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Antimicrobial Agents and Chemotherapy Mar 2020The purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of... (Clinical Trial)
Clinical Trial
The purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of fosamprenavir) and ritonavir intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy and postpartum. Plasma concentrations of amprenavir and ritonavir were measured using high-performance liquid chromatography. The target amprenavir area under the concentration-versus-time curve (AUC) was higher than the 10th percentile (27.7 μg · h/ml) of the median area under the curve for ritonavir-boosted fosamprenavir in adults receiving twice-daily fosamprenavir-ritonavir at 700 mg/100 mg. Twenty-nine women were included in the analysis. The amprenavir AUC from time zero to 12 h (AUC) was lower (geometric mean ratio [GMR], 0.60 [confidence interval {CI}, 0.49 to 0.72] [ < 0.001]) while its apparent oral clearance was higher (GMR, 1.68 [CI, 1.38 to 2.03] [ < 0.001]) in the third trimester than postpartum. Similarly, the ritonavir AUC was lower in the second (GMR, 0.51 [CI, 0.28 to 0.91] [ = 0.09]) and third (GMR, 0.72 [CI, 0.55 to 0.95] [ = 0.005]) trimesters than postpartum, while its apparent oral clearance was higher in the second (GMR, 1.98 [CI, 1.10 to 3.56] [ = 0.06]) and third (GMR, 1.38 [CI, 1.05 to 1.82] [ = 0.009]) trimesters than postpartum. The amprenavir area under the curve exceeded the target for 6/8 (75%) women in the 2nd trimester, 18/28 (64%) in the 3rd trimester, and 19/22 (86.4%) postpartum, and the trough concentrations () of amprenavir were 4- to 16-fold above the mean amprenavir-protein-adjusted 50% inhibitory concentration (IC) of 0.146 μg/ml. Although amprenavir plasma concentrations in women receiving ritonavir-boosted fosamprenavir were lower during pregnancy than postpartum, the reduced amprenavir concentrations were still above the exposures needed for viral suppression.
Topics: Adult; Area Under Curve; Carbamates; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Maternal Age; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimesters; RNA, Viral; Ritonavir; Sulfonamides; Viral Load
PubMed: 32015036
DOI: 10.1128/AAC.02260-19 -
Expert Opinion on Therapeutic Patents Jul 2018Sulfonamide compounds are significant class of synthetic bacteriostatic antibiotics still which used today for the therapy of bacterial infections and those caused by... (Review)
Review
INTRODUCTION
Sulfonamide compounds are significant class of synthetic bacteriostatic antibiotics still which used today for the therapy of bacterial infections and those caused by other microorganisms. They are also known as sulfa drugs and were the main source of therapy against bacterial infections before the introduction of penicillin in 1941. Additionally, The first sulfonamide section is present inmany clinically used drugs such as diuretics, carbonic anhydrase inhibitors and antiepileptics.
AREAS COVERED IN THIS REVIEW
The article presents the main classes of sulfonamide inhibitors investigated between 2013 and present. Specifically, the authors review the scientific and patent literature on tyrosine kinase, human immunodeficieny virus protease-1 (HIV‑1), histone deacetylase 6, protein tyrosine phosphatase 1B, sphingosine kinase, phosphatidyl inositol 3-kinase, angiogenesis, pyrazole kinase, tyrosyl DNA phosphodiesterase inhibitors were evaluated. Expert opinion: Sulfonamides are utilized as the antiviral HIV protease inhibitor amprenavir, as an anticancer agent, and in Alzheimer's disease drugs. All these data show that although known for more than 100 years, the primary sulfonamides constitute an important class of compounds which leads to highly valuable drugs and drug candidates for many conditions, such as cancer, glaucoma, inflammation, dandruff, just to mention the most investigated ones.
Topics: Alzheimer Disease; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Antineoplastic Agents; Drug Design; Humans; Patents as Topic; Sulfonamides
PubMed: 29886770
DOI: 10.1080/13543776.2018.1487400 -
International Journal of Molecular... Apr 2023Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett's esophagus (BE) and...
Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs in the world, but do not protect against nonacid components of reflux such as pepsin, or prevent reflux-associated carcinogenesis. We recently identified an HIV protease inhibitor amprenavir that inhibits pepsin and demonstrated the antireflux therapeutic potential of its prodrug fosamprenavir in a mouse model of laryngopharyngeal reflux. In this study, we assessed the capacity of amprenavir to protect against esophageal epithelial barrier disruption in vitro and related molecular events, E-cadherin cleavage, and matrix metalloproteinase induction, which are associated with GERD severity and esophageal cancer. Herein, weakly acidified pepsin (though not acid alone) caused cell dissociation accompanied by regulated intramembrane proteolysis of E-cadherin. Soluble E-cadherin responsive matrix metalloproteinases (MMPs) were transcriptionally upregulated 24 h post-treatment. Amprenavir, at serum concentrations achievable given the manufacturer-recommended dose of fosamprenavir, protected against pepsin-induced cell dissociation, E-cadherin cleavage, and MMP induction. These results support a potential therapeutic role for amprenavir in GERD recalcitrant to PPI therapy and for preventing GERD-associated neoplastic changes.
Topics: Animals; Mice; Pepsin A; Protease Inhibitors; Quality of Life; Esophageal Neoplasms; Enzyme Inhibitors; Laryngopharyngeal Reflux; Proton Pump Inhibitors
PubMed: 37047737
DOI: 10.3390/ijms24076765 -
Laryngoscope Investigative... Aug 2023Laryngopharyngeal reflux (LPR) causes chronic cough, throat clearing, hoarseness, and dysphagia and can promote laryngeal carcinogenesis. More than 20% of the US...
BACKGROUND
Laryngopharyngeal reflux (LPR) causes chronic cough, throat clearing, hoarseness, and dysphagia and can promote laryngeal carcinogenesis. More than 20% of the US population suffers from LPR and there is no effective medical therapy. Pepsin is a predominant source of damage during LPR which disrupts laryngeal barrier function potentially via E-cadherin cleavage proteolysis and downstream matrix metalloproteinase (MMP) dysregulation. Fosamprenavir (FDA-approved HIV therapeutic and prodrug of amprenavir) is a pepsin-inhibiting LPR therapeutic candidate shown to rescue damage in an LPR mouse model. This study aimed to examine amprenavir protection against laryngeal monolayer disruption and related E-cadherin proteolysis and MMP dysregulation in vitro.
METHODS
Laryngeal (TVC HPV) cells were exposed to buffered saline, pH 7.4 or pH 4 ± 1 mg/mL pepsin ± amprenavir (10-60 min). Analysis was performed by microscopy, Western blot, and real time polymerase chain reaction (qPCR).
RESULTS
Amprenavir (1 μM) rescued pepsin acid-mediated cell dissociation ( < .05). Pepsin acid caused E-cadherin cleavage indicative of regulated intramembrane proteolysis (RIP) and increased 24-h postexposure ( < .05). Acid alone did not cause cell dissociation or E-cadherin cleavage. Amprenavir (10 μM) protected against E-cadherin cleavage and induction ( < .05).
CONCLUSIONS
Amprenavir, at serum concentrations achievable provided the manufacturer's recommended dose of fosamprenavir for HIV, protects against pepsin-mediated cell dissociation, E-cadherin cleavage, and MMP dysregulation thought to contribute to barrier dysfunction and related symptoms during LPR. Fosamprenavir to amprenavir conversion by laryngeal epithelia, serum and saliva, and relative drug efficacies in an LPR mouse model are under investigation to inform development of inhaled formulations for LPR.
