. cVDPV2 isolates closely related with the Tajikistan one were isolated from two children, and nOPV2-derived viruses were detected in specimens from 106 children from 37 regions of Russia. The duration of nOPV2 excretion ranged from 24 to 124 days post-vaccination. nOPV2 isolates contained 27 mutations per genome (0.36%) on average, with no critical genetic changes, which confirms the genetic stability of nOPV2 during field use. The possibility of epidemiologically significant poliovirus introduction into polio-free countries has been confirmed. The screening of special populations, including migrants, is required to maintain epidemiological well-being.
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Everybody deserves access to evidence-based information to make decisions about their health. However, in many situations, clinical trial eligibility criteria mean that specific data do not exist for certain groups of individuals. These include pregnant and breastfeeding women, children, older people, those with hepatic and renal dysfunction, those with acute severe illness, and those with multiple co-morbidities and interacting medications. Resultantly, there may not be specific drug-dosing information for many patients who are treated in a clinical setting. The ASCPT2024 Dolores Shockley Lecture focused on the equitable access to research with a specific focus on clinical pharmacology studies in pregnancy and breastfeeding. To ensure the safe, effective use of medication in pregnancy and breastfeeding, women should be included in clinical trials and pharmacokinetic studies when a medication is anticipated to be used in women of childbearing potential. Community groups should be involved at all stages of research to maintain transparency and trust. This ensures that local priorities are investigated, that communities understand the findings and are empowered to make evidence-based decisions about their own medication use. Principles informing the design of such studies in pregnancy and lactation are in existence. Mathematical techniques such as physiologically-based pharmacokinetic modeling and stochastic simulation and estimation can enhance study design, and population pharmacokinetic modeling be used to understand variability within and between individuals. Data should be made findable, accessible, interoperable, and reusable (FAIR). Information (and where necessary, training) regarding the use of these approaches should be provided to decision-making stakeholders such as ethics committees and regulatory bodies.
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AIMS: Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS: We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. RESULTS: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) µmol.L-1. Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [ß] = 2.78 µmol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use (ß = 2.30 [0.53, 4.06]), male sex (ß = 5.20 [2.92, 7.48]), baseline serum creatinine (ß = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 AâG polymorphism with a dominant model (ß = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS: Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.
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Creatinina , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Humanos , Piridonas/farmacocinética , Oxazinas/farmacocinética , Oxazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Masculino , Creatinina/sangre , Femenino , Infecciones por VIH/tratamiento farmacológico , Adulto , Sudáfrica , Persona de Mediana Edad , Glucuronosiltransferasa/genética , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , VIH-1/genética , VIH-1/efectos de los fármacos , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de Integrasa VIH/efectos adversos , Tenofovir/farmacocinética , Tenofovir/uso terapéutico , Emtricitabina/uso terapéutico , Emtricitabina/farmacocinética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Exclusive breastfeeding of infants under 6 months of age is recommended by the World Health Organization. In 2021, over 300 million combined incident cases of malaria, tuberculosis, and neglected tropical diseases (NTDs) were reported, predominantly in low-income countries. For many of the drugs used as first-line treatments for these conditions, there is limited knowledge on infant exposure through breastfeeding with poorly understood consequences. This review summarized available knowledge on mother-to-infant transfer of these drugs to inform future lactation pharmacokinetic studies. METHODOLOGY: A list of first-line drugs was generated from the latest WHO treatment guidelines. Using standard online databases, 2 independent reviewers searched for eligible articles reporting lactation pharmacokinetics studies and extracted information on study design, participant characteristics, and the mathematical approach used for parameter estimation. A third reviewer settled any disagreements between the 2 reviewers. All studies were scored against the standardized "ClinPK" checklist for conformity to best practices for reporting clinical pharmacokinetic studies. Simple proportions were used to summarize different study characteristics. FINDINGS: The most remarkable finding was the scarcity of lactation pharmacokinetic data. Only 15 of the 69 drugs we listed had lactation pharmacokinetics fully characterized. Most studies enrolled few mothers, and only one evaluated infant drug concentrations. Up to 66% of the studies used non-compartmental analysis to estimate pharmacokinetic parameters rather than model-based compartmental analysis. Unlike non-compartmental approaches, model-based compartmental analysis provides for dynamic characterization of individual plasma and breast milk concentration-time profiles and adequately characterizes variability within and between individuals, using sparsely sampled data. The "ClinPK" checklist inadequately appraised the studies with variability in the number of relevant criteria across different studies. CONCLUSIONS/SIGNIFICANCE: A consensus is required on best practices for conducting and reporting lactation pharmacokinetic studies, especially in neglected diseases such as malaria, tuberculosis, and NTDs, to optimize treatment of mother-infant pairs.
