Validation of LC-MS/MS methods for quantitative analysis of kynurenine pathway metabolites in human plasma and cerebrospinal fluid.

Background: Dysregulation of the kynurenine metabolic pathway has been reported in several neurological conditions. Methods & results: Sensitive and selective LC-MS/MS methods have been validated for six kynurenine pathway metabolites in human cerebrospinal fluid and plasma. For each matrix, we validated three methods - one for the simultaneous determination of kynurenine, kynurenic acid, anthranilic acid and 3-hydroxy-kynurenine (four-analyte assay), one for quinolinic acid and one for tryptophan - using stable-isotopically labeled internal standards. The dynamic range and quantitation limits were based on endogenous concentrations for each analyte. Conclusion: The use of validated methods for kynurenine pathway metabolites in human cerebrospinal fluid and plasma will provide definitive information in neurological diseases.

Health risk implications of iron in wastewater soil-food crops grown in the vicinity of peri urban areas of the District Sargodha.

Irrigation using sewage water can be beneficial, as it can increase the productivity of crops but has negative consequences on crops, soil contamination, and human health. It contains a variety of toxins, such as chemicals and heavy metals, which damage the soil and crops. In this regard, the aim of the research was to assess the potential health hazards of iron (Fe) metal in food crops (leafy and root crops) treated with wastewater (T_1), canal water (T_2), and tube well water (T_3). Water, soil, and edible components of food crops were collected at random from three distinct locations. Fe concentration in samples was estimated using atomic absorption spectrophotometer, following wet digestion method. The Fe concentrations, ranged from 0.408 to 1.03 mg/l in water, 31.55 to 187.47 mgkg-1 in soil and 4.09 to 32.583 mgkg-1 in crop samples; which were within permissible limits of the World Health Organization (WHO). There was a positive correlation between soils and crops. The bioconcentration factor, enrichment factor (EF), daily intake of metals (DIM), health risk index (HRI), and target hazard quotient (THQ) all values were <1, except for a pollution load index >1, which indicated soil contamination, but there was no Fe toxicity in crops, no health risk, and no-carcinogenic risk for these food crops in humans. To prevent the excessive accumulation of Fe metal in the food chain, regular monitoring is needed.

Effects of diverse irrigation with wastewater in soil and plants: assessing the risk of metal to the animal food chain.

In District Jhang, farmers use municipal wastewater to irrigate fodder crops as an alternative source to the deficient availability of fresh water. Therefore, the present study selected the three irrigation sources in District Jhang (canal water, ground water and municipal wastewater) to study the iron (Fe) concentration in the soil, fodder crops and ultimately their transfer into the animal body. Analysed Fe concentration varied as 16.40-27.53 mg/kg in soil samples, 19.72-30.34 mg/kg in fodder crops and 2.49-5.11 mg/kg in animals. Analysed Fe concentration in soil was higher on the wastewater irrigation site while canal water-irrigated fodder crop Zea mays exhibit the higher Fe concentration. In animal samples, higher Fe concentration was observed in the cow blood (4.09 mg/l), cow hairs (3.39 mg/kg) and cow faeces (5.11 mg/kg). Results of pollution load index (0.288-0.484 mg/kg) and enrichment factor (0.112-0.197 mg/kg) indicated that Fe concentration was minimally dispersed and enriched in these sites. Health risk and daily intake values were observed between the 0.029-0.059 and 0.042-0.084 mg/kg/day. Bio-concentration factor (0.834-1.47 mg/kg) for Fe which was greater than 1 explains that Fe contamination was transferred from the soil to fodder tissues and may raise health issues in the grazing animals if they are continuously exposed to these contaminated forages. Wastewater irrigation in study area has increased the Fe content in soil-plant environment that is a risking factor for animal and human health. Hence, this study recommended that wastewater should be treated prior to their irrigation on agricultural lands.

Appraising growth, daily intake, health risk index, and pollution load of Zn in wheat (Triticum aestivum L.) grown in soil differentially spiked with zinc.

