Nonlinear Mixed-Effect Pharmacokinetic Modeling and Distribution of Doxycycline in Healthy Female Donkeys after Multiple Intragastric Dosing-Preliminary Investigation.
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SUBMITTER: Chapuis RJJ
PROVIDER: S-EPMC8300337 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Loop is an open-source automated insulin dosing system that allows users unrivaled control over system settings that affect future glucose prediction. Thousands use Loop, but little is known about those who discontinue. Methods: In a large observational study, 874 Loop participants completed surveys and provided glycemic data, 46 (5.3%) of those self-identified as discontinuing Loop use during the observation window, 45 completed a discontinued use survey, 22 provided system settings data, and 19 participated in semistructured interviews about their discontinuation. Qualitative data were transcribed, coded, and analyzed. Results: Older age and not trusting Loop were associated with discontinued use, although no other demographic or clinical characteristics were significant correlates. The most endorsed reasons were "I decided to try something else" (27.8%) followed by "It just didn't help as much as I thought it would" (22.2%). Qualitative analyses revealed prominent themes centered upon mental and emotional burden and adjusting settings. Other reasons for discontinued use included fear of disapproval of Loop use from diabetes provider, barriers to acquiring component devices, a desire to try new/different technologies, concerns that Loop could not accommodate specific exercise or low insulin dose regimens, and worry about Loop use during pregnancy. It was noted that burdens might be alleviated by enhanced technical assistance and expert guidance. Conclusions: Although the majority of individuals in the Loop observational study continued use, those who discontinued reported similar challenges. Technical support and education specific to setting calculations could expand Loop benefits, alleviate burden, and support sustained use among new Loop users. Clinical Trial Registration: clinicaltrials.gov (NCT03838900).
| S-EPMC9057870 | biostudies-literature
Project description:Doxycycline, a member of the tetracycline family, is a drug used as an antibiotic (dosage of 100?mg/day) and as an anti-inflammatory drug on the dosage of 20?mg twice a day, this use has Matrix Metalloproteinases (MMP) inhibitor action. Doxycycline is a calcium chelator and therefore interferes in bone remodeling. The main objective of this study was to evaluate the action of the drug doxycycline in the control of osteopenia. Sixty three Wistars rats were divided into 9 groups with n?=?7 each, as follow: the control group with doxycycline 10?mg/kg/day (C10), control with doxycycline 30?mg/kg/day (C30) and control (C), ovariectomized group with doxycycline 10?mg/kg/day (OVX10), ovariectomized with doxycycline 30?mg/kg/day (OVX30), and ovariectomized with water (OVX), sedentary group with 10?mg/kg/day (Se10), sedentary with doxycycline 30?mg/kg/day (Se30), and sedentary group with water (Se). Left femoral bone was used for bone densitometry, right femoral bone for histological analysis. The right tibia was intended for chemical quantifications, the total serum was used for cholesterol and calcium quantification. The length of the left femoral bone was measured after the densitometry analysis. Statistical analysis was performed using multivariate general linear model (ANOVA two factors with Bonferroni adjustment) and the TRAP analysis was subjected to normality test and then were subjected to nonparametric test, both with p?<?0.05 significance. Statistically significant differences were found, with better results for the groups exposed to the medication (10 and 30?mg/kg/day): Se vs. Se10 and Se vs. Se30 for BMC, quantification of magnesium, amount of cancellous bone in the distal portion; OVX vs. OVX10 for BMC, BMD and calcium in serum; OVX vs. OVX10 and OVX30 for quantification in proximal and distal portion of cancellous bone; Se vs. Se30 and OVX vs. OVX30 for immunostaining for TRAP, all results with minimum of p???0.05. Doxycycline had a deleterious effect on control groups and positive action for bone organization on female rats affected by bilateral ovariectomy-induced osteopenia and sedentary lifestyle.
