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Sofosbuvir (SOF) is a P-glycoprotein (P-gp) substrate, and carvedilol (CAR) is an inhibitor of P-gp, suggesting that it may affect the oral pharmacokinetics and safety of SOF. The current study investigated the pharmacokinetic interaction of CAR with SOF and its metabolite, GS-331007, and the possible consequent toxicities in rats. To assess the pharmacokinetics of SOF and GS-331007, rats were divided into three groups; all received a single oral dose of SOF preceded with saline (SAL), verapamil (VER) as a standard P-gp inhibitor, or CAR, respectively. The serosal, plasma, and hepatic tissue contents of SOF and GS-331007 were assessed using LC-MS/MS. Renal and hepatic toxicities were assessed using biochemical and histopathological tests. Serosal and plasma concentrations of SOF and GS-331007 were increased in the presence of CAR, suggesting a significant inhibitory effect of CAR on intestinal P-gp. Simultaneously, the pharmacokinetic profile of SOF showed a significant increase in the Cmax, AUC(0-t), AUC (0-∞), t1/2, and a reduction in its apparent oral clearance. While the pharmacokinetic profile of GS-331007 was not significantly affected. However, this notable elevation in drug oral bioavailability was corroborated by a significant alteration in renal functions. Hence, further clinical investigations are recommended to ensure the safety and dosing of CAR/SOF combination. [ABSTRACT FROM AUTHOR]

This article discusses a case of virological failure in a woman with HIV who switched to long-acting cabotegravir and rilpivirine (LACR) treatment. The woman had a high BMI and underwent weight loss surgery, which may have affected the drug's effectiveness. Despite drug deposits in the adipose tissue, the drug concentrations were above the target. The reasons for the virological failure are unclear, but it may be due to inadequate drug distribution or sanctuary penetration. The patient ultimately switched back to oral antiretroviral therapy to avoid further virological failure. [Extracted from the article]

Atherosclerosis (AS), an inflammatory disease characterized by lipid accumulation, has a high global incidence and mortality rate. Recently, nanotherapeutic approaches that target pathological sites and improve drug bioavailability and biocompatibility hold great promise for AS treatment. In this study, a biomimetic ROS-responsive hyaluronic acid–based nanomaterial was prepared for targeted anti-AS. Specifically, a safe ROS-responsive carrier based on hyaluronic acid (HSP) was prepared to load methotrexate (MTX), a drug known for its ability to enhance lipid excretion, resulting in the formation of MTX-loaded nanoparticles (MTXNPs). Furthermore, the macrophage membrane was coated on the surface of MTXNPs to obtain MM/MTXNPs. Both MTXNPs and MM/MTXNPs exhibited ROS responsiveness and demonstrated excellent biocompatibility. In vitro experiments revealed that MM/MTXNPs could evade macrophage phagocytosis and exhibited high uptake rates by inflamed endothelial cells. MM/MTXNPs also reduced lipid accumulation in foam cells. In vivo experiments showed that MM/MTXNPs exhibited superior accumulation at AS plaque sites, facilitated by the surface membrane layer containing integrin α4β1 and CD47, resulting in an enhanced therapeutic effect in inhibiting plaque development compared to free MTX and MTXNPs. Therefore, HSP represents a promising nanocarrier to load hydrophobic MTX, enabling effective and biocompatible enhancement of AS treatment. [ABSTRACT FROM AUTHOR]

Omics data from clinical samples are the predominant source of target discovery and drug development. Typically, hundreds or thousands of differentially expressed genes or proteins can be identified from omics data. This scale of possibilities is overwhelming for target discovery and validation using biochemical or cellular experiments. Most of these proteins and genes have no corresponding drugs or even active compounds. Moreover, a proportion of them may have been previously reported as being relevant to the disease of interest. To facilitate translational drug discovery from omics data, we have developed a new classification tool named O mics and T ext driven T ranslational M edicine (OTTM). This tool can markedly narrow the range of proteins or genes that merit further validation via drug availability assessment and literature mining. For the 4489 candidate proteins identified in our previous proteomics study, OTTM recommended 40 FDA-approved or clinical trial drugs. Of these, 15 are available commercially and were tested on hepatocellular carcinoma Hep-G2 cells. Two drugs—tafenoquine succinate (an FDA-approved antimalarial drug targeting CYC1) and branaplam (a Phase 3 clinical drug targeting SMN1 for the treatment of spinal muscular atrophy)—showed potent inhibitory activity against Hep-G2 cell viability, suggesting that CYC1 and SMN1 may be potential therapeutic target proteins for hepatocellular carcinoma. In summary, OTTM is an efficient classification tool that can accelerate the discovery of effective drugs and targets using thousands of candidate proteins identified from omics data. The online and local versions of OTTM are available at http://otter-simm.com/ottm.html. [ABSTRACT FROM AUTHOR]