Zinc (Zn) is a vital nutrient element required for plants normal growth and development. It performs imperative functions in numerous metabolic pathways in the plants. However, potentially noxious levels of Zn in terrestrial environment can lead to inhibited photosynthesis, growth, respiratory rate and imbalanced mineral nutrition. In micronutrient malnutrition, Zn deficiency is a global human health problem owing to the human dependence on cereals grains especially wheat-based diet. Therefore, this study investigated the Zn uptake efficacy in Triticum aestivum that is grown under two different doses (100 g/kg or 200 g/kg) of various soil amendments in both pot and field experimentation. Results of this study revealed that mean Zn concentration in different wheat varieties and treatments were varied from 1.53 to 6.03 mg/kg, 11.27 to 40.65 mg/kg, 11.28 to 39.93 mg/kg, and 11.32 to 37.70 mg/kg in amended soil, root, shoot, and grains, respectively. All observed Zn values in soil and wheat parts were lower than the FAO/WHO standards. Zinc values observed for pollution load index (0.034-0.134 mg/kg), daily intake (0.00492-0.01533 mg/kg), and health risk (0.0164-0.0570 mg/kg) index were lower than 1 except bio-concentration factor. Bio-concentration factor (5.076-10.165 mg/kg) revealed that DHARABI-11 variety showed maximum Zn uptake efficacy in farmyard manure treatment. The daily intake and health risk index values also showed that Zn level in grains is safe for inhabitants consumption. Overall, study recommended that these organic amendments are a good source of fertilizers, essentially required for the sustainable management of soil and increases the Zn accumulation in wheat grains which can ultimately reduce the Zn malnutrition in human food chain.

Assessment of cobalt in wheat grains as affected by diverse fertilizers: implications for public health.

Present study was conducted to check the heavy metal content in wheat treated with municipal solid waste, Although municipal solid waste was enriched with organic nutrient, micronutrients, and macro-nutrients, considerable amount of cobalt was also witnessed in municipal solid waste that s why pot experiment was executed. The concentration of cobalt in different parts of wheat (root, shoot, and grain) was analyzed by atomic absorption spectrophotometer (AA-6300 Shimadzu Japan). Highest concentration of cobalt in root, shoot, and grain of wheat was observed in the range of 0.91-1.02 mg/kg, 0.92-1.04 mg/kg, and 0.93-1.00 mg/kg, respectively, under the influence of different fertilizer's used, while in field experiment, level of Co was greater in roots followed by shoots and grain. The metal concentration in wheat grown in field was ranged from 0.67 to 0.72 mg/kg for roots, 0.64 to 0.71 mg/kg for shoots, and 0.66 to 1.71 mg/kg for grains. Concentrations of cobalt were found below the permissible limits suggested by FAO/WHO. Various indices (PLI, BCF, DIM, HRI) were calculated and results showed that PLI was above 1 indicating that metal was causing pollution in treatments while value of BCF, DIM, and HRI was within the permissible range. Higher Co content in wheat may cause damage to the pancreatic cells of animals, cause respiratory problems, and effects their kidney, liver, and lungs, if exposure is for long period through feed.

Prevalence and nature of injuries among young professional cricketers of academies and clubs in Lahore; cross sectional survey.

A cross-sectional survey was conducted from February 2021 to June 2021, to assess the prevalence and nature of injuries among young professional cricketers from various academies and clubs in Lahore. The study comprised 149 cricketers representing different academies and clubs of Lahore. Injuries acquired between January and December 2019 were included as retrospective data. The findings revealed that 93 injuries were reported by 149 cricketers with a prevalence of 62.4%. Of these 41 (44%) injuries occurred during matches, 50 (54%) during practice, and 2 (2.1%) injuries were caused during fitness training. The head, neck, and face sustained 3 (3.2%) injuries, while the upper extremities received 35 (37.6%), the lower extremities 39 (41.9%), and the back and trunk 16 (17.2%). The most commonly injured players were fast bowlers 23 (24.7%). First time reported injuries were 66 (70.9%), while those repeated in the past were 16 (17.2%). Severe injuries were 21 (22%), due to which the players returned to the play after more than 21 days.

