Preparation,optimisation, and in vitro–in vivo evaluation of febuxostat ternary solid dispersion

Abstract

The research aimed to prepare febuxostat (FEB) solid dispersion through solvent evaporation. Optimised solid dispersion composed of FEB, polyvinylpyrrolidone (PVP K30) and poloxamer at a ratio of 1:3:3 was characterised. Powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) indicated FEB was transformed from crystalline into the amorphous state in solid dispersion and scanning electron microscopy (SEM) revealed the morphology. Fourier transform infrared spectroscopy (FT-IR) suggested the interactions formed between FEB and polymers. A remarkable increase was observed of the optimised formulation in saturation solubility, dissolution studies (96.17?±?0.79% in pH 6.0), and bioavailability (C_max 18.25?±?2.44 vs. 7.72?±?0.48?μg/mL and AUC_0–∞ 53.62?±?7.63 vs. 34.76?±?2.45?μg·h/mL). Besides, the FEB solid dispersion showed great stability after 90 days storage. Thus, the present study supports the rationality of PVP K30 and poloxamer188 as co-carriers for the preparation of FEB solid dispersion.     

Press coverage and sales of Xenical in Sweden, 1998–2000

OBJECTIVE: The anti-obesity drug Xenical (orlistat, Roche) was launched on the Swedish market in February 1999. The sales peaked in May 1999 and then declined. The purpose of this study was to investigate the press coverage of Xenical during the period 1998-2000 and, if possible, relate press attention to Xenical sales during this period. METHODS: We analysed all articles published in Sweden's four biggest-selling newspapers mentioning Xenical during the period 1998-2000. Promotion activities aimed at healthcare professionals were measured by registering the number of advertisements in the Journal of the Swedish Medical Association. Sales figures for Xenical were obtained from the National Corporation of Swedish Pharmacies. RESULTS: Approximately twice as many positive-effect messages were published than negative or neutral messages. Only six out of 42 positive messages referred to results from scientific studies. The initial high peaks for sales and positive-effect articles coincided with the launch of Xenical on the Swedish market. CONCLUSIONS: It is not possible to discern a causal relationship between press coverage and sales; however, it seems safe to say that the large number of positive articles published before and during the launch greatly increased public awareness of Xenical, thus promoting sales.     

Evolution of interventional vancomycin trials in light of new antibiotic development in the USA, 1999–2012

Use of vancomycin has increased following the emergence of resistant Gram-positive bacterial infections. Investigation into recent vancomycin clinical studies provides insight into the optimal use of vancomycin and the development of novel antibiotics for the treatment of resistant infections. Interventional vancomycin trials registered in ClinicalTrials.gov from January 1999 to December 2012 were identified. Trial trends and characteristics were evaluated in the context of vancomycin use and new antibiotic development. Overall, 122 interventional vancomycin trials were identified, with a significant increase in the number of registered trials per year (P < 0.001). The top three indications studied were skin and soft-tissue infections (28.7%), Clostridium difficile infections (13.1%) and surgical prophylaxis (12.3%). Trials testing vancomycin as an experimental agent differed from trials using vancomycin as an active comparator. Experimental agent trials commonly investigated new formulations, dosing regimen optimisation and combination therapy, which were less likely to be in phase 2 or 3 (25% vs. 70%; P < 0.001), adopt a randomisation procedure (70% vs. 98%; P < 0.001), report results (15% vs. 35%; P = 0.02) or be funded by industry (8% vs. 76%; P < 0.001). Active comparator trials mainly focused on monotherapy, which led to six FDA-approved drug products and ten investigational new drugs in late-phase development. This study demonstrated a significant increase in interventional vancomycin trials and its recent success, which resulted in several novel agents against resistant Gram-positive bacteria. Further studies are warranted to determine how these agents can best be incorporated within clinical practice.     

Analysis of mushroom exposures in texas requiring hospitalization, 2005–2006

Introduction

Texas has approximately 200 species of wild mushrooms, including toxic and hallucinogenic varieties. Mushroom ingestions in Texas were studied for 2005–2006.

Methods

Data was obtained via Texas Poison Control Centers and retrospectively reviewed. Case notes were reviewed individually regarding initial reporting, age, signs and symptoms, toxic effect, management, and patient outcomes.

Results

A total of 742 exposures occurred during the study period. All exposures were acute and intentional. Of these exposures, 59 (7.9%) were admitted to the hospital, with 17 (28.8% of admissions) requiring admission to a critical care unit. Four cases required inpatient psychiatric admission. The average age of admitted exposures was 20.5 years, with a male-to-female predominance of 3.3:1. Eleven (22.9%) of the admitted exposures were identified, with Psilocybin being the most common agent (n = 10, 91%). Among the admissions, co-ingestions were identified with the mushroom ingestion in eleven patients (40.7%). The most common symptoms in admitted patients were vomiting (n = 34, 57.6%), nausea (n = 19, 32.2%), altered mental status (n = 17, 28.8%), abdominal pain (n = 13, 22%), and diarrhea (n = 10, 16.9%).