PubMed: 37621274
DOI: 10.1002/lio2.1102 -
Endocrinology and Metabolism Clinics of... Sep 2014Molecular mechanisms behind the defects in insulin production and secretion associated with antihuman immunodeficiency virus (anti-HIV) therapy and the development of... (Review)
Review
Molecular mechanisms behind the defects in insulin production and secretion associated with antihuman immunodeficiency virus (anti-HIV) therapy and the development of HIV-associated lipodystrophy syndrome (HALS) are discussed in this article. Data suggesting insulin resistance on the beta cell and defects in first-phase insulin release of HALS patients are presented. Hepatic extraction of insulin, nonglucose insulin secretagogues and insulin-like growth factor release may exert influence on the demand of circulating insulin and on insulin secretion in HIV-infected patients. Finally, the paucity in understanding the incretin effects in HIV and HIV therapy in relation to insulin secretion is highlighted.
Topics: Carbamates; Furans; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Nelfinavir; Ritonavir; Sulfonamides
PubMed: 25169562
DOI: 10.1016/j.ecl.2014.06.004 -
Pharmaceutics Feb 2023It has been seventy years since a water-soluble version of vitamin E called tocophersolan (also known as TPGS) was produced; it was approved by USFDA in 1998 as an... (Review)
Review
It has been seventy years since a water-soluble version of vitamin E called tocophersolan (also known as TPGS) was produced; it was approved by USFDA in 1998 as an inactive ingredient. Drug formulation developers were initially intrigued by its surfactant qualities, and gradually it made its way into the toolkit of pharmaceutical drug delivery. Since then, four drugs with TPGS in their formulation have been approved for sale in the United States and Europe including ibuprofen, tipranavir, amprenavir, and tocophersolan. Improvement and implementation of novel diagnostic and therapeutic techniques for disease are goals of nanomedicine and the succeeding field of nanotheranostics. Specifically, imaging and treating tumors with nanohybrid theranostics shows promising potential. Docetaxel, paclitaxel, and doxorubicin are examples of poorly bioavailable therapeutic agents; hence, much effort is applied for developing TPGS-based nanomedicine, nanotheranostics, and targeted drug delivery systems to increase circulation time and promote the reticular endothelial escape of these drug delivery systems. TPGS has been used in a number of ways for improving drug solubility, bioavailability improvement, and prevention of drug efflux from the targeted cells, which makes it an excellent candidate for therapeutic delivery. Through the downregulation of P-gp expression and modulation of efflux pump activity, TPGS can also mitigate multidrug resistance (MDR). Novel materials such as TPGS-based copolymers are being studied for their potential use in various diseases. In recent clinical trials, TPGS has been utilized in a huge number of Phase I, II, and III studies. Additionally, numerous TPGS-based nanomedicine and nanotheranostic applications are reported in the literature which are in their preclinical stage. However, various randomized or human clinical trials have been underway for TPGS-based drug delivery systems for multiple diseases such as pneumonia, malaria, ocular disease, keratoconus, etc. In this review, we have emphasized in detail the review of the nanotheranostics and targeted drug delivery approaches premised on TPGS. In addition, we have covered various therapeutic systems involving TPGS and its analogs with special references to its patent and clinical trials.