A study on the contamination assessment, health risk and mobility of two heavy metals in the soil-plants-ruminants system of a typical agricultural region in the semi arid environment.

This study's aim was to investigate iron (Fe) and zinc (Zn) concentration in the soil, forage crops, and sheep blood with respect to the seasonal availability of these metals. Soil, forage, and sheep blood samples were sampled from five different locations in Chakwal (Pidh, Tobar, Ratoccha, Choa Saiden Shah-Kalar Kahar road, and Choa Saiden Shan-Chakwal Road) during two seasons, i.e., winter and summer. All the samples were processed through wet acid digestion for evaluation of metal contents. Because of proximity of site-1 and site-2 to coal mines, higher Fe concentration was observed than Zn. Overall, varied Fe concentrations obtained in soil were 12.95-24.31 mg/kg, 1.29-9.61 mg/kg in forage and 1.17-24 mg/l in blood, whereas Zn values were 1.04-31.9 mg/kg, 1.96-7.02 mg/kg, and 0.16-6.52 mg/l for soil, forages, and blood respectively. The pollution load index value for both Fe (0.01-0.14 mg/kg) and Zn (0.02-0.72 mg/kg) was lesser than 1. Bio-concentration (0.09-2.64mg/kg) and enrichment factor (0.08-7.51 mg/kg) were showing efficient transfer of metals through the food chain. Daily intake and health risk index values of iron were ranged from 0.01 to 1.1 mg/kg/day and 0.02 to 1.05 mg/kg/day. There was a probable chance of upsurge in metal values in coming years due to continued mining activities. Anthropogenic input, mainly mining activities in the study area, have increased the Fe and Zn content in the environment which can ultimately find their way up the food chain, thereby risking the health of grazing livestock.

Quantitative evaluation of zinc metal in meadows and ruminants for health assessment: implications for humans.

Heavy metal pollution in soil, forage, and animals is serious concern nowadays. Current research was conducted in Sargodha to find out the relationship of animals related to the forages and soil pollution. Three sites were selected with three different treatments; site I irrigated with ground water, site II irrigated with the canal water, and site III irrigated with the wastewater. Samples of soil, forage, and animals (blood, hair, feces) were collected from selected sites and were analyzed for metal analysis using atomic absorption spectroscopy. Results indicated that Zn in soil ranged from 24.12 to 37.39 mg/kg; forage, 31.98-44.47 mg/kg; blood of animals, 1.49-2.72 mg/L; hair of animals, 1.37-2.41 mg/kg; and feces of animals, 1.06-2.97 mg/kg. The concentration of zinc in soil and forage was less than permissible limit, but concentration in blood of animals was greater than critical limit suggesting the presence of metal. Bio-concentration factor indicated that metal was accumulated in forages growing at irrigated site. HRI concentration (2.024 mg/kg/day) suggests the accumulation of zinc in animal tissues. Pollution load index and enrichment factor were within the range.

Evaluation of nickel toxicity in wheat as function of diverse type of fertilizers: implications for public health.