Conclusions

All mushroom exposures examined were acute and intentional. Major toxic reactions were uncommon, and no deaths were reported. Serious poisoning from mushroom ingestion is rare in Texas; however, there is greater need for information dissemination on morbidity.     

Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2–p53 interaction,in rats,dogs and monkeys: in vitro–in vivo correlation

Abstract

1. AMG 232 is a novel inhibitor of the p53–MDM2 protein–protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data.

2. AMG 232 exhibited low clearance (<0.25?×?Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74?×?Qh) and low oral exposure in dogs (18%).

3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered ¹⁴C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species.

4. The in vitro–in vivo correlation of AMG 232 clearance was within 2-fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials.     

Synthesis,in vitro antiplasmodial and antiproliferative activities of a series of quinoline–ferrocene hybrids

Series of quinoline–ferrocene hybrids containing various linkers were synthesized and evaluated for antimalarial and anticancer activities as well as cytotoxicity. The hybrids with rigid linkers were found to be inactive, while those with flexible spacers showed activity against both the D10 and Dd2 strains of Plasmodium falciparum, and demonstrated a good selectivity towards these parasitic cells in comparison with emetine. The hybrid 16, featuring 3-aminopropyl methylamine linker, was the most antimalarial active compound, exhibiting a significantly better potency than chloroquine against the Dd2 strain (IC₅₀ = 0.008 vs. 0.148 μM; 19-fold), and was also found to be significantly more active than the equimolar chloroquine–ferrocene combination (IC₅₀ = 3.7 vs. 41 ng/ml, tenfold) against the Dd2 strain. Anticancer activity screening showed that all the antimalarial active hybrids also exhibited potent cytostatic (GI₅₀ = 0.6–3.3 μM) and had good cytotoxic effects (LC₅₀ = 6–8 μM) against all three cancer cell lines. The hybrid 11 possessing 1,4-butanediamine linker was distinctively the most antiproliferative of all. It was found to be more cytostatic (GI₅₀: 0.7 vs. 5.9 μM, eightfold) and (LC₅₀: 6.4 vs. 92.6 μM, 14-fold) more cytotoxic than etoposide against the TK10 (renal) cell line.     

Interactions of NADPH oxidase,renin–angiotensin–aldosterone system and reactive oxygen species in mequindox-mediated aldosterone secretion in Wistar rats

High doses of mequindox (MEQ) are associated with oxidative stress and pathological toxicity in the kidney. In this study, we demonstrated long term effects of MEQ on intra- or extra-adrenal renin–angiotensin–aldosterone system (RAAS) in vivo. RAAS plays a major role in aldosterone secretion. High doses of MEQ in the diet for 180 days in male rats led to inhibition of intra- and extra-adrenal RAAS, concident with down-regulation of Na⁺/K⁺-ATPase (NAKA) and mineralocorticoid receptor (MR), the downstream of aldosterone action. Significant changes of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) in kidney were also observed in the high doses (110, 275 mg/kg) groups. The mRNA levels of most subunits of NADPH oxidase were significantly upregulated at low doses (25–110 mg/kg) but the upregulation was diminished at higher doses in both kidney and adrenal gland, indicating a complicated and contradictory effect of MEQ on NADPH. These results highlight the complex interactions of drug metabolism, RAAS, NADPH oxidase and oxidative stress in response to MEQ-induced tissue toxicity and aldosterone secretion.     

L-Carnitine Transport in Kidney of Normotensive,Wistar–Kyoto Rats: Effect of Chronic L-Carnitine Administration

Purpose. To examine the effect of long-term administration of L-carnitine on L-carnitine transport in renal brush-border membrane vesicles (BBMVs) from normotensive, Wistar-Kyoto rats. Methods. Rats (n = 20) were orally administered 0.2 g carnitine/kg body weight per day for a total period of 8 weeks. Kinetic parameters of L-carnitine uptake were calculated by non-linear regression, and the relative abundance of the carnitine transporter, OCTN2, was determined by Western blot analysis. Results. Initial rates and maximal overshoot levels of Na⁺-dependent L-carnitine transport were significantly reduced in BBMVs from L-carnitine-treated rats compared with untreated animals. Similarly, the maximal transport rate (V_max) of OCTN2 was lower in treated rats. However, no differences were observed in the Michaelis constant (K _m) or the diffusion constant (K _d) between the two groups of animals. The amount of OCTN2 protein was also decreased in L-carnitine-fed rats, this reduction being similar to that of the V _max. These results were accompanied by an increase in the serum levels and also in the renal excretion of both free and esterified carnitine in treated rats, indicating that the long-term administration of L-carnitine leads to increased renal carnitine clearance. Conclusion. These findings suggest a downregulation of OCTN2 at the renal level, in the presence of high levels of carnitine.     