Background The use of oral antimicrobial agents in patients with short bowel syndrome (SBS) is challenging due to the changes in gastrointestinal anatomy that may result in diminished absorption and altered drug bioavailability. Prospective studies evaluating bioavailability of antimicrobial agents after oral administration in SBS patients are lacking. Objectives To determine the bioavailability of orally administered antimicrobial agents commonly used for treatment in SBS patients to guide clinical decision making when faced with infections. Methods We performed an explorative, clinical study investigating the pharmacokinetics (PK) of clindamycin, ciprofloxacin, flucloxacillin and fluconazole in SBS patients with intestinal failure. Participants received a combination of two antimicrobial agents simultaneously. To determine the oral bioavailability, participants received a single oral and IV dose of both agents on two occasions, after which they underwent intensive PK sampling on six predefined time points up to 12 hours after administration. Primary outcome was the oral bioavailability of these antimicrobial agents. Secondary outcomes were intravenous PK characteristics following non-compartmental analysis. Results Eighteen SBS patients were included: the mean (SD) age was 59 (17) years and 61% of participants were female. The median observed (IQR) bioavailability of ciprofloxacin, clindamycin, flucloxacillin and fluconazole were 36% (24–50), 93% (56–106), 50% (32–76) and 98% (61–107), respectively. Conclusion The bioavailability of selected antimicrobial agents in certain patients with SBS appeared to be better than expected, providing a feasible treatment option. Due to the large observed differences between patients, therapeutic drug monitoring should be part of the treatment to safeguard adequate exposure in all patients. Trial registration Registered in the Dutch Trial Register (NL7796) and EudraCT number 2019-002587-28 [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is a conventional synthetic disease-modifying antirheumatic drug, which is used in the treatment of rheumatoid arthritis. However, insufficient responses to oral MTX at lower doses as well as increased variation of drug bioavailability and a deteriorated safety profile during dose escalation are regularly observed in patients. Some of its main side effects may be overcome by temporary drug hiatus or dose reduction or can be counterbalanced with folic acid. Especially gastrointestinal side effects are a major reason for permanent treatment discontinuation. Recent data suggest that MTX in a subcutaneous injection formulation can reduce gastrointestinal effects and thus may allow us to overcome oral intolerance and improve drug survival. Here, we review the currently available literature on the efficacy and safety of subcutaneous MTX in comparison to oral MTX in the treatment of patients with rheumatoid arthritis. Despite some inconsistency between data, an improvement in the efficacy and/or safety profile of subcutaneous MTX has been demonstrated. In the USA, subcutaneous MTX is an established second-line treatment already, while in European countries this formulation is even recommended as a first-line treatment. With the recent approval of subcutaneous MTX in Japan, another beneficial treatment option is now available for Japanese patients with rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are a major global health burden particularly with the increasing ageing population. Hereditary predisposition and environmental risk factors contribute to the heterogeneity of existing pathological phenotypes. Traditional clinical interventions focused on the use of small drugs have often led to failures due to the difficulties in crossing the blood–brain barrier and reaching the brain. In this regard, nanosystems can specifically deliver drugs and improve their bioavailability, overcoming some of the major challenges in neurodegenerative disease treatment. This review focuses on the use of nanosystems as an encouraging therapeutic approach targeting molecular pathways involved in localized and systematic neurodegenerative diseases. Among the latter, Friedreich's ataxia is an untreatable complex multisystemic disorder and the most widespread type of ataxia; it represents a test case to validate the clinical potential of therapeutic strategies based on nanoparticles with pleiotropic effects. [ABSTRACT FROM AUTHOR]

A recent study published in the Journal of Clinical Endocrinology & Metabolism examined the impact of tumor fibrosis on surgical outcomes for patients with prolactinomas. The study found that patients who were pretreated with dopamine agonists (DAs) had more extensive tumor fibrosis, higher rates of surgical complications, and lower rates of surgical remission for microadenomas. While DAs are effective in treating prolactinomas, they can induce tumor fibrosis, making surgical removal more challenging and reducing the chances of surgical cure. The study suggests that upfront surgical resection may be a better alternative in certain cases, but patient choice should also be considered. [Extracted from the article]

In an on‐going investigation of bioactive metabolites producing potential endophytic fungi, the strain Lasiodiplodia theobromae (SJF‐1) was isolated from a medicinal plant Syzygium cumini. The cultural, morphological and molecular identification was done with the SJF‐1 strain. The obtained gene sequence was deposited in NCBI with accession number MG 938644. The methanolic extract of SJF‐1 strain possessed one major bioactive fraction, and it was purified by column chromatography. Further, it was identified as Mellein by various spectroscopic studies (1H, 13C, DEPT‐135°, FT‐IR, ESI‐HR‐MS and 2D NMR). Biologically, Mellein showed potent anti‐Xanthomonas activity with minimum inhibitory concentration (MIC) values ranging from 1·9 to 62·5 μg ml−1 against 11 Xanthomonas strains, a broad‐spectrum antimicrobial activity with MIC 7·8–31·25 μg ml−1 and 1·9–31·25 μg ml−1 towards both bacterial and fungal strains, respectively. The scanning electron microscope analysis proved the antimicrobial efficacy of a Mellein by rupturing the cell walls of Xanthomonas sp. Molecular docking studies further supported that the Mellein showed good binding interactions with the proteins of Xanthomonas sp. to reduce pathogenicity. Further, in silico pharmacological studies showed that this metabolite exhibited high gastrointestinal absorption properties and promising oral drug bioavailability. We report, anti‐Xanthomonas, in silico docking and pharmacological studies of Mellein from (SJF‐1) strain for the first time. [ABSTRACT FROM AUTHOR]