Many studies have described the physiological, biochemical, and molecular responses to heavy metal toxicity and deficiencies individually in plants. The present study assess nickel (Ni) concentration in amended soil, plant vegetative parts, and wheat grains, grown under diverse types of fertilizers in Sargodha, Punjab, Pakistan. Different varieties of wheat were grown in pot and fields. Different treatments (municipal solid waste, poultry waste, press mud, farm yard manure) of fertilizers were applied in order to study the metal level increased in different parts (root, shoot, grain) of wheat due to fertilization. Results indicated that metal level was found highest in roots followed by shoot and grain. The highest level of nickel in root was present in V1 (2.35 mg/kg) due to T2 (2.60 mg/kg) treatment. Higher nickel levels in wheat shoot and grains were observed in V5 (2.36 mg/kg) and V8 (2.29 mg/kg), respectively, due to applied treatment T2 (2.57 mg/kg). This study concluded that treatment T9 was proven safe in view of the observed Ni concentration, while treatment T2 (municipal solid waste) resulted in higher accumulation of nickel in wheat grains which showed that municipal solid waste should be treated before their application in agriculture fields to secure the public health. This study recommended that although application of fertilizers increased the plant growth and nutritional value, it also enhanced metal accumulation in the wheat grains which could be harmful for consumers especially human being. Government should take actions to prevent metal toxicity in human food chain.

Two Phase 1, Open-Label, Mass Balance Studies to Determine the Pharmacokinetics of 14 C-Labeled Isavuconazonium Sulfate in Healthy Male Volunteers.

Isavuconazonium sulfate is the water-soluble prodrug of the active triazole isavuconazole. Two phase 1 studies were conducted to identify the metabolic profile and mass balance of isavuconazole and BAL8728 (inactive cleavage product). Seven subjects in study 1 (isavuconazole mass balance) received a single oral dose of [cyano-14 C]isavuconazonium sulfate corresponding to 200 mg isavuconazole. Six subjects in study 2 (BAL8728 mass balance) received a single intravenous dose of [pyridinylmethyl-14 C]isavuconazonium sulfate corresponding to 75 mg BAL8728. Pharmacokinetic parameters of radioactivity in whole blood and plasma and of isavuconazole and BAL8728 in plasma were assessed. Radioactivity ratio of blood/plasma, percentage of dose, and cumulative percentage of radioactive dose recovered in urine and feces for isavuconazole and BAL8728 were assessed. Metabolic profiling was carried out by high-performance liquid chromatography and mass spectrometry. Mean plasma isavuconazole pharmacokinetic parameters included apparent clearance (2.3 ± 0.7 L/h), apparent volume of distribution (301.8 ± 105.7 L), and terminal elimination half-life (99.9 ± 44.6 hours). In study 1, isavuconazole-derived radioactivity was recovered approximately equally in urine and feces (46.1% and 45.5%, respectively). In study 2, BAL8728-derived radioactivity was predominantly recovered in urine (96.0%). Isavuconazole (study 1) and M4 (cleavage metabolite of BAL8728; study 2) were the predominant circulating components of radioactivity in plasma.

Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics.

PURPOSE: The purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal disease (ESRD) on the pharmacokinetics (PK) of isavuconazole and the inactive cleavage product, BAL8728. METHODS: A single intravenous dose of the prodrug isavuconazonium sulfate (372 mg, equivalent to 200 mg isavuconazole and 75 mg of BAL8728 cleavage product) was administered to healthy controls (parts 1 and 2) and participants with mild, moderate, or severe RI (part 2) or ESRD (part 1); ESRD participants received two doses of 200 mg isavuconazole, 1 h post-dialysis (day 1) and prior to dialysis (day 15). Plasma PK parameters for isavuconazole included maximum concentration (C max), area under the concentration-time curve (AUC) from time of dose to 72 h (AUC72), AUC extrapolated to infinity (AUC∞), AUC to last measurable concentration (AUClast), half-life (t ½ h), volume of distribution (V z), and total clearance (CL), for the healthy control group versus those with mild, moderate, or severe RI or ESRD. RESULTS: Isavuconazole C max values were 4% higher in mild RI and 7, 14, and 21% lower in participants with moderate RI, severe RI, or ESRD versus the healthy control group, respectively. When hemodialysis occurred post-dose (day 15), participants with ESRD had a 30% increase in AUC72 for isavuconazole in parallel with reduction of extracellular volume induced by dialysis. Exposure (AUC∞ and AUClast) was not significantly different for participants with mild, moderate, or severe RI versus healthy controls although there was considerable variability. The t1/2 (day 1) was 125.5 ± 63.6 h (healthy control group), 204.5 ± 82.6 h (ESRD group) in part 1, and 140.5 ± 77.7 h (healthy control group), 117.0 ± 66.2 h (mild RI), 158.5 ± 56.4 h (moderate RI), and 145.8 ± 65.8 L/h (severe RI) in part 2. CL was 2.4 ± 0.8 L/h (healthy control group) and 2.9 ± 1.3 L/h (ESRD group) in part 1 and 2.4 ± 1.2 L/h (healthy control group), 2.5 ± 1.0 L/h (mild RI), 2.2 ± 0.8 L/h (moderate RI), and 2.4 ± 0.8 L/h (severe RI) in part 2. The V z was 382.6 ± 150.6 L in the healthy control group and 735.6 ± 277.3 L in ESRD patients on day 1 in part 1 of the study. In part 2 of the study, V z was 410.8 ± 89.7 L in the healthy control group, 341.6 ± 72.3 L in mild RI, 509.1 ± 262.2 L in moderate RI, and 439.4 L in severe RI. CONCLUSIONS: Based on the findings of this study, dose adjustments of isavuconazole are unlikely to be required in individuals with RI or in those with ESRD who receive hemodialysis.