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Malaria , Tuberculosis , Femenino , Lactante , Humanos , Leche Humana , Enfermedades Desatendidas/tratamiento farmacológico , Lactancia Materna , Lactancia , Tuberculosis/tratamiento farmacológicoRESUMEN
BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.
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Enfermedades Raras , Enfermedades no Diagnosticadas , Estados Unidos , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Enfermedades Raras/terapia , Atención Terciaria de Salud , Medicina Genómica , Pruebas Genéticas , Asesoramiento GenéticoRESUMEN
The efficacy of photodynamic therapy (PDT) strictly depends on the availability of molecular oxygen to trigger the light-induced generation of reactive species. Fluorocarbons have an increased ability to dissolve oxygen and are attractive tools for gas delivery. We synthesized three fluorous derivatives of chlorin with peripheral polyfluoroalkyl substituents. These compounds were used as precursors for preparing nanoemulsions with perfluorodecalin as an oxygen depot. Therefore, our formulations contained hydrophobic photosensitizers capable of absorbing monochromatic light in the long wavelength region and the oxygen carrier. These modifications did not alter the photosensitizing characteristics of chlorin such as the generation of singlet oxygen, the major cytocidal species in PDT. Emulsions readily entered HCT116 colon carcinoma cells and accumulated largely in mitochondria. Illumination of cells loaded with emulsions rapidly caused peroxidation of lipids and the loss of the plasma membrane integrity (photonecrosis). Most importantly, in PDT settings, emulsions potently sensitized cells cultured under prolonged (8 weeks) hypoxia as well as cells after oxygen depletion with sodium sulfite (acute hypoxia). The photodamaging potency of emulsions in hypoxia was significantly more pronounced compared to emulsion-free counterparts. Considering a negligible dark cytotoxicity, our materials emerge as efficient and biocompatible instruments for PDT-assisted eradication of hypoxic cells.
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Fluorocarburos , Fotoquimioterapia , Porfirinas , Humanos , Fármacos Fotosensibilizantes/química , Porfirinas/química , Fluorocarburos/farmacología , Hipoxia/metabolismo , Oxígeno , Emulsiones/química , Línea Celular TumoralRESUMEN
OBJECTIVES: There have been recent advances assessing copeptin levels in adults with suspected disorders of vasopressin release. Very limited data exits on copeptin levels in children and infants, especially in a critically-ill hospitalized population where hyper- and hypo-natremia are very common. Our objective is to describe the institutional experience assessing copeptin levels in hospitalized infants and children with hyper- or hypo-natremia. METHODS: We performed a single-center retrospective case series of all infants, children, and adolescents who had an ultrasensitive plasma copeptin level obtained between 2019-2021. RESULTS: A total of 29 critically ill patients (6 infants) were identified with 38 % of patients having copeptin levels after neurosurgical procedures for tumors or trauma. Approximately 13/17 children with hypernatremia had central diabetes insipidus (central diabetes insipidus) to diagnose CDI, A copeptin level ≤ 4.9 pmol/L resulted in an 88 % sensitivity (95 % CI 47-99 %), and 66 % specificity (95 % CI 30-93 %). Amongst those with hyponatremia levels were more variable, 8/12 children had syndrome of inappropriate antidiuresis (SIAD) with copeptin levels ranging 4.7-72.6 pmol/L. CONCLUSIONS: While difficult to conclude due to multiple limitations, this case series highlights that typical copeptin cutoffs used to diagnose DI in adults in an ambulatory setting may also translate to a critically-ill pediatric population. Large prospective studies are needed to confirm this observation. In addition, postoperative copeptin levels could potentially be utilized as an additional marker to predict permanent from transient DI, but much larger studies are needed. Further work is needed to establish normative copeptin levels in infants and patients with SIAD.