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Project description:Background and objectivesModel-informed precision dosing (MIPD) frequently uses nonlinear mixed-effects (NLME) models to predict and optimize therapy outcomes based on patient characteristics and therapeutic drug monitoring data. MIPD is indicated for compounds with narrow therapeutic range and complex pharmacokinetics (PK), such as voriconazole, a broad-spectrum antifungal drug for prevention and treatment of invasive fungal infections. To provide guidance and recommendations for evidence-based application of MIPD for voriconazole, this work aimed to (i) externally evaluate and compare the predictive performance of a published so-called 'hybrid' model for MIPD (an aggregate model comprising features and prior information from six previously published NLME models) versus two 'standard' NLME models of voriconazole, and (ii) investigate strategies and illustrate the clinical impact of Bayesian forecasting for voriconazole.MethodsA workflow for external evaluation and application of MIPD for voriconazole was implemented. Published voriconazole NLME models were externally evaluated using a comprehensive in-house clinical database comprising nine voriconazole studies and prediction-/simulation-based diagnostics. The NLME models were applied using different Bayesian forecasting strategies to assess the influence of prior observations on model predictivity.ResultsThe overall best predictive performance was obtained using the aggregate model. However, all NLME models showed only modest predictive performance, suggesting that (i) important PK processes were not sufficiently implemented in the structural submodels, (ii) sources of interindividual variability were not entirely captured, and (iii) interoccasion variability was not adequately accounted for. Predictive performance substantially improved by including the most recent voriconazole observations in MIPD.ConclusionOur results highlight the potential clinical impact of MIPD for voriconazole and indicate the need for a comprehensive (pre-)clinical database as basis for model development and careful external model evaluation for compounds with complex PK before their successful use in MIPD.
| S-EPMC10520167 | biostudies-literature
Project description:Dapagliflozin is a sodium-glucose co-transporter 2 inhibitor in development for the treatment of type 2 diabetes mellitus. A semi-mechanistic population pharmacokinetic (PK) model was developed for dapagliflozin and its inactive metabolite dapagliflozin 3-O-glucuronide (D3OG) with emphasis on renal and hepatic contribution to dapagliflozin metabolism. Renal and hepatic impairment decreased the clearance of dapagliflozin to D3OG and the clearance of D3OG. The fraction of D3OG formed via the renal route decreased from 40-55% in subjects with normal renal function (creatinine clearance (CLcr) > 80 ml/min) to 10% in subjects with severe renal insufficiency (CLcr = 13 ml/min). The model-based simulations suggested that the increase of systemic exposure (AUCss) of dapagliflozin and D3OG was less than twofold in subjects with mild or moderate renal impairment. This population modeling analysis presents a useful approach to evaluate the impact of renal and hepatic function on the PK of dapagliflozin.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e42; doi:10.1038/psp.2013.20; advance online publication 8 May 2013.
| S-EPMC3674329 | biostudies-literature
Project description:ObjectivesWe evaluated the efficacy of gold thread implantation (GTI) in the vulva and vagina to improve female sexual dysfunction (FSD) and vaginal laxity.MethodsA retrospective chart review was conducted on 46 women who underwent GTI between 2017 and 2018 at our institution. Physicians interviewed patients using questionnaires at baseline and 1-3 months post-treatment. The questionnaires consisted of eight questions: vaginal laxity, vaginal dryness, pain during intercourse, sexual satisfaction during intercourse, sexual arousal confidence, sexual satisfaction of partner, frequency, and maintaining lubrication.ResultsOverall, participants experienced significant improvement after GTI treatment (P < 0.0001). The median score of vaginal laxity was 3 (slightly loose) at baseline and 5 (slightly tight) at post-treatment. Vaginal dryness also improved from 4 (moderate) at baseline to 2 (little) at post-treatment. The degree of pain during intercourse decreased from 3 to 1. The sexual satisfaction score was 3 (moderately dissatisfied) at baseline and 4 (about equally satisfied and dissatisfied) at post-treatment. Sexual confidence of arousal increased from a score of 3 (low confidence) at baseline to 4 (moderate confidence) at post-treatment. They perceived greater partner sexual satisfaction, moving from a score of 2 to 4. Participants reported lubrication was more frequent during sexual activity, which was maintained until completion of sexual activity. Both scores regarding lubrication increased from 3.5 at baseline to 5 at post-treatment.ConclusionsGTI may be an option for FSD and vaginal laxity.
| S-EPMC7475290 | biostudies-literature
Project description:OBJECTIVE:This study aims to demonstrate the effect of oral doxycycline on fecal microbiota of mice. Doxycycline is a common effector for control of gene expression using the tet-inducible system in transgenic mice. The effect of oral doxycycline on murine gut microbiota has not been reported. We evaluated the effect of doxycycline treatment by sequencing the V4 hypervariable region of the 16S rRNA gene from fecal samples collected during a 4 week course of treatment at a dose of 2 mg/ml in the drinking water. RESULTS:The fecal microbiota of treated animals were distinct from control animals; the decreased richness and diversity were characterized primarily by Bacteroides sp. enrichment. These effects persisted when the treatment was temporarily discontinued for 1 week. These data suggest that doxycycline treatment can induce significant dysbiosis, and its effects should be considered when used in animal models that are or maybe sensitive to perturbation of the gut microbiota.
