Last data update: Sep 16, 2024. (Total: 47680 publications since 2009)
Records 1-4 (of 4 Records) |
Query Trace: Garcίa-Lerma G [original query] |
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Defining blood hematology reference values in female pig-tailed macaques (Macaca nemestrina) using the Isolation Forest algorithm
Kim D , Derton A , Khalil G , Pan Y , Bachman S , Kelley K , Garcίa-Lerma G , Dobard CW , Daly MB . J Med Primatol 2024 53 (4) e12723 BACKGROUND: Pig-tailed macaques (PTMs) are commonly used as preclinical models to assess antiretroviral drugs for HIV prevention research. Drug toxicities and disease pathologies are often preceded by changes in blood hematology. To better assess the safety profile of pharmaceuticals, we defined normal ranges of hematological values in PTMs using an Isolation Forest (iForest) algorithm. METHODS: Eighteen female PTMs were evaluated. Blood was collected 1-24 times per animal for a total of 159 samples. Complete blood counts were performed, and iForest was used to analyze the hematology data to detect outliers. RESULTS: Median, IQR, and ranges were calculated for 13 hematology parameters. From all samples, 22 outliers were detected. These outliers were excluded from the reference index. CONCLUSIONS: Using iForest, we defined a normal range for hematology parameters in female PTMs. This reference index can be a valuable tool for future studies evaluating drug toxicities in PTMs. |
Author Correction: Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection
Young IC , Massud I , Cottrell ML , Shrivastava R , Maturavongsadit P , Prasher A , Wong-Sam A , Dinh C , Edwards T , Mrotz V , Mitchell J , Seixas JN , Pallerla A , Thorson A , Schauer A , Sykes C , De la Cruz G , Montgomery SA , Kashuba ADM , Heneine W , Dobard CW , Kovarova M , Garcia JV , Garcίa-Lerma JG , Benhabbour SR . Nat Commun 2024 15 (1) 1054 |
Pharmacokinetic study of islatravir and etonogestrel implants in macaques
Daly MB , Wong-Sam A , Li L , Krovi A , Gatto GJ , Norton C , Luecke EH , Mrotz V , Forero C , Cottrell ML , Schauer AP , Gary J , Nascimento-Seixas J , Mitchell J , van der Straten A , Heneine W , Garcίa-Lerma JG , Dobard CW , Johnson LM . Pharmaceutics 2023 15 (12) The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the antiretroviral islatravir (ISL) and the contraceptive etonogestrel (ENG). Three implants were tested: ISL-62 mg, ISL-98 mg, and ENG-33 mg. Animals received one or two ISL-eluting implants, with doses of 42, 66, or 108 µg of ISL/day with or without an additional ENG-33 mg implant (31 µg/day). Drug release increased linearly with dose with median [range] plasma ISL levels of 1.3 [1.0-2.5], 1.9 [1.2-6.3] and 2.8 [2.3-11.6], respectively. The ISL-62 and 98 mg implants demonstrated stable drug release over three months with ISL-triphosphate (ISL-TP) concentr54ations in PBMCs above levels predicted to be efficacious for PrEP. Similarly, ENG implants demonstrated sustained drug release with median [range] plasma ENG levels of 495 [229-1110] pg/mL, which suppressed progesterone within two weeks and showed no evidence of altering ISL pharmacokinetics. Two of the six ISL-98 mg implants broke during the study and induced implant-site reactions, whereas no reactions were observed with intact implants. We show that ISL and ENG biodegradable implants are safe and yield sufficient drug levels to achieve prevention targets. The evaluation of optimized implants with increased mechanical robustness is underway for improved durability and vaginal efficacy in a SHIV challenge model. |
Safety and efficacy of a biodegradable implant releasing tenofovir alafenamide for vaginal protection in a macaque model
Massud I , Krovi A , Nishiura K , Ruone S , Li L , Holder A , Gary J , Mills P , Mitchell J , Khalil G , Pan Y , Luecke E , Gatto G , Heneine W , Garcίa-Lerma JG , Johnson L , van der Straten A , Dobard C . J Antimicrob Chemother 2022 77 (11) 2964-2971 OBJECTIVES: To advance the initiative of ending the global epidemic, long-lasting HIV protection is needed through sustained release of antiretroviral drugs for months to years. We investigated in macaques the safety and efficacy of biodegradable polycaprolactone implants releasing tenofovir alafenamide for HIV pre-exposure prophylaxis (PrEP). METHODS: Implants were administered subcutaneously in the arm using a contraceptive trocar. Efficacy against vaginal simian-HIV (SHIV) infection was investigated in six pigtailed macaques that received two tenofovir alafenamide implants (0.35 mg/day), one in each arm, for a total release rate of tenofovir alafenamide at 0.7 mg/day. Macaques were exposed to SHIV twice weekly for 6 weeks. Statistical analyses were used to compare outcome with eight untreated controls. Histological assessments were performed on skin biopsies collected near implantation sites. RESULTS: Median (range) tenofovir diphosphate level in PBMCs was 1519 (1068-1898) fmol/106 cells. All macaques with tenofovir alafenamide implants were protected against vaginal SHIV infection. In contrast, 7/8 controls were infected after a median of 4 SHIV exposures (P = 0.0047). Histological assessment of tissues near tenofovir alafenamide implant sites showed inflammation and necrosis in 5/6 animals, which were not evident by visual inspection. CONCLUSIONS: We demonstrated complete protection against vaginal SHIV infection with two implants releasing a total of 0.7 mg of tenofovir alafenamide per day. We also identified tenofovir diphosphate concentrations in PBMCs associated with complete vaginal protection. Consistent with previous findings, we observed adverse local toxicity and necrosis near the tenofovir alafenamide implant site. Improved tenofovir alafenamide implants that are safe and maintain high efficacy have the potential to provide long-lasting protection against vaginal HIV infection. |
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