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Diabetes Insípida Neurogénica , Adolescente , Niño , Humanos , Lactante , Enfermedad Crítica , Estudios Retrospectivos , VasopresinasRESUMEN
Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are prodrugs of the nucleotide analogue tenofovir, which acts intracellularly to inhibit HIV replication. Whereas TDF converts to tenofovir in plasma and may cause kidney and bone toxicity, TAF mostly converts to tenofovir intracellularly, so it can be administered at lower doses. TAF leads to lower tenofovir plasma concentrations and lower toxicity, but there are limited data on its use in Africa. We used data from 41 South African adults living with HIV from the ADVANCE trial and described, with a joint model, the population pharmacokinetics of tenofovir given as TAF or TDF. The TDF was modeled to appear in plasma as tenofovir with a simple first-order process. Instead, two parallel pathways were used for a TAF dose: an estimated 32.4% quickly appeared as tenofovir into the systemic circulation with first-order absorption, whereas the rest was sequestered intracellularly and released into the systemic circulation as tenofovir slowly. Once in plasma (from either TAF or TDF), tenofovir disposition followed two-compartment kinetics and had a clearance of 44.7 L/h (40.2-49.5), for a typical 70-kg individual. This semimechanistic model describes the population pharmacokinetics of tenofovir when dosed as either TDF or TAF in an African population living with HIV and can be used as a tool for exposure prediction in patients, and to simulate alternative regimes to inform further clinical trials.
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Fármacos Anti-VIH , Infecciones por VIH , Adulto , Humanos , Adenina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , TenofovirRESUMEN
BACKGROUND: Tenofovir is a component of preferred combination antiretroviral therapy (ART) regimens in Africa. Few pharmacogenetic studies have been conducted on tenofovir exposure in Africa, where genetic diversity is greatest. OBJECTIVE: We characterized the pharmacogenetics of plasma tenofovir clearance in Southern Africans receiving tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). METHODS: Adults randomized to TAF or TDF in dolutegravir-containing arms of the ADVANCE trial (NCT03122262) were studied. Linear regression models stratified by study arm examined associations with unexplained variability in tenofovir clearance. We investigated genetic associations with polymorphisms selected a priori followed by genome-wide associations. RESULTS: A total of 268 participants (138 and 130 in the TAF and TDF arm, respectively) were evaluable for associations. Among polymorphisms previously associated with any drug-related phenotype, IFNL4 rs12979860 was associated with more rapid tenofovir clearance in both arms (TAF: P = 0.003; TDF: P = 0.003). Genome-wide, the lowest P values for tenofovir clearance in TAF and TDF arms were LINC01684 rs9305223 (P = 3.0 × 10-8) and intergenic rs142693425 (P = 1.4 × 10-8), respectively. CONCLUSION: Among Southern Africans randomized to TAF or TDF in ADVANCE, unexplained variability in tenofovir clearance was associated with a polymorphism in IFNL4, an immune-response gene. It is unclear how this gene would affect tenofovir disposition.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Tenofovir/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Farmacogenética , Pueblo Africano , InterleucinasRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, leading to fibrosis, cirrhosis and hepatocellular carcinoma and also associated with increased cardiovascular disease mortality. The pathogenesis of NAFLD is not fully understood, although NAFLD is thought to be a hepatic form of metabolic syndrome. There is an increasing understanding of the role of microbiota disturbances in NAFLD pathogenesis, and as with many other conditions affecting the microbiota, NAFLD may be a novel risk factor for Clostridioides difficile (C. difficile) colonization (CDC) and C. difficile infection (CDI). CDI is an emerging nosocomial disease, and community-acquired cases of infection are growing, probably due to an increase in CDC rates. The association of NAFLD with CDI has been shown in only 4 studies to date, three of which included less than 1000 patients, although the frequency of NAFLD in these studies was observed in almost 20% of the total patient cohort. These data revealed that NAFLD is a risk factor for CDI development and, moreover, is a risk factor for intestinal complications of CDI. More studies are needed to investigate this association and move forward CDC and CDI screening efforts for this group of patients.