Background: Egypt has aimed to treat 250000 people annually up to 2020 in the first phase of their treatment program aiming at reducing the number of viremic patients, thus limiting the ongoing HCV transmission. Egypt is struggling to eliminate HCV and HCV-related morbidity by 2030. Aim and Objectives: to measure the frequency rate of HCV infection among ESRD patients and identify the reasons of un-treatment among those who were offered the treatment free of charge. Subjects and Methods: This multi-center cross sectional study included 500 patients receiving hemodialysis sessions on regular basis for more than 3 months in Dakahlia Governorate, patient recruitment from November 2022 to April 2023. Result: According to patients' medical history we found that, 23.4% of patients had previous HCV infection from them 12.6% received treatment and 10.8% didn't receive treatment due to several causes as one patient didn't know about the drug availability, five patients (1%) fear from occurrence of side effects, 43 patients (8.6%) didn't need treatment and five patients (1%) had other causes as had contraindication of drugs, non-compliance and deterioration of health status. Also, 20.4% of patients had been informed that they completely recovered and 0.8% had recurrence. After investigations, 1% of patients had positive HbsAg, 23.4% had positive HCV Ab, 4.2% positive HCV PCR. Conclusion: The low prevalence of HCV among hemodialysis patients of HCV in HD patients confirm that HCV infection doesn't become a major health problem among patients on maintenance HD. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in the Comprehensive in vitro Proarrhythmia Assay (CiPA). The notable difference of the electrophysiological (EP) responses of hiPSC-CMs in serum and serum-free media (SFM) is puzzling and may impact regulatory decision-making on the cardiac safety of candidate drugs in inducing QT prolongation and torsade de pointes (TdP). In this study, we compared the EP responses of hiPSC-CMs to 10 CiPA compounds and moxifloxacin in serum and SFM; explained the potential reason behind the different EP responses—abiotic compound loss to plastic tubes/plates of hydrophobic compounds prepared in SFM; and investigated the impact of compound preparation methods on drug bioavailability in exposure media, which affects the TdP risk prediction of drugs tested in serum-containing and SFM. For assays to be conducted in SFM, awareness of abiotic compound loss of hydrophobic compounds in serum-free preparations is critical for delay repolarization evaluation and data extrapolation from in vitro to in vivo. [ABSTRACT FROM AUTHOR]

Summary: Background: Evidence demonstrates that parenteral administration of methotrexate (MTX) has a higher drug bioavailability than oral administration. This difference is even more pronounced for medium to high dosages. Aim: To compare the efficacy, safety, and tolerability of oral and subcutaneous (SC) MTX for treatment of psoriasis. Methods: A randomized, comparative, single‐blind, 32‐week study was conducted. The clinical response was evaluated using the Psoriasis Area Severity Index (PASI) and patient global satisfaction was assessed using a visual analogue scale (VAS). Results: In total, 77 completed the study: 38 in the SC and 39 in the oral MTX group. No significant between‐group differences were found in the number attaining PASI improvement of 75% (PASI75), 90% (PASI90) and 100% (PASI100) at Weeks 16 and 32: PASI75 (P = 0.14 and P = 0.21, respectively), PASI90 (P = 0.23 and P = 0.18) and PASI100 (P = 0.62 and P = 0.22). According to the mean VAS, no significant differences between the groups were found at any time points except at Week 32 that the mean VAS was significantly higher in the SC group (P = 0.03). Adverse events were comparable in both groups. Conclusion: SC and oral administration of MTX had similar efficacies in improving the PASI score even at the highest tolerable dose; however, the SC MTX group had higher overall patient satisfaction than the oral MTX group. No difference in tolerability was found. [ABSTRACT FROM AUTHOR]

*Based on the available data the risk of statin-associated muscle symptoms with pitavastatin is similar to placebo [3]; #with low-to moderate intensity statin therapy; $ moderate intensity statin therapy for partial statin intolerance patients; **preferably with ezetimibe. We can consider four different scenarios when a patient presents with adverse effects that they perceive to be due to statin therapy, each requiring a different approach: (i) The adverse effect may be entirely unrelated to statin therapy. This enables the treatment regimen to be matched to the patients' needs at the outset, potentially commencing therapy with more than one drug, rather than starting the patient on a single drug, which could not conceivably enable them to reach treatment targets. [Extracted from the article]

Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by articular synovitis that eventually leads to the destruction of cartilage and bone in the joints with resulting pain and disability. The current therapies for RA are divided into 4 categories: non‐steroidal anti‐inflammatory drugs (NSAIDs), glucocorticoids, nonbiological disease‐modifying anti‐rheumatic drugs (DMARDs), and biological DMARDs. Each drug grouping is beset with significant setbacks that not only include limited drug bioavailability and high clearance, but also varying degrees of drug toxicity to normal tissues. Recently, nanotechnology has provided a promising tool for the development of novel therapeutic and diagnostic systems in the area of malignant and inflammatory diseases. Among these, magnetic nanoparticles (MNPs) have provided an attractive carrier option for delivery of therapeutic agents. Armed with an extra magnetic probe, MNPs are capable of more accurately targeting the local lesion with avoidance of unpleasant systemic side effects. This review aims to provide an introduction to the applications of magnetic nanoparticles in RA, focusing on the latest advances, challenges, and opportunities for future development. [ABSTRACT FROM AUTHOR]

Objectives: Grapefruit (Citrus paradisi) juice enhances the oral bioavailability of drugs that are metabolized by intestinal cytochrome P450 3A4 (CYP3A4). Patients are advised to avoid drinking grapefruit juice to prevent this drug–grapefruit juice interaction. The aim of this study was to investigate whether processing grapefruit juice with cyclodextrins (CDs) would result in preventing or inhibiting this interaction. Methods: Grapefruit juice and the major furanocoumarins found in grapefruit, bergamottin (BG) and 6′, 7′‐dihydroxy bergamottin (DHBG) were mixed with α, β and γCDs. The effects of these processed juice samples and furanocoumarins on CYP3A activity were compared with the corresponding values for unprocessed juices and furanocoumarins. Interactions between CDs and these furanocoumarins were also investigated by phase solubility and 1H NMR studies. Key findings: The inhibition of CYP3A by grapefruit juice was significantly attenuated by processing particularly with γCD. Similar attenuation effects by γCD were observed in the cases of BG and DHBG. Furthermore, BG and DHBG were suggested to be strongly encapsulated in the cavity of γCD. Conclusion: The encapsulation of BG and DHBG by γCD and the resulting attenuation of the inhibition of CYP3A activity by grapefruit juice may be applicable to juice processing for preventing drug‐grapefruit juice interactions. [ABSTRACT FROM AUTHOR]