Pharmacokinetic Interaction Between Isavuconazole and a Fixed-Dose Combination of Lopinavir 400 mg/Ritonavir 100 mg in Healthy Subjects.

This phase 1, open-label study evaluated the pharmacokinetic effects of coadministration of the antifungal agent, isavuconazole (administered as its water-soluble prodrug isavuconazonium sulfate), with the antiretroviral agent lopinavir/ritonavir in healthy adults. In part 1, 13 subjects were randomized to 2 arms to receive multiple doses of oral isavuconazole 100 mg either alone or with lopinavir/ritonavir 400/100 mg. In part 2, a different group of 55 subjects were randomized to 3 arms to receive multiple doses of oral isavuconazole 200 mg, either alone or with lopinavir/ritonavir 400/100 mg, or to receive oral lopinavir/ritonavir 400/100 mg alone. Mean area under the concentration-time curve (AUC) following the last dose (AUCτ ) and Cmax of isavuconazole increased by 113% and 96% in part 1 and by 96% and 74% in part 2 in the presence vs absence of lopinavir/ritonavir, respectively. Mean AUCτ and Cmax of lopinavir were 27% and 23% lower, and mean AUCτ and Cmax of ritonavir were 31% and 33% lower in the presence vs absence of isavuconazole, respectively. Mild to moderate gastrointestinal disorders were the most common adverse events experienced. These findings indicate that coadministration of lopinavir/ritonavir with isavuconazole can decrease the exposure of lopinavir/ritonavir and increase the exposure of isavuconazole. Patients should be monitored for reduced antiviral efficacy if these agents are coadministered.

Pharmacokinetic Assessment of Drug-Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults.

This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased the area under the concentration-time curves (AUC0-∞ ) of tacrolimus, sirolimus, and cyclosporine by 125%, 84%, and 29%, respectively, and the AUCs of mycophenolic acid and prednisolone by 35% and 8%, respectively. Maximum concentrations (Cmax ) of tacrolimus, sirolimus, and cyclosporine were 42%, 65%, and 6% higher, respectively; Cmax of mycophenolic acid and prednisolone were 11% and 4% lower, respectively. Isavuconazole pharmacokinetics were mostly unaffected by the immunosuppressants. Two subjects experienced elevated creatinine levels in the cyclosporine study; most adverse events were not considered to be of clinical concern. These results indicate that isavuconazole is an inhibitor of cyclosporine, mycophenolic acid, sirolimus, and tacrolimus metabolism.

Pharmacokinetic Evaluation of CYP3A4-Mediated Drug-Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults.