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BACKGROUND: Optimal physical activity is known to reduce cardiovascular, respiratory and endocrine system diseases and, as a consequence, improve quality of life. An important risk factor for reinjuries during normal exercise is the initial connective tissue pathology. The variety of clinical dysplastic manifestations significantly complicate the timely diagnosis of this comorbidity. AIM: To establish pathognomonic sex-specific dysplasia phenotypes that indicate a particular sensitivity to physical exertion. METHODS: The study involved 117 participants with recurrent musculoskeletal injuries that occurred during normal exercise. There were 67 women (57.26%) and 50 men (42.74%), which made it possible to compare the presence of the identified signs between sexes. A validated questionnaire was used to screen their connective tissue status. RESULTS: Ranking the most commonly revealed dysplasia signs depending on their clinical significance made it possible to establish pathognomonic sex-specific phenotypes that indicated a particular susceptibility to injuries. Individualized programs of optimal physical activity are necessary for men with chest deformities, flat-valgus feet, dolichostenomelia, arachnodactylia, hemorrhoids, abdominal muscle diastasis and recurrent hernias. In women, special sensitivity to physical exertion was associated with a combination of signs such as asthenic body, joint hypermobility, overly soft auricles, thin hyperelastic skin, atrophic striae, telangiectasias and varicose veins. Of particular importance were universal signs such as gothic palate, scoliosis, kyphosis, leg deformities, temporomandibular joint crunching, and moderate to high myopia. CONCLUSION: Participants' connective tissue condition should be considered when designing optimal physical activity programs. Identifying the established sex-specific dysplasia phenotypes will allow timely optimization of training loads, thus reducing the risk of injury.
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Rifampicin, a potent enzyme inducer, causes marked reduction of dolutegravir exposure. Rifabutin, a less potent enzyme inducer, may offer an alternative to rifampicin. We aimed to characterize the population pharmacokinetics of dolutegravir when co-administered with rifabutin. We extended an existing dolutegravir model to include data from volunteers co-administered with dolutegravir 50 mg and rifabutin 300 mg once daily. We ran simulations of dolutegravir with and without rifabutin co-administration and compare dolutegravir trough concentrations with the IC90 and EC90 of 0.064 and 0.3 mg/L, respectively. Rifabutin decreased dolutegravir's volume of distribution by 33.1% (95% confidence interval 25.1%-42.3%) but did not affect the area under the concentration-time curve. Simulations showed that when 50 mg dolutegravir is co-administered with rifabutin once daily, the probability to attain trough concentrations above the IC90 of 0.064 mg/L is more than 99%. Therefore, there is no need for dolutegravir dose adjustment. Rifabutin may offer an alternative to rifampicin for the treatment of HIV/tuberculosis co-infected individuals.
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Infecciones por VIH , Rifabutina , Humanos , Rifabutina/farmacocinética , Rifabutina/uso terapéutico , Rifampin , Infecciones por VIH/tratamiento farmacológico , Interacciones FarmacológicasRESUMEN
OBJECTIVES: The detection of a vaccine-derived poliovirus (VDPV) requires an epidemiological assessment and response. Using repeated stool sampling from a child who is immunocompetent and was vaccinated against poliomyelitis with acute flaccid paralysis, a case of an extremely rapid evolution of Sabin-like poliovirus (PV) type 3 was traced in the child's body. METHODS: The case was independently identified in two countries-Tajikistan and Russia. Stool samples for the study were also independently collected in two countries on different days from the onset of paralysis. Virological, serological, and molecular methods; full genome Sanger; and high-throughput sequencing were performed to characterize isolates. RESULTS: PV isolates from samples collected on days 2, 3, and 14 contained eight, seven, and seven mutations in the VP1-coding region, respectively, and were classified as Sabin-like PV type 3. The isolates from samples collected on days 15 and 18 had 11 mutations and were classified as vaccine-derived PVs, which required an epidemiological response in the two countries. CONCLUSION: The results indicate the need to continue acute flaccid paralysis surveillance, maintain high vaccination coverage, and develop and introduce new effective, genetically stable PV vaccines.
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Poliomielitis , Vacuna Antipolio Oral , Poliovirus , Niño , Humanos , Lactante , Poliomielitis/prevención & control , Poliovirus/genética , Vacuna Antipolio Oral/efectos adversos , Tayikistán , Federación de RusiaRESUMEN
This study demonstrates a new and sustainable methodology for recycling continuous carbon fibers from end-of-life thermoset composite parts using Joule heating. This process addresses the longstanding challenge of efficiently recovering carbon fibers from composite scrap and reusing them to make fresh composites. The conductive carbon fibers volumetrically heat up when an electric current is passed through them, which in turn rapidly heats up the surrounding matrix sufficiently to degrade it. Fibers can be easily separated from the degraded matrix after the direct current (DC) heating process. Fibers reclaimed using this method were characterized to determine their tensile properties and surface chemistry, and compared against both as-received fibers and fibers recycled using conventional oven pyrolysis. The DC- and oven-recycled fibers yielded similar elastic modulus when compared against as-received fibers; however, an around 10-15 % drop was observed in the tensile strength of fibers recycled using either method. Surface characterization showed that DC-recycled fibers and as-received fibers had similar types of functional groups. To demonstrate the reusability of recycled fibers, composites were fabricated by impregnation with epoxy resin and curing. The mechanical properties of these recycled carbon fiber composites (rCFRCs) were compared against conventional recycling methods, and similar modulus and tensile strength values were obtained. This study establishes DC heating as a scalable out-of-oven approach for recycling carbon fibers.