Introduction: Oral phosphodiesterase type 5 inhibitor (PDE5i) is recognized as an effective first-line medical therapy for males with erectile dysfunction. However, oral PDE5i drug adherence and satisfaction rates were not high due to the need for oral ingestion, lack of sexual spontaneity, and delay in time to clinical effect. Hence, a nasal delivery of PDE5i drug may circumvent these limitations. Objective: To assess the bioavailability and safety profile of SDS-089 nasal Vardenafil spray compared to oral Vardenafil 10mg tablet. Methods: Following approval from Institutional Review Board and Biosafety Committee (FB18/IRB/099), 13 subjects out of the 32 healthy volunteers met the study criteria and were randomized to receive SDS-089 nasal Vardenafil spray (4 mg) or oral Vardenafil tablet (10 mg). The vardenafil HCl formulation SDS-089 was prepared with the active pharmaceutical ingredient meeting the United States Pharmacopeia (USP) standard (batch 1704002361). Blood tests were conducted on the subjects to evaluate Vardenafil drug bioavailability and treatment-related adverse events (TRAEs) data was collected. Results: All 13 subjects completed the study. Based on the drug pharmacokinetics data, SDS-089 nasal spray was shown to have a faster onset and achieve optimal dose with a lower amount of drug compared to oral formulation. Of the 42 recorded TRAEs, 33 TRAEs were associated with the nasal spray, and 9 TRAEs were related to oral drugs. Transient headache is the most common TRAE in the nasal group and was very tolerable. The reported headaches showed no relationship with Cmax (peak concentration) and AUC0-inf (the total drug exposure across time) based on the Vardenafil drug levels. Conclusions: SDS-089 nasal spray formulation Vardenafil HCl at 4 mg successfully achieved a similar Cmax with that of oral Vardenafil 10 mg tablet, and while it appeared to have more TRAEs, these were transient and well-tolerated by the subjects. Disclosure: Yes, this is sponsored by industry/sponsor: LTR Pharma. Clarification: Industry funding only - investigator initiated and executed study. [ABSTRACT FROM AUTHOR]

Objective: Pulmonary delivery is an effective way to improve the bioavailability of drugs with extensive metabolism. This research was designed to study the different pharmacokinetic behaviours of small molecule drug after pulmonary delivery and intragastric (i.g) administration. Methods: Raloxifene, a selective estrogen receptor modulator with low oral bioavailability (~2%), was chosen as the model drug. Studies were conducted systematically in rats, including plasma pharmacokinetics, excretion, tissue distribution and metabolism. Key findings: Results showed that raloxifene solution dosed by intratracheal (i.t) administration exhibited relatively quick plasma elimination (t1/2 = 1.78 ± 0.14 h) and undetected absorption process, which was similar with intravenous injection. Compared with i.g administration, the bioavailability increased by 58 times, but the major route of excretion remained faecal excretion. Drug concentration on the bone and the target efficiency were improved by 49.6 times and five times, respectively. Benefited from quick elimination in the lung, chronic toxicity might be ignored. Conclusions: Pulmonary administration improved the bioavailability of raloxifene and further increased the distribution on the target organ (bone), with no obvious impact on its excretory pattern. [ABSTRACT FROM AUTHOR]

Objectives: Co‐ingestion of oral dosage forms with meals can cause substantial changes in bioavailability relative to the fasted state. Food‐mediated effects on bioavailability can have significant consequences in drug development, regulatory and clinical settings. To date, the primary focus of research has focused on the ability to mechanistically understand the causes and predict the occurrence of these effects. Key findings: The current review describes the mechanisms underpinning the occurrence of food effects, sheds new insights on the relative frequency for newly licensed medicines and describes the various methods by which they can be overcome. Analysis of oral medicines licensed by either the EMA or FDA since 2010 revealed that over 40% display significant food effects. Due to altered bioavailability, these medicines are often required to be dosed, rather restrictively, in either the fed or the fasted state, which can hinder clinical usefulness. Summary: There are clinical and commercial advantages to predicting the presence of food effects early in the drug development process, in order to mitigate this risk of variable food effect bioavailability. Formulation approaches aimed at reducing variable food‐dependent bioavailability, through the use of bio‐enabling formulations, are an essential tool in addressing this challenge and the latest state of the art in this field are summarised here. [ABSTRACT FROM AUTHOR]

Background: Nepal is facing an increasing burden of diabetes and relies almost entirely on insulin imported through India. Methods: We employed a modified version of the WHO/Health Action International standard survey to assess insulin availability and prices, along with qualitative interviews with insulin retailers (pharmacists) and wholesalers in the Kathmandu Valley, Nepal. Results: The mean availability of the two human insulins listed on the 2011 Nepal Essential Medicine List were 14.3% and 42.85% in the surveyed private- and public-sector pharmacies, respectively, compared with the WHO target of 80% availability. The median consumer price of human insulin cartridges, analogue insulin cartridges and pens was, respectively, 2.1, 4.6 and 5.3 times that of human insulin vials (US$5.54). The insulin cartridges made in India were less expensive (p<0.001) than those made elsewhere. The lowest-paid worker would need to spend between 3 and 17 days' wages to purchase a monthly insulin supply out of pocket. Conclusion: Insulin access is limited in Kathmandu owing to low availability and the highly unaffordable price. Insulin access could improve with the government exploring additional suppliers, pooling insulin tenders, auditing insulin utilization and developing independent prescribing guidelines. Furthermore, there is a need to educate physicians and develop a consensus statement on insulin initiation to curb the growing analogue use and promote rational use. [ABSTRACT FROM AUTHOR]