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Project description:Immune check-point inhibitors are drugs that are markedly different from other anticancer drugs because of their indirect mechanisms of antitumoral action and their apparently random effect in terms of efficacy and toxicity. This marked pharmacodynamics variability in patients calls for reconsidering to what extent approved dosing used in clinical practice are optimal or whether they should require efforts for customization in outlier patients. To better understand whether or not dosing could be an actionable item in oncology, in this review, preclinical and clinical development of immune checkpoint inhibitors are described, particularly from the angle of dose finding studies. Other issues in connection with dosing issues are developed, such as the flat dosing alternative, the putative role therapeutic drug monitoring could play, the rise of combinatorial strategies, and pharmaco-economic aspects.
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Project description:High level arsenic exposure is associated with reproductive toxicity in experimental and observational studies; however, few data exist to assess risks at low levels. Even less data are available to evaluate the impact of low level arsenic exposure on human fecundity. Our aim in this pilot study was a preliminary evaluation of associations between low level drinking water arsenic contamination and female fecundity. This retrospective study was conducted among women previously recruited to a hospital-based case-control study of spontaneous pregnancy loss in Timiṣ County, Romania. Women (n=94) with planned pregnancies of 5-20 weeks gestation completed a comprehensive physician-administered study questionnaire and reported the number of menstrual cycles attempting to conceive as the time to pregnancy (TTP). Drinking water samples were collected from residential drinking water sources and we determined arsenic levels using hydride generation-atomic absorption spectrometry (HG-AAS). Multivariable Cox-proportional hazards regression with Efron approximation was employed to evaluate TTP as a function of drinking water arsenic concentrations among planned pregnancies, adjusted for covariates. There was no main effect for drinking water arsenic exposure, yet the conditional probability for pregnancy was modestly lower among arsenic exposed women with longer TTPs, relative to women with shorter TTPs, and relative to unexposed women. For example, 1µg/L average drinking water arsenic conferred 5%, 8%, and 10% lower likelihoods for pregnancy in the 6th, 9th, and 12th cycles, respectively (P=0.01). While preliminary, our results suggest that low level arsenic contamination in residential drinking water sources may further impair fecundity among women with longer waiting times; however, this hypothesis requires confirmation by a future, more definitive study.
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Project description:Early detection of cystitis in equine is essential to improve the prognosis and outcome of therapy. However, the conventional white light endoscopy is not sufficiently accurate for this purpose. Hence, this study evaluated chromoendoscopy as a recent diagnostic tool for cystitis in female donkeys. For this purpose, 5 apparently normal donkeys (control group) and 5 female donkeys with cystitis (diseased group) were used. Physical and rectal examinations, urine analysis, white light cystoscopy, methylene blue-based chromoendoscopy and histopathology were performed in all animals. Turbid urine exhibiting an alkaline pH and a significant (P = .02) increase in the numbers of RBCs and WBCs was observed in the diseased group compared to the control one. In the control group, white light cystoscopy showed a smooth pale pink glistening mucosa with two openings of the ureters and visible submucosal blood vessels. During chromocystoscopy, faint bluish discoloration of the mucosal surface with clearly visible submucosal blood vessels was detectable. These findings were correlated with the histopathological findings of the biopsies collected from the urinary bladder. In the diseased group, white-light cystoscopy showed clearly visible blood vessels, mildly hyperaemic mucosa in focal or diffuse forms and small vesicle formation. Chromocystoscopy revealed dark bluish oedematous and irregular mucosa either in a focal form or a diffuse form (marbled appearance) with deeply stained submucosal blood vessels. Histopathologically, the urothelium was hyperplastic with squamous metaplasia and the lamina propria was infiltrated with few leukocytes and congested blood vessels. Small bluish dots representing the absorbed methylene blue dye were seen in the inflamed areas against the lightly stained mucosa of the bladder. Severe diffuse necrotic cystitis was also seen with bacterial aggregations on the surface. Gram's staining revealed both gram positive bacilli and Gram positive coccobacilli. In conclusion, chromoendoscopy is a helpful tool for early diagnosis of cystitis in female donkeys and enables targeted biopsies, which improves the prognosis and outcome of therapy.
| S-EPMC6114856 | biostudies-literature
Project description:The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P < 0.01) and then backward deletion (P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.
| S-EPMC5328550 | biostudies-literature