This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUCτ ) during a dosing interval by 90% and maximum concentration (Cmax ) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC0-∞ ) and Cmax by 422% and 9%, respectively. Isavuconazole was coadministered (200 mg 3 times daily for 2 days, then 200 mg once daily) with single doses of oral midazolam (3 mg; CYP3A4 substrate) or ethinyl estradiol/norethindrone (35 µg/1 mg; CYP3A4 substrate). Following coadministration, AUC0-∞ increased 103% for midazolam, 8% for ethinyl estradiol, and 16% for norethindrone; Cmax increased by 72%, 14%, and 6%, respectively. Most adverse events were mild to moderate in intensity; there were no deaths, and serious adverse events and adverse events leading to study discontinuation were rare. These results indicate that isavuconazole is a sensitive substrate and moderate inhibitor of CYP3A4.

Pharmacokinetic and Pharmacodynamic Evaluation of the Drug-Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects.

This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration-time curves from time 0 to infinity of S- and R-warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S- and R-warfarin by 12% and 7%, respectively, relative to warfarin alone. Mean area under the international normalized ratio curve and maximum international normalized ratio were 4% lower in the presence vs absence of isavuconazole. Mean warfarin area under the prothrombin time curve and maximum prothrombin time were 3% lower in the presence vs absence of isavuconazole. There were no serious treatment-emergent adverse events (TEAEs), and no subjects discontinued the study due to TEAEs. All TEAEs were mild in intensity. These findings indicate that coadministration with isavuconazole has no clinically relevant effects on warfarin pharmacokinetics or pharmacodynamics.

Pharmacokinetic Interactions Between Isavuconazole and the Drug Transporter Substrates Atorvastatin, Digoxin, Metformin, and Methotrexate in Healthy Subjects.

This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein-1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion-transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P-glycoprotein (P-gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P-gp substrate), digoxin (0.5 mg; P-gp substrate), metformin (850 mg; OCT1, OCT2, and MATE1 substrate), or methotrexate (7.5 mg; BCRP, OAT1, and OAT3 substrate) in the presence and absence of clinical doses of isavuconazole (200 mg 3 times a day for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased mean area under the plasma concentration-time curves (90% confidence interval) of atorvastatin, digoxin, and metformin to 137% (129, 145), 125% (117, 134), and 152% (138, 168) and increased mean maximum plasma concentrations to 103% (88, 121), 133% (119, 149), and 123% (109, 140), respectively. Methotrexate parameters were unaffected by isavuconazole. There were no serious adverse events. These findings indicate that isavuconazole is a weak inhibitor of P-gp, as well as OCT1, OCT2, MATE1, or a combination thereof but not of BCRP, OATP1B1, OAT1, or OAT3.

Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects.

This report describes phase 1 clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg, administered as isavuconazonium sulfate 372 mg, 3 times a day for 2 days; 200 mg once daily [QD] thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23). Compared with each drug alone, coadministration with isavuconazole changed the area under the concentration-time curves (AUC∞ ) and maximum concentrations (Cmax ) as follows: bupropion, AUC∞ reduced 42%, Cmax reduced 31%; repaglinide, AUC∞ reduced 8%, Cmax reduced 14%; caffeine, AUC∞ increased 4%, Cmax reduced 1%; dextromethorphan, AUC∞ increased 18%, Cmax increased 17%; R-methadone, AUC∞ reduced 10%, Cmax increased 3%; S-methadone, AUC∞ reduced 35%, Cmax increased 1%. In all studies, there were no deaths, 1 serious adverse event (dextromethorphan study; perioral numbness, numbness of right arm and leg), and adverse events leading to study discontinuation were rare. Thus, isavuconazole is a mild inducer of CYP2B6 but does not appear to affect CYP1A2-, CYP2C8-, or CYP2D6-mediated metabolism.

Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study).