Background. Fluoroquinolones have equivalent oral and intravenous bioavailability, but hospitalized patients with communityacquired pneumonia (CAP) generally are treated intravenously. Our objectives were to compare outcomes of hospitalized CAP patients initially receiving intravenous vs oral respiratory fluoroquinolones. Methods. This was a retrospective cohort study utilizing data from 340 hospitals involving CAP patients admitted to a non- intensive care unit (ICU) setting from 2007 to 2010, who received intravenous or oral levofloxacin or moxifloxacin. The primary outcome was in-hospital mortality. Secondary outcomes included clinical deterioration (transfer to ICU, initiation of vasopressors, or invasive mechanical ventilation [IMV] initiated after the second hospital day), antibiotic escalation, length of stay (LOS), and cost. Results. Of 36 405 patients who met inclusion criteria, 34 200 (94%) initially received intravenous treatment and 2205 (6%) received oral treatment. Patients who received oral fluoroquinolones had lower unadjusted mortality (1.4% vs 2.5%; P = .002), and shorter mean LOS (5.0 vs 5.3; P < .001). Multivariable models using stabilized inverse propensity treatment weighting revealed lower rates of antibiotic escalation for oral vs intravenous therapy (odds ratio [OR], 0.84; 95% confidence interval [CI], .74-.96) but no differences in hospital mortality (OR, 0.82; 95% CI, .58-1.15), LOS (difference in days 0.03; 95% CI, -.09-.15), cost (difference in $-7.7; 95% CI, -197.4-182.0), late ICU admission (OR, 1.04; 95% CI, .80-1.36), late IMV (OR, 1.17; 95% CI, .87-1.56), or late vasopressor use (OR, 0.94; 95% CI, .68-1.30). Conclusions. Among hospitalized patients who received fluoroquinolones for CAP, there was no association between initial route of administration and outcomes. More patients may be treated orally without worsening outcomes. [ABSTRACT FROM AUTHOR]

Acotiamide is a new prokinetic drug that is used to treat functional dyspepsia (FD). A sensitive and specific LC-MS-MS method has been developed and validated for the analysis of acotiamide in rat plasma. The assay involved a simple protein precipitation (PPT) step with methanol-acetonitrile (50:50, v/v) and a gradient elution using a mobile phase consisting of water containing 0.1% formic acid and methanol containing 0.1% formic acid. The analytes were chromatographed on a reversephase Agilent Zorbax XDB C18 column (2.1 mm× 50 mm, 3.5 μm) with a flowrate of 0.50 mL/min. The analytes were monitored by tandem-mass spectrometry with positive electrospray ionization. The precursor-product transitions (m/z) in the positive ion mode were 451.4→271.3 and 386.2→122.2 for acotiamide and buspirone (internal standard, IS), respectively. The assay was shown to be linear over the range of 0.10-200 ng/mL, with a lower limit of quantification of 0.10 ng/mL. The method was shown to be reproducible and reliable with the inter- and intra-batch accuracy and precision were within ±15%. The assay has been successfully used for pharmacokinetic evaluation of acotiamide after intravenous and oral administration of 10 mg/kg acotiamide in rats. The oral absolute bioavailability (F) of acotiamide in rats was estimated to be 38.4 ± 13.5% with an elimination half-life (t1/2) value of 9.11 ± 0.40 h. [ABSTRACT FROM AUTHOR]

Objectives This study was conducted to investigate the effect of food and coadministration of omeprazole on the relative bioavailability (BA) of faldaprevir (FDV). Methods Fifteen healthy participants participated in this open-label, randomized, three-way cross-over study. Faldaprevir was administered as a 240 mg single dose during fasting state, following intake of a high-fat breakfast, or following omeprazole 40 mg q.d. dosing for 5 days. PK samples were collected on the day of faldaprevir administration. Key findings We found geometric mean ( gMean) AUC0-∞ values for faldaprevir of 48 200, 37 900 and 36 000 ng h/ ml under the fed, fasted and omeprazole coadministration conditions respectively. Similarly, gMean Cmax values for faldaprevir were 2600, 2030, 1920 ng/ml under the same respective conditions. The adjusted gMean ratio between the fed and fasted condition was approximately 120% for both AUC0-∞ and Cmax, while the ratio of omeprazole coadministration to fasted condition was approximately 94%. Faldaprevir was safe and well tolerated in the study. Conclusions Administration of a single dose of 240 mg faldaprevir after high-fat breakfast led to a modest, clinically irrelevant increase in faldaprevir exposure, while coadministration of omeprazole did not influence faldaprevir exposure. [ABSTRACT FROM AUTHOR]

Objectives To compare the properties of solid dispersions of felodipine for oral bioavailability enhancement using two different polymers, polyvinylpyrrolidone ( PVP) and hydroxypropyl methylcellulose acetate succinate ( HPMCAS), by hot-melt extrusion ( HME) and spray drying. Methods Felodipine solid dispersions were prepared by HME and spray drying techniques. PVP and HPMCAS were used as polymer matrices at different drug : polymer ratios (1 : 1, 1 : 2 and 1 : 3). Detailed characterization was performed using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy and in-vitro dissolution testing. Dissolution profiles were evaluated in the presence of sodium dodecyl sulphate. Stability of different solid dispersions was studied under accelerated conditions (40° C/75% RH) over 8 weeks. Key findings Spray-dried formulations were found to release felodipine faster than melt extruded formulations for both polymer matrices. Solid dispersions containing HMPCAS exhibited higher drug release rates and better wettability than those produced with a PVP matrix. No significant differences in stability were observed except with HPMCAS at a 1 : 1 ratio, where crystallization was detected in spray-dried formulations. Conclusions Solid dispersions of felodipine produced by spray drying exhibited more rapid drug release than corresponding melt extruded formulations, although in some cases improved stability was observed for melt extruded formulations. [ABSTRACT FROM AUTHOR]