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Calefacción , Reciclaje , Fibra de Carbono , Resistencia a la Tracción , PirólisisRESUMEN
Carbon-based nanomaterials (CBNs) are often used for potential agricultural applications. Since CBNs applied to plants can easily enter plant organs and reach the human diet, the consequences of the introduction of CBNs into the food chain need to be investigated. We created a platform for a comprehensive investigation of the possible health risks of multiwalled carbon nanotubes (CNTs) accumulated in the organs of exposed tomato plants. Quantification and visualization of CNTs absorbed by plant organs were determined by microwave-induced heating (MIH) and radio frequency (RF) heating methods. Feeding mice with CNT-contaminated tomatoes showed an absence of toxicity for all assessed animal organs. The amount of CNTs accumulated inside the organs of mice fed with CNT-containing fruits was assessed by an RF heating technique and was found to be negligible. Our work provides the experimental evidence that the amount of CNTs accumulated in plant organs as a result of nanofertilization is not sufficient to induce toxicity in mice.
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Nanotubos de Carbono , Solanum lycopersicum , Humanos , Ratones , Animales , Nanotubos de Carbono/toxicidad , Plantas , Agricultura , Medición de RiesgoRESUMEN
Sex is a biological variable in experimental models. In our previous diisopropylfluorophosphate (DFP) studies, female rats required a higher dose of DFP to achieve a somewhat similar severity of status epilepticus (SE) as males. In those studies, male and female rats were bought separately from the same vendor, housed in different rooms, and the DFP used was from different batches. We had also shown that surgery for epidural electrodes implantation reduces the threshold for SE. Our recent study in the soman (GD) model using a mixed-sex cohort of rats housed individually but in the same room showed that females achieved significantly higher SE severity than males for the same dose of GD. In this study, we demonstrate that housing the mixed-sex cohorts in the same room and treating them with DFP (4 mg/kg, s.c.) from the same pool, though from different batches, yielded reproducible SE severity in both sexes and both telemetry (surgery) and non-telemetry (non-surgery) groups. We conducted experiments in four mixed-sex cohorts of adult Sprague-Dawley rats. In females, the surgery for implanting the telemetry devices reduced the latency to convulsive seizure (CS) and increased SE severity compared to non-telemetry females. However, there were no sex differences in latency or SE severity within telemetry or non-telemetry groups. Once animals reached CS stage ≥3, they remained in CS stage in both sexes until midazolam was administered. Midazolam (3 mg/kg, i.m.) treatment 1-one-hour post-DFP significantly reduced epileptiform spikes in both sexes. The mortality was only 2% in 24 h. Irrespective of sex or stage of estrous cycle or surgery, the animals had continuous convulsive SE for â¼40 min. In telemetry rats, electrographic changes correlated with behavioral seizures. However, there was a significant difference in SE severity and the latency between directly-observed behavioral CS and EEG-based CS quantification in both sexes. Overall, these results suggest that housing both sexes in the same room and treating with DFP in a mixed-sex cohort from the same pool of reagents will minimize variability in SE severity. Such rigorous experiments will yield better outcomes while testing disease-modifying agents in epilepsy models.
