Biology subjects

Doncel, G. F.

Publications and source records attributed to Doncel, G. F..

3 recordsLinked to original sources

bioRxiv2026

Formulation Development of Topical Inserts Containing Doxycycline and Doxycycline Combined with Tenofovir Alafenamide and Elvitegravir for the Prevention of Sexually Transmitted Infections

PurposeDespite advances in oral and injectable HIV prevention options and oral prophylaxis for sexually transmitted infections (STIs) of bacterial origin, there remains a critical need for effective on-demand topical (vaginal/rectal) products for pre- and post-exposure prophylaxis (PrEP and PEP). To fill this gap, we have developed single and first-in-kind multi-active topical inserts for bacterial STIs and HIV/STIs prevention. MethodsWe have formulated two different inserts, one containing doxycycline (DOX) at 10, 50, and 100mg doses for bacterial STI prevention, and a multipurpose prevention product (TED insert) that combines DOX (10mg) with the antiretrovirals tenofovir alafenamide (TAF; 20mg) and elvitegravir (EVG; 16mg) to target both bacterial STIs and HIV. ResultsInserts were manufactured through a simple, cost-effective process. Drug loading was within 95-105% of the labeled amount, confirming a robust manufacturing process. In vitro, they disintegrated within 10min with >95% drug release within 60min. The dissolution behavior of DOX inserts showed surface erosion but was affected by medium volume and drug amount. The inserts met key physicochemical targets: hardness (5-8kg), friability (<1%), moisture content (<2%), and osmolality (<550mOsm/kg). Based on 6-month storage stability, DOX inserts maintained their physicochemical properties, suggesting a shelf life of >2years. Preliminary 1-month stability of TED inserts under accelerated conditions showed preservation of their physicochemical properties. ConclusionThis study represents the first formulation development report on topical inserts containing DOX alone or in combination with antiretrovirals. Both inserts offer a novel, on-demand topical STI prevention option that supports flexible PrEP/PEP use by both women and men.

bioengineering↗

bioRxiv2025

MICRORNAS AS REGULATORS OF DRUG METABOLISM AND TRANSPORT IN PREGNANT AND LACTATING WOMEN

BackgroundPhysiological changes during pregnancy result in altered maternal drug metabolism that impacts efficacy and safety of therapeutics in pregnant women. Pregnancy induced hormonal, immunologic, or metabolic changes may also influence and alter drug disposition. Despite research efforts focused on pharmacokinetics of medications used in pregnant women in the past decade, knowledge gaps exist in understanding how pregnancy influences drug disposition and placental drug transporters. Moreover, there is a scarcity of research in understanding the safety and effectiveness of therapeutics in lactating women. This study aimed to determine the effect of pregnancy on levels of miRNAs regulating drug metabolizing enzymes and transporters (DMET). MethodsWe utilized longitudinal serum specimens collected in 3-month intervals from 88 women who became pregnant during follow-up in a large prospective study of hormonal contraception and HIV acquisition in Uganda and Zimbabwe. We used the HTG EdgeSeq platform coupled with Illumina sequencing to obtain the global miRNA transcriptome in paired specimens collected before, during and after pregnancy. To identify differentially expressed (DE) miRNAs that distinguish pregnancy from pre-conception or breastfeeding we used mixed effect model accounting for multiple samples from the pregnancy event and controlling for fixed effects of batch, country, Nugent score category and sexually transmitted infections. To identify hormonally regulated miRNAs independently associated with Box-Cox-transformed levels of progesterone (P4), {beta}-estradiol (E2), and sex-hormone binding protein (SHBG) we controlled in addition for age, pregnancy and breastfeeding P-values were corrected using the Benjamini-Hochberg false discovery rate (FDR). DMET-targeting miRNAs were identified using miRTarBase focusing on interactions verified by 3-UTR luciferase reporter assay and overlapped with DE miRNAs with FDR < 0.05. ResultsOf 140 DMET-targeting miRNAs among the 2079 miRNAs in the global peripheral blood transcriptome, 41 unique DMET-targeting miRNAs were found to be DE during pregnancy - 38 differentiating pregnancy from preconception and 9 differentiating pregnancy from breastfeeding. The 56 DMETs confirmed as targets of the DE miRNAs included 8 members of the ABC (ATP-binding cassette) transporter family, all abundantly expressed in the placenta, and 4 members of the cytochrome P450 Phase 1 enzyme family with major role in xenobiotics detoxification. The study also revealed a strong (FDR<0.05), predominantly positive association between specific DMET-targeting miRNAs and sex hormone-binding globulin (SHBG) levels, suggesting a miRNA-mediated downregulation of DMETs as SHBG levels rise during pregnancy. ConclusionThis research provides crucial insights into the molecular mechanisms underlying altered drug disposition in pregnant and lactating women, paving the way for improved therapeutic management and personalized medicine in these populations.

molecular biology↗

bioRxiv2025

Abnormal Vaginal Microbiota Associated with miRNA Targeting the HIV-Host Interactome

Understanding the molecular mechanisms underlying the ability of vaginal dysbiosis to alter the mucosal barrier to HIV acquisition is an essential step toward prevention. We hypothesized that micro(mi)-RNAs dysregulated by vaginal pathobiont bacteria epigenetically control host pathways exploited by the virus. The impact of these endogenous non-coding short RNAs on the anti-viral mucosal barrier function in the female reproductive tract is largely unknown. This study utilized cervicovaginal specimens collected during the luteal and follicular phase of the menstrual cycle along with data on age, race, ethnicity, education, and body mass index from 141 healthy reproductive-age women confirmed negative for sexually transmitted infections. Vaginal microbiota was classified by Nugent scoring. Shot-gun vaginal microbiome sequencing and metagenome taxonomic classification was performed on a subset of 21 women. Levels of miRNAs in exosomes isolated from cervicovaginal secretions were quantified using the EdgeSeq-NextGen global transcriptome platform. Differential expression (DE) was determined using R. Epigenetic target prediction was performed using MirTarBase. MiRNA profiles varied by both Nugent score categories (0-3 scores = normal, 4-6 = intermediate, and 7-10 = bacterial vaginosis, BV) and by metagenome classification. Higher microbiome diversity was associated with higher number of significantly dysregulated miRNAs (588 in BV compared to Nugent 0-3 versus 42 in Nugent 4-6 compared to Nugent 0-3, false discovery rate FDR<0.01) affecting over 400 experimentally validated genes targeted for post-transcriptional regulation. The miRNAs dysregulated by G. vaginalis-dominated compared to L. crispatus-dominated metagenomes included 24 DE miRNAs (92% overlap with BV by Nugent score) and 112 validated target genes. BV-dysregulated miRNA mediated the immunosuppressive effects of BV on cytokine levels previously associated with HIV acquisition risk. The gene ontology predictions based on BV-dysregulated miRNAs identified enrichment for 445 downregulated and 50 upregulated genes previously validated as part of the HIV-host interactome. miRNAs mediation revealed a mechanism of suppressed immunity by BV predictive of HIV risk. In conclusion, miRNAs dysregulated by vaginal dysbiosis may facilitate immune imbalance and cellular pathways associated with HIV risk.

molecular biology↗