Vemurafenib is a first-in-class, small molecule B-Raf kinase inhibitor for the treatment of patients with unresectable or metastatic melanoma carrying the BRAFV600E mutation, commercially available since 2011. A general phototoxic potential was identified early during development; however, based on results of an animal study in hairless rats, it was concluded that there would exist no relevant risk for humans. Surprisingly, signs of clinical photosensitivity were reported in many patients during clinical development. Therefore, it became a fundamental question to understand this discrepancy. An established mouse model (oral UV-Local Lymph Node Assay, UV-LLNA) for the assessment of in vivo photosafety was used to investigate the impact of formulations, dose levels, duration of treatment, and timing of irradiation. Moreover, a basic pharmacokinetic profile was established within the same mouse strain. We were able to demonstrate dose- and time-dependent phototoxicity of vemurafenib using commercially available tablets (stabilized amorphous material). The lowest phototoxic dose was 350mg/kg administrated for 3 consecutive days followed by exposure to UV-visible irradiation at a UVA-normalized dose of 10 J/cm2. In comparison, pure vemurafenib, which easily forms crystalline variants and is known to have poor bioavailability, was tested at 350mg/kg, and no signs of phototoxicity could be seen. The most apparent difference between the early study in hairless rats and this study in mice was the spectral range of the irradiation light source (350–400nm vs 320–700nm). Because vemurafenib does not absorb sufficiently light above 350nm, this difference can easily explain the negative earlier study result in hairless rats. [ABSTRACT FROM AUTHOR]

Intravenous ketamine (0.5 mg/kg) produces robust, rapid and long-lasting antidepressant effects, but is unpractical. Sublingual administration of ketamine renders better bioavailability (∼30%) and less conversion to norketamine than oral administration. We evaluated the therapeutic effects and tolerability of very low dose sublingual (VLDS) racemic ketamine (10 mg from a 100 mg/ml solution for 5 min and swallowed), repeatedly administered every 2–3 d or weekly, in 26 out-patients with refractory unipolar or bipolar depression. According to patients’ reports, VLDS ketamine produced rapid, clear and sustained effects, improving mood level and stability, cognition and sleep in 20 patients (77%), with only mild and transient light-headedness as a common side-effect (no euphoria, psychotic or dissociative symptoms). Remission remained in some patients after stopping ketamine. Thus, VLDS ketamine may have broad spectrum effects beyond its antidepressant properties, with rapid onset of action, high efficacy, good tolerability and low cost, allowing extended treatment as needed. [ABSTRACT FROM PUBLISHER]

Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo. [ABSTRACT FROM AUTHOR]

Objectives The current studies entail successful formulation of optimized gastroretentive tablets of lamivudine using the floating-bioadhesive potential of carbomers and cellulosic polymers, and their subsequent in-vitro and in-vivo evaluation in animals and humans. Methods Effervescent floating-bioadhesive hydrophilic matrices were prepared and evaluated for in-vitro drug release, floatation and ex-vivo bioadhesive strength. The optimal composition of polymer blends was systematically chosen using central composite design and overlay plots. Pharmacokinetic studies were carried out in rabbits, and various levels of in-vitro/in-vivo correlation (IVIVC) were established. In-vivo gamma scintigraphic studies were performed in human volunteers using 99mTc to evaluate formulation retention in the gastric milieu. Key findings The optimized formulation exhibited excellent bioadhesive and floatational characteristics besides possessing adequate drug-release control and pharmacokinetic extension of plasma levels. The successful establishment of various levels of IVIVC substantiated the judicious choice of in-vitro dissolution media for simulating the in-vivo conditions. In-vivo gamma scintigraphic studies ratified the gastroretentive characteristics of the optimized formulation with a retention time of 5 h or more. Conclusions Besides unravelling the polymer synergism, the study helped in developing an optimal once-a-day gastroretentive drug delivery system with improved bioavailability potential exhibiting excellent swelling, floating and bioadhesive characteristics. [ABSTRACT FROM AUTHOR]

In May 2011, hepatitis C virus (HCV) protease inhibitors (PIs) were approved by the US Food and Drug Administration to treat persons with genotype 1 chronic hepatitis C virus (HCV) infection, but not those dually infected with human immunodeficiency virus (HIV). Although critical safety and efficacy data are lacking, the availability of the drugs and substantial medical need justify the off-label use of HCV PIs in select HIV/HCV-coinfected persons. Pending results of ongoing investigations, this article represents provisional guidance on the use of HCV PIs in HIV-infected persons. [ABSTRACT FROM AUTHOR]

High-throughput in vitro toxicity screening can provide an efficient way to identify potential biological targets for chemicals. However, relying on nominal assay concentrations may misrepresent potential in vivo effects of these chemicals due to differences in bioavailability, clearance, and exposure. Hepatic metabolic clearance and plasma protein binding were experimentally measured for 239 ToxCast Phase I chemicals. The experimental data were used in a population-based in vitro–to–in vivo extrapolation model to estimate the daily human oral dose, called the oral equivalent dose, necessary to produce steady-state in vivo blood concentrations equivalent to in vitro AC50 (concentration at 50% of maximum activity) or lowest effective concentration values across more than 500 in vitro assays. The estimated steady-state oral equivalent doses associated with the in vitro assays were compared with chronic aggregate human oral exposure estimates to assess whether in vitro bioactivity would be expected at the dose-equivalent level of human exposure. A total of 18 (9.9%) chemicals for which human oral exposure estimates were available had oral equivalent doses at levels equal to or less than the highest estimated U.S. population exposures. Ranking the chemicals by nominal assay concentrations would have resulted in different chemicals being prioritized. The in vitro assay endpoints with oral equivalent doses lower than the human exposure estimates included cell growth kinetics, cytokine and cytochrome P450 expression, and cytochrome P450 inhibition. The incorporation of dosimetry and exposure provide necessary context for interpretation of in vitro toxicity screening data and are important considerations in determining chemical testing priorities. [ABSTRACT FROM AUTHOR]