Changes in the Sharing of Drug Injection Equipment among Street-Recruited Injection Drug Users in Chicago,Illinois, 1994–1996

This study examines changes in the multi-person use of drug injection paraphernalia during the mid-1990s, a time of increasing awareness of HIV transmission modes and availability of prevention programs. Beginning in 1994, 794 street-recruited injection drug users in Chicago were interviewed and followed at 6 and 12 months postbaseline. Random-effects, pattern-mixture logistic regression models were used to determine correlates of five injection-equipment sharing practices, while accounting for repeated measurement and study attrition. At baseline, 45.7% of participants reported receptive syringe sharing in the previous 6 months. Syringe-mediated sharing was reported by 28.7% of participants and the sharing of cookers (65.1%), cotton filters (55.7%), and rinse water (46.9%) was common. During follow-up, the proportion of all sharing behaviors decreased significantly, especially receptive syringe sharing. Participation in a syringe exchange program was associated with reductions in receptive syringe sharing and syringe-mediated sharing, but not the sharing of cookers.     

Clinical disposition,metabolism and in vitro drug–drug interaction properties of omadacycline

1.?Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects.

2.?Omadacycline was metabolically stable in human liver microsomes and hepatocytes and did not inhibit or induce any of the nine cytochrome P450 or five transporters tested. Omadacycline was a substrate of P-glycoprotein, but not of the other transporters.

3.?Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300?mg oral dose of [¹⁴C]-omadacycline (36.6 μCi). Absorption was rapid with peak radioactivity (～610 ngEq/mL) between 1–4?h in plasma or blood. The AUC_last of plasma radioactivity (only quantifiable to 8?h due to low radioactivity) was 3096 ngEq?h/mL and apparent terminal half-life was 11.1?h. Unchanged omadacycline reached peak plasma concentrations (～563?ng/mL) between 1–4?h. Apparent plasma half-life was 17.6?h with biphasic elimination. Plasma exposure (AUC_inf) averaged 9418?ng?h/mL, with high clearance (CL/F, 32.8?L/h) and volume of distribution (Vz/F 828?L). No plasma metabolites were observed.

4.?Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.     

Imported malaria in Slovenia, 2001–2011

Background  

A retrospective analysis was conducted to determine the epidemiological and clinical characteristics of imported malaria in Slovenia.     

Carisoprodol abuse in Texas, 1998–2003

Introduction

Texas poison centers identified carisoprodol as a skeletal muscle relaxant that is subject to abuse, and this investigation explores the abuse reported by Texas poison centers.

Methods

This study used data from six Texas poison centers to describe the epidemiology of carisoprodol abuse and drug identification (ID) calls from 1998 to 2003.

Results

Drug ID and abuse calls were 217% higher in 2003 than in 1998. Although eastern and central Texas contains 43% of the state’s population, this region reported 77% of all drug ID calls and 64% of abuse calls. Male patients accounted for 51% of abuse calls and 37% of other human exposure calls. Patients from 13 to 19 years of age accounted for 17% of abuse calls and 9% of other human exposure calls. Among those human exposure calls with a known medical outcome, a higher percentage of abuse calls involved minor effects while a greater proportion of other human exposure calls involved outcomes that ranged from moderate effects to death.

Conclusions

Carisoprodol abuse is increasing in Texas and is substantially more common in the eastern part of the state. Carisoprodol abuse is much more likely, than other types of adverse carisoprodol exposures, to involve males and adolescents; and it less likely to involve adverse medical outcomes.     

Evaluation of the polyethylene glycol–KF–water system in the context of purifying PEG–protein adducts

Covalent binding of PEG to proteins leads to conjugates widely investigated in several biotechnological processes. Their use as pharmaceuticals requires both careful purification and proper characterization. In this context, this paper examines the potentialities offered by hydrophobic interaction chromatography and compares aqueous potassium fluoride and ammonium sulfate as the eluents. Relative contribution of the various forces which dictate the chromatographic behaviour of PEG–protein adducts on Fractogel TSK–Butyl 650 is discussed.     