Isavuconazonium sulfate (Cresemba; Astellas Pharma Inc.), a water-soluble prodrug of the triazole antifungal agent isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis. A population pharmacokinetic (PPK) model was constructed using nonparametric estimation to compare the pharmacokinetic (PK) behaviors of isavuconazole in patients treated in the phase 3 VITAL open-label clinical trial, which evaluated the efficacy and safety of the drug for treatment of renally impaired IA patients and patients with invasive fungal disease (IFD) caused by emerging molds, yeasts, and dimorphic fungi. Covariates examined were body mass index (BMI), weight, race, impact of estimated glomerular filtration rate (eGFR) on clearance (CL), and impact of weight on volume. PK parameters were compared based on IFD type and other patient characteristics. Simulations were performed to describe the MICs covered by the clinical dosing regimen. Concentrations (n = 458) from 136 patients were used to construct a 2-compartment model (first-order absorption compartment and central compartment). Weight-related covariates affected clearance, but eGFR did not. PK parameters and intersubject variability of CL were similar across different IFD groups and populations. Target attainment analyses demonstrated that the clinical dosing regimen would be sufficient for total drug area under the concentration-time curve (AUC)/MIC targets ranging from 50.5 for Aspergillus spp. (up to the CLSI MIC of 0.5 mg/liter) to 270 and 5,053 for Candida albicans (up to MICs of 0.125 and 0.004 mg/liter, respectively) and 312 for non-albicans Candida spp. (up to a MIC of 0.125 mg/liter). The estimations for Candida spp. were exploratory considering that no patients with Candida infections were included in the current analyses. (The VITAL trial is registered at ClinicalTrials.gov under number NCT00634049.).

Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-ß and behavior in Tg2576 mice.

RATIONALE: Previous studies indicate that psychosocial stressors could accelerate amyloid-ß (Aß) levels and accelerate plaque deposition in mouse models of Alzheimer disease (AD). Stressors enhanced the release of corticotrophin-releasing factor (CRF), and exogenous CRF administration mimicked the effects of stress on Aß levels in mouse models of AD. However, whether CRF receptor 1 (CRF1) antagonists could influence the stress-induced acceleration of an AD-like process in mouse models has not been well studied. OBJECTIVE: We sought to examine whether CRF1 antagonists inhibit the effects of isolation stress on tissue Aß levels, Aß plaque deposition, and behaviors related to anxiety and memory in Tg2576 mice, and to investigate the molecular mechanism underlying such effects. METHODS: Cohorts of Tg2576 mouse pups were isolated or group-housed at 21 days of age, and then the subgroups of these cohorts received daily intraperitoneal injections of the CRF1 antagonists, antalarmin or R121919 (5, 10, and 20 mg/kg), or vehicle for 1 week. Other cohorts of Tg2576 mouse pups were isolated or group-housed at 21 days of age, and then at 4 months of age, subgroups of these mice were administered antalarmin (20 mg/kg) or vehicle in their drinking water for 6 months. Finally, cultured primary hippocampal neurons from regular Tg2576 pups (P0) were incubated with CRF (0.1, 1, and 10 nM), antalarmin (100 nM) or H-89 (1 µM) for 48 h. Brain tissues or cultured neurons were collected for histological and biochemical analyses, and behavioral measures were collected in the cohorts of mice that were chronically stressed. RESULTS: Administration of antalarmin at 20 mg/kg dose for 1 week significantly reduced Aß1-42 levels in isolation stressed mice. Administration of antalarmin for 6 months significantly decreased plasma corticosterone levels, tissue Aß1-42 levels, and Aß plaque deposition in the brain and blocked the effects of isolation stress on behaviors related to anxiety and memory. Finally, incubation of neurons with 100 nM antalarmin inhibited the ability of 10 nM CRF to increase Aß1-42 levels and protein kinase A IIß expression. The effect of CRF1 on Aß1-42 levels was also diminished by treatment with H-89, a c-AMP/PKA inhibitor. CONCLUSIONS: These results suggest that CRF1 antagonists can slow an AD-like process in Tg2576 mice and that the c-AMP/PKA signaling pathway may be involved in this effect.