Aims The goal was to terminate atrial fibrillation (AF) by targeting atrioventricular differences in ionic properties. Methods and results Optical mapping was used to record electrical activity during carbachol (0.25–0.5 μM)-induced AF in pig hearts. The atrial-specific current, IKur, was blocked with 100 μM 4-aminopyridine (4-AP) or with 0.5 μM DPO-1. Hearts in AF and ventricular fibrillation (VF) were also subjected to increasing levels of extracellular K+ ([K+]o: 6–12 mM), compared with controls (4 mM). We hypothesized that due to the more negative steady-state half inactivation voltage for the atrial Na+ current, INa, compared with the ventricle, AF would terminate before VF in hyperkalaemia. Mathematical models were used to interpret experimental findings. The IKur block did not terminate AF in a majority of experiments (6/9 with 4-AP and 3/4 with DPO-1). AF terminated in mild hyperkalaemia ([K+]o ≤ 10.0 mM; N = 8). In contrast, only two of five VF episodes terminated at the maximum ([K+]o: 12 mM [K+]o). The IKur block did not terminate a simulated rotor in cholinergic AF because its contribution to repolarization was dwarfed by the large magnitude of the acetylcholine-activated K+ current (IK,ACh). Simulations showed that the lower availability of the atrial Na+ current at depolarized potentials, and a smaller atrial tissue size compared with the ventricle, could partly explain the earlier termination of AF compared with VF during hyperkalaemia. Conclusion IKur is an ineffective anti-arrhythmic drug target in cholinergic AF. Manipulating Na+ current ‘availability’ might represent a viable anti-arrhythmic strategy in AF. [ABSTRACT FROM AUTHOR]

The number of opioid analgesic prescriptions has increased since 1990. Opioids are being prescribed for longer periods of time for both cancer- and noncancer-associated moderate to severe chronic pain. Concurrent with the increased prescribing of opioids has been an increase in their diversion from prescribed use and their abuse; frequently, this abuse occurs after the opioid analgesic has been physically or chemically manipulated to increase the concentration or bioavailability of the active ingredient. Formulations of opioids have been designed to resist the extraction of the active opioid from prescribed products through the incorporation of physical barriers or to deter the reinforcing effects of opioids through the incorporation of antagonists or other ingredients that only become active when the analgesic is used improperly. However, none of these formulations are currently commercially available in the United States. This paper describes the formulations now under development and their potential clinical utility and impact on society. These emerging opioid formulations designed to reduce the risk of misuse and/or abuse may be useful to physicians in meeting the important goals of maximizing pain relief and minimizing prescription opioid abuse. [ABSTRACT FROM AUTHOR]

Although animal-derived remedies constitute an integral part of folk medicine in many parts of the world, particularly for people with limited or no access to mainstream medical services, their role in health care has generally been overlooked in discussions about public health, conservation and management of faunistic resources, and ecosystem protection. In this article, we report on the use of 283 medicinal animal species in Brazil, 96% of which are wild caught and 27% of which are on one or more lists of endangered species. Further population declines may limit users' access to these bioresources and diminish the knowledge base upon which traditional medicine is built. [ABSTRACT FROM AUTHOR]

Purpose. Several new oral chemotherapeutic agents have recently been introduced. Many possess novel mechanisms of action and specific targets that result in different adverse effect profiles from those associated with traditional chemotherapies and hormonal therapies. The potential advantages and challenges associated with oral chemotherapy are discussed. Summary. Use of the oral route is convenient and allows administration to take place at home or in non-traditional settings. However, nausea, difficulty swallowing, patient nonadherence, interactions with drugs and food, other pharmacokinetic factors, and the high cost of treatment can present problems in using these agents by the oral route. Awareness by clinicians of the potential problems with oral chemotherapy can help to avoid or minimize problems that might affect patient outcomes. Conclusion. While bioavailability studies are often an integral part of developing oral agents, their comparisons with parenteral forms are less well documented. However, studies comparing intravenous 5-fluorouracil (5-FU) with oral 5-FU prodrugs have demonstrated that efficacy, safety, and quality of life are not compromised by the use of oral therapy. Finally, these studies, as well as others, reveal patients prefer the oral route of administration. [ABSTRACT FROM AUTHOR]

Examines a liquid chromatographic method for the determination of quinocetone (QCT), an antimicrobial growth promotant of quinoxalines, and its main metabolites, desoxyquinocetone (DQCT) and 3-methyl- quinoxaline-2-carboxylic acid, in muscle, liver, kidney, and fat of swine and chicken. Extraction of QCT and DQCT with ethyl acetate and purification with iso-octane; Observed limit of detection; Use of the method to accelerate the pharmacokinetic and residue study of QCT in food animals.