Application of solid-phase extraction in the method development for determination of SEPA,an acronym for soft enhancement of percutaneous absorption,in human,rat, and rabbit serum using GC–FID method

A new nonaqueous topical minoxidil formulation containing SEPA (2-n-nonyl-1,3-dioxolane) for enhancement of percutaneous absorption was under evaluation. SEPA does not have chromophore for either ultraviolet or fluorescence detection using liquid chromatography and has no functional groups for derivatization. Therefore, a direct gas-chromatographic method with flame-ionization detection (GC–FID) was developed. Owing to the limited detection response of the FID detection, it needs a selective and concentrated extract for GC–FID analysis to improve the assay sensitivity to meet the requirement for pharmacokinetic evaluation after topical application. In addition, SEPA is a very volatile compound. Any extraction procedures involving evaporation will result in a poor recovery. The application of solid-phase extraction (SPE) makes it possible to achieve a selective and a 10-fold concentrated extract with an absolute extraction recovery of approximately 90%, which greatly improved the assay sensitivity. This method involved the extraction of SEPA and the internal standard (2-n-heptyl-1,3-dioxolane) from serum (0.1–1 ml) with 100 μl of hexane-chloroform (1:1, v:v) using a 50 mg 1.0 ml⁻¹ phenyl SPE column (Varian, Harbor City, CA, USA), followed by direct GC–FID analysis on a fused-silica column chemically bonded with cross-linked methyl silicone gum phase (Hewlett Packard Ultra-1, 12 m×0.2 mm×0.33 μm, Avondale, PA, USA). The assay demonstrated a lower limit of quantitation of 2.5 ng ml⁻¹ and a linear range of 2.5 to 250 ng ml⁻¹ with intra- and inter-assay precision and accuracy of ≤10%.     

Enhanced ocular bioavailability of fluconazole from niosomal gels and microemulsions: formulation,optimization, and in vitro–in vivo evaluation

Fungal keratitis may cause vision loss if it is not treated. Methods other than ocular delivery exhibited several limitations. No previous studies investigated and compared ocular bioavailability of fluconazole (FLZ) from niosomal gels and microemulsions. Niosomal gels of FLZ (0.3% w/w) based on Span^® 60 and cholesterol (CH) using 1% w/w carbopol^® 934 (CP) were evaluated. FLZ microemulsions (0.3% w/v) containing isopropyl myristate (IPM, as oil phase) and a 3:1 mixture of Tween^® 80 (as surfactant) and polyethylene glycol 400 (PEG 400, as cosurfactant) were characterized. Optimized formulations were compared for their ocular bioavailability in rabbit’s. Nanoscopic niosomes (63.67–117.13?nm) and microemulsions (57.05–59.93?nm) showed respective negative zeta potential ranges of ?45.37 to ?61.40 and ?20.50 to ?31.90?mV and sustained release up to 12?h. Entrapment efficiency (EE%) of niosomes ranged from 56.48% to 70.67%. Niosomal gels were more sustainable than niosomes and microemulsions. The most stable niosomal gel based on Span^® 60 and CH at a molar ratio of 5:5 and microemulsion containing 45% w/w IPM and 40% w/w of 3:1 Tween^® 80-PEG 400 mixture significantly (p?<?0.0001) enhanced FLZ ocular bioavailability compared with its solution. Niosomal gel showed higher bioavailability than microemulsion by ≈2-fold.     

Preparation and in vivo evaluation of anti-plasmodial properties of artemisinin-loaded PCL–PEG–PCL nanoparticles

Abstract

Purpose: Artemisinin (ART) has anti-inflammatory, antimicrobial, antioxidant, anti-amyloid, and anti-malarial effects, but its application is limited due to its low water solubility and poor oral bioavailability. In this study, the bioavailability, water solubility, and anti-plasmodial property of ART were improved by PCL–PEG–PCL tri-block copolymers.

Methods: The structure of the copolymers was characterized by ¹H NMR, FT-IR, DSC, and GPC techniques. ART was encapsulated within micelles by a single-step nano-precipitation method, leading to the formation of ART-loaded PCL–PEG–PCL micelles. The obtained micelles were characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM). The in vivo anti-plasmodial activity of ART-loaded micelles was measured against Plasmodium berghei infected Swiss albino mice.

Results: The results showed that the zeta potential of ART-loaded micelles was about ?8.37?mV and the average size was 91.87?nm. ART was encapsulated into PCL–PEG–PCL micelles with a loading capacity of 19.33?±?0.015% and encapsulation efficacy of 87.21?±?3.32%. In vivo anti-plasmodial results against P. berghei showed that multiple injections of ART-loaded micelles could prolong the circulation time and increase the therapeutic efficacy of ART.

Conclusion: These results suggested that PCL–PEG–PCL micelles would be a potential carrier for ART for the treatment of malaria.