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Dolutegravir-based regimens are recommended as first-line therapy for HIV in low- and middle-income countries where tuberculosis is the most common opportunistic infection. Concurrent HIV/tuberculosis treatment is challenging because of drug-drug interactions. Our analysis aimed to characterize dolutegravir's population pharmacokinetics when coadministered with rifampicin and assess alternative dolutegravir dosing regimens. We developed a population pharmacokinetic model of dolutegravir in NONMEM with data from two healthy-volunteer studies (RADIO and ClinicalTrials.gov identifier NCT01231542) and validated it with data from the INSPIRING study, which consisted of participants living with HIV. The model was developed with 817 dolutegravir plasma concentrations from 41 participants. A 2-compartment model with first-order elimination and lagged absorption best described dolutegravir's pharmacokinetics. For a typical 70-kg individual, we estimated a clearance, absorption rate constant, central volume, and peripheral volume of 1.03 L/h, 1.61 h-1, 12.7 L, and 3.85 L, respectively. Rifampicin coadministration increased dolutegravir clearance by 144% (95% confidence interval [CI], 126 to 161%). Simulations showed that when 50 or 100 mg once-daily dolutegravir is coadministered with rifampicin in 70-kg individuals, 71.7% and 91.5% attain trough concentrations above 0.064 mg/L, the protein-adjusted 90% inhibitory concentration (PA-IC90), respectively. The model developed from healthy-volunteer data describes patient data reasonably well but underpredicts trough concentrations. Although 50 mg of dolutegravir given twice daily achieves target concentrations in more than 99% of individuals cotreated with rifampicin, 100 mg of dolutegravir, once daily, in the same population is predicted to achieve satisfactory pharmacokinetic target attainment. The efficacy of this regimen should be investigated since it presents an opportunity for treatment simplification.
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Infecciones por VIH , Tuberculosis , Estudios Clínicos como Asunto , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Oxazinas/farmacocinética , Piperazinas , Piridonas/uso terapéutico , Rifampin/farmacocinética , Tuberculosis/tratamiento farmacológicoRESUMEN
BACKGROUND: Dolutegravir is a component of preferred antiretroviral therapy (ART) regimens. We characterized the pharmacogenetics of dolutegravir exposure after ART initiation in the ADVANCE trial in South Africa. METHODS: Genome-wide genotyping followed by imputation was performed. We developed a population pharmacokinetic model for dolutegravir using nonlinear mixed-effects modeling. Linear regression models examined associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR). RESULTS: Genetic associations were evaluable in 284 individuals. Of 9 polymorphisms previously associated with dolutegravir pharmacokinetics, the lowest P value with AUCVAR was UGT1A1 rs887829 (P = 1.8 × 10-4), which was also associated with log10 bilirubin (P = 8.6 × 10-13). After adjusting for rs887829, AUCVAR was independently associated with rs28899168 in the UGT1A locus (P = .02), as were bilirubin concentrations (P = 7.7 × 10-8). In the population pharmacokinetic model, rs887829 T/T and C/T were associated with 25.9% and 10.8% decreases in dolutegravir clearance, respectively, compared with C/C. The lowest P value for AUCVAR genome-wide was CAMKMT rs343942 (P = 2.4 × 10-7). CONCLUSIONS: In South Africa, rs887829 and rs28899168 in the UGT1A locus were independently associated with dolutegravir AUCVAR. The novel rs28899168 association warrants replication. This study enhances understanding of dolutegravir pharmacogenetics in Africa.
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Infecciones por VIH , Farmacogenética , Humanos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Piridonas , Bilirrubina , VIH , SudáfricaRESUMEN
Dolutegravir is associated with more weight gain than efavirenz in people starting antiretroviral therapy (ART). We investigated the concentration-response relationships of efavirenz and dolutegravir with weight gain. We determined concentration-response relationships of dolutegravir and efavirenz (both combined with tenofovir disoproxil fumarate and emtricitabine) with changes in weight and fat distribution, derived from dual-energy x-ray absorptiometry scans, in a nested study of ART-naïve participants from a randomised controlled trial. Pharmacokinetic parameters used in analyses were efavirenz mid-dosing interval concentrations and estimated dolutegravir area under the concentration-time curve using a population pharmacokinetic model developed in the study population. Study outcomes were percentage changes from baseline to week 48 in weight, and visceral and subcutaneous adipose tissue mass. Pharmacokinetic data were available for 158 and 233 participants in the efavirenz arm and dolutegravir arms respectively; 57.0% were women. On multivariable linear regression there were independent negative associations between efavirenz concentrations and changes in both weight (P < .001) and subcutaneous adipose tissue mass (P = .002). Estimated dolutegravir area under the concentration-time curve up to 24 hours was not associated with change in weight (P = .109) but was negatively associated with change in visceral adipose tissue mass (P = .025). We found an independent negative concentration-response relationship between efavirenz concentrations and weight change in ART-naïve participants. Dolutegravir concentrations were not independently associated with weight change. These findings suggest that weight gain differences between efavirenz and dolutegravir are driven by efavirenz toxicity impairing weight gain rather than by off-target effects of dolutegravir causing weight gain.