Describes a spectrofluorimetric method for the determination of drugs containing active methylene groups adjacent to carbonyl groups. Application of the method to the determination of warfarin sodium in laboratory-prepared mixtures, in commercial tablets and in spiked human plasma samples; Use in the determination of the steady-state concentration of warfarin sodium in the blood of a hospitalized patient; Optimal wavelengths of excitation and emission determined using a synchronous wavelength search; Specificity and precision of the method; Suitability for quality-control applications, drug monitoring, and bioavailability and bioequivalency studies

Evaluates the Fast Antimicrobial Screen Test (FAST), a screening test for detecting antibiotic and sulfonamide residues in food animal carcasses in slaughter establishments. Comparison with the Swab Test on Premises; Sensitivity to antibiotic and sulfonamide residues in animal kidneys; Range of detection by FAST for all antimicrobials.

Studies the use of the Calf Antibiotic and Sulfonamide Test, a microbial inhibition screening test, to detect antibiotics and sulfonamides in calf carcasses. Bacillus megaterium as the indicator organism and Mueller Hinton agar as the growth medium; Comparison to Swab Test on Premises; Sensitivity and ability to detect a wider range of veterinary antimicrobial residual drugs at lower concentrations.

Studies the use of an ion-pair liquid chromatographic assay for the determination of the antibiotic ceftriaxone in cerebrospinal fluid. Chromatographic separation; Use of cephradine was used as the internal standard; Coefficients of variation for precision; Detection and quantitation limits; Results supporting the use of the method for the determination of ceftriaxone in cerebrospinal fluid.

Investigates the effects of quercetin on the pharmacokinetics of oral cyclosporine. Levels of cyclosporine concentration in the blood; Bioavailability of cyclosporine; Half-life of cyclosporine.

The bioavailability of pantoprazole when administered as a suspension in sodium bicarbonate solution and as the oral tablet was studied. In an open-label, randomized, two-period crossover study, healthy fasting subjects received either one enteric-coated 40-mg pantoprazole tablet by mouth with 240 mL of water or 20 mL of a suspension prepared from one crushed pantoprazole tablet and 840 mg of sodium bicarbonate solution and administered via a nasogastric tube. Treatments were separated by a 48-hour washout period. Blood samples were collected at intervals up to 24 hours after drug administration for measurement of pantoprazole concentration by high-performance liquid chromatography (HPLC) and estimation of pharmacokinetic values. A separate study was conducted to determine pantoprazole's stability in the suspension for up to three months at 25, 5, and -20 °C; concentrations were measured by HPLC. Twelve subjects completed the study. The suspension yielded pantoprazole C[SUBmax] values similar to those of the tablet formulation, but the drug was 25% less bioavailable. There was no lag time for the suspension. The suspension was stable for up to two weeks at 5 °C and up to three months at -20 °C. A suspension of pantoprazole in sodium bicarbonate solution yielded a C[SUBmax] similar max to that of the tablet formulation, and the drug was quickly absorbed. However, bioavailability was slightly lower with the suspension than with the tablet. [ABSTRACT FROM AUTHOR]

In this study, the bioavailability of fluconazole and ketoconazole in the stratum corneum and oral mucosa after multiple oral dosages were compared. It is well recognized that such evaluation is heavily dependent on the test methods employed. A method of culture of fungi on human stratum corneum and superficial mucosal cells, a model close to the in-vivo situation, was used. A significant difference in the bioavailability of the two antifungals in stratum corneum and superficial cells of oral mucosa was found. The activity of ketoconazole proved to be more rapid against T. mentagrophytes while fluconazole appeared slightly more active against C. albicans. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editors discuss various articles within the issue on topics including advances in polymers based topical drug delivery systems, increase in the ocular bioavailability of poor soluble drugs by nanpaticles derived from co-polymers and cationic nanoemulsions.

TREatment of ATopic eczema (TREAT) Registry Taskforce: consensus on how and when to measure the core dataset for atopic eczema treatment research registries. Serum cytokeratin 19 fragment 21-1 and carcinoembryonic antigen combination assay as a biomarker of tumour progression and treatment response in extramammary Paget disease. Serum cytokeratin 19 fragment 21-1 and carcinoembryonic antigen combination assay as a biomarker of tumour progression and treatment response in extramammary Paget disease. [Extracted from the article]

Objectives The availability of antimicrobials that may be used for the treatment of infections caused by Neisseria gonorrhoeae has been limited by the emergence of antimicrobial resistance, particularly fluoroquinolone resistance. Few data exist regarding the pharmacodynamics of fluoroquinolone resistance selection in N. gonorrhoeae. Methods We used mutant prevention concentration (MPC) testing to define the risk of fluoroquinolone resistance induction in N. gonorrhoeae by ciprofloxacin, levofloxacin and moxifloxacin in a wild-type isolate (ATCC 49226) and its corresponding gyrA mutant (m-49226). Results MIC/MPC values (mg/L) of ciprofloxacin, levofloxacin and moxifloxacin for ATCC 49226 were 0.0078/0.03125, 0.0078/0.125 and 0.0156/0.0625, respectively. The MIC of all fluoroquinolones for m-49226 was 0.125 mg/L; MPCs of ciprofloxacin, levofloxacin and moxifloxacin for this isolate were 4, 0.5 and 0.25 mg/L, respectively. Concentrations of all agents are predicted to exceed the MPC for ATCC 49226 for the entire dosage interval, while concentrations of moxifloxacin alone will exceed the MPC for m-49226. The hierarchy of tested agents with respect to %TMSW [percentage of the dosage interval that concentrations fall within the mutant selection window (MSW)] for m-49226 was ciprofloxacin > levofloxacin > moxifloxacin. Multiple-dose fluoroquinolone regimens are predicted to achieve superior pharmacodynamics in comparison with single-dose regimens for m-49226, with increased AUC/MPC values and a reduced %TMSW. Conclusions Evaluation of the use of moxifloxacin against N. gonorrhoeae is warranted, as is use of multiple-dose fluoroquinolone regimens. [ABSTRACT FROM AUTHOR]