PubMed: 36986583
DOI: 10.3390/pharmaceutics15030722 -
Drug Metabolism and Disposition: the... Mar 2020Organic anion transporting polypeptides (OATPs), expressed in human liver (OATP1B1, OATP1B3, and OATP2B1) and intestine (OATP2B1), govern the pharmacokinetics (PK) of... (Review)
Review
Organic anion transporting polypeptides (OATPs), expressed in human liver (OATP1B1, OATP1B3, and OATP2B1) and intestine (OATP2B1), govern the pharmacokinetics (PK) of drugs (e.g., statins) and endogenous substrates (e.g., coproporphyrin I [CPI]). Their expression is known to be modulated (e.g., disease, age, and environmental factors), and they also present as the loci of clinically relevant polymorphisms and drug interactions involving inhibition. In comparison, relatively few clinical reports describe the induction of OATPs, although the effect of inducers (e.g., rifampicin [RIF], carbamazepine [CBZ]) on OATP biomarker plasma levels and statin PK has been reported. Of note, available human tissue (e.g., biopsy) protein and messenger RNA expression profiling data indicate that OATPs in gut and liver are not induced by prototypical inducers such as RIF when compared with cytochrome P450 3A4 (CYP3A4), P-glycoprotein (Pgp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP). Such results are consistent with in vitro human hepatocyte data. Therefore, the observed impact of RIF, and possibly CBZ, on statin PK (>20% decrease in the area under the plasma concentration vs. time curve) cannot be ascribed to OATP induction with certainty. In fact, most statins and CPI have been shown to present variously as substrates of RIF-inducible proteins such as CYP3A4, Pgp, MRP2, and BCRP. Interpretation of multidose RIF data is further complicated by its autoinduction, which likely leads to decreased inhibition of OATP. In the absence of more conclusive OATP induction data, caution is needed when modeling drug-drug interactions involving multidose inducers such as RIF. SIGNIFICANCE STATEMENT: Presently, there is limited direct clinical evidence supporting the notion that human liver and gut organic anion transporting polypeptides (OATPs) are inducible by agents like rifampicin (RIF). Such data need to be reconciled and will pose challenges for attempting to incorporate OATP induction into physiologically based pharmacokinetics models. Although disparate sets of tissue biopsy (atorvastatin and carbamazepine) and in vitro hepatocyte (phenobarbital, chenodeoxycholate, and amprenavir) data present OATP messenger RNA induction (≥2-fold) by agents beyond RIF, the clinical relevance of such data needs to be determined.
Topics: Animals; Drug Interactions; Hepatocytes; Humans; Intestines; Liver; Organic Anion Transporters; Pharmaceutical Preparations
PubMed: 31879282
DOI: 10.1124/dmd.119.089615 -
The Laryngoscope Jan 2023More than 20% of the US population suffers from laryngopharyngeal reflux. Although dietary/lifestyle modifications and alginates provide benefit to some, there is no...
OBJECTIVE
More than 20% of the US population suffers from laryngopharyngeal reflux. Although dietary/lifestyle modifications and alginates provide benefit to some, there is no gold standard medical therapy. Increasing evidence suggests that pepsin is partly, if not wholly, responsible for damage and inflammation caused by laryngopharyngeal reflux. A treatment specifically targeting pepsin would be amenable to local, inhaled delivery, and could prove effective for endoscopic signs and symptoms associated with nonacid reflux. The aim herein was to identify small molecule inhibitors of pepsin and test their efficacy to prevent pepsin-mediated laryngeal damage in vivo.
METHODS
Drug and pepsin binding and inhibition were screened by high-throughput assays and crystallography. A mouse model of laryngopharyngeal reflux (mechanical laryngeal injury once weekly for 2 weeks and pH 7 solvent/pepsin instillation 3 days/week for 4 weeks) was provided inhibitor by gavage or aerosol (fosamprenavir or darunavir; 5 days/week for 4 weeks; n = 3). Larynges were collected for histopathologic analysis.
RESULTS
HIV protease inhibitors amprenavir, ritonavir, saquinavir, and darunavir bound and inhibited pepsin with IC in the low micromolar range. Gavage and aerosol fosamprenavir prevented pepsin-mediated laryngeal damage (i.e., reactive epithelia, increased intraepithelial inflammatory cells, and cell apoptosis). Darunavir gavage elicited mild reactivity and no discernable protection; aerosol protected against apoptosis.
CONCLUSIONS
Fosamprenavir and darunavir, FDA-approved therapies for HIV/AIDS, bind and inhibit pepsin, abrogating pepsin-mediated laryngeal damage in a laryngopharyngeal reflux mouse model. These drugs target a foreign virus, making them ideal to repurpose. Reformulation for local inhaled delivery could further improve outcomes and limit side effects.
LEVEL OF EVIDENCE
NA. Laryngoscope, 133:S1-S11, 2023.
Topics: Animals; Mice; Laryngopharyngeal Reflux; Larynx; Pepsin A; Sulfonamides; Carbamates; Furans
PubMed: 35678265
DOI: 10.1002/lary.30242