Maximum Serum Concentration Research Articles

Therapeutic Drug Monitoring of Protein Unbound Ciprofloxacin Concentrations to avoid inadequate Treatment of severe Bacterial Infections in Critically ill Patients

OBJECTIVES: To develop a reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for therapeutic drug monitoring (TDM) of unbound ciprofloxacin concentrations in critically ill patients. METHODS: Total and unbound ciprofloxacin concentrations of five randomly selected intensive care unit (ICU) patients were measured using UPLC-MS/MS. Method validation included accuracy, linearity, precision, repeatability, and limits of detection and quantification. RESULTS: The median unbound ciprofloxacin fraction was 74.8%, with a median area under the curve from 0-24 h (AUC0-24) and maximum serum concentration (Cmax) of 28.51 h·mg/L and 4.45 mg/L respectively. Median free AUC0-24 (fAUC0-24) and free Cmax (fCmax) were 21.57 h·mg/L and 3.53 mg/L respectively; 20% of patients reached the pharmacodynamic target. The UPLC-MS/ MS method was validated using an intra-assay and inter-assay precision < 3%. Recoveries were between 90-110% CONCLUSIONS: This UPLC-MS/MS method provided reliable unbound ciprofloxacin concentrations, allowing target attainment in critically ill patients and exploration of different dosing regimens.

Temperature-dependent pharmacokinetics of florfenicol in Nile tilapia (Oreochromis niloticus) following single oral and intravenous administration

Temperature-dependent pharmacokinetics (PK) have rarely been reported in tilapia despite there are popularly cultured worldwide, ranging from tropical to temperate climates. The present study aims to investigate the PK characteristics of florfenicol (FF) in Nile tilapia at 3 temperature levels (24, 28, and 32 °C) after single intravenous (IV) and oral (PO) dose of 15 mg/kg to evaluate the effects of temperature on PK. The serum concentrations of FF were analyzed by HPLC-UV method and PK characteristics were analyzed by 2-compartmental model. It was revealed that temperature has profound influences on certain PK parameters. The results from both IV and PO experiments were generally similar. Increasing water temperature from 24 to 32 °C led to significantly increased elimination rate constant (β) from 0.056 to 0.095 1/h and shortened elimination half-life (t1/2β) from 12–13 h to 7–8 h. The absorption half-life (t1/2Ka) were decreased from 2.28 to 1.18 h as well as the maximum serum concentration (Cmax) from 23.14 to 16.71 μg/mL and time to reach Cmax (Tmax) from 1.40 to 0.75 h. The area under the serum concentration-time curves (AUC) were reduced by half while the clearances were doubled and the volume of distributions (Vd) were significantly increased. Our results also demonstrated that for FF in Nile tilapia the temperature coefficient (Q10) values could be applied to predict the CL and β at a specific temperature with high accuracy (94–116%). The temperature-sensitive PK parameters such as the increase in Ka, Vd, and β significantly affected the serum concentrations and its overall exposure (AUC), thereby could potentially implicate that proper dosing regimen should take water temperature into consideration. The study highlighted the possibility of water temperature effect on therapeutic outcome of FF used in tilapia and likely other cichlids.

Soluble HLA-I and HLA-II Molecules Are Potential Prognostic Markers of Progression of Systemic and Local Inflammation in Patients with COPD.

Soluble molecules of the major histocompatibility complex play an important role in the development of various immune-mediated diseases. However, there is not much information on the participation of these proteins in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of our work was to determine the content of soluble molecules of the major histocompatibility complex of classes I and II (sHLA-I and sHLA-II) in the exhaled breath condensate (EBC) and in the blood serum in patients with moderate to severe COPD during the exacerbation and stable phase. We investigated 105 patients (male) with COPD aged 46–67 and 21 healthy nonsmoking volunteers (male) comparable in age. The content of sHLA-I and sHLA-II molecules was studied using ELISA. We found an increase in the level of sHLA-I and sHLA-II molecules in EBC, as well as an enhancement in the serum content of sHLA-II in all the examined COPD patients compared to healthy nonsmoking volunteers. The revealed negative correlation between the serum concentration of sHLA-II and values of FEV1 and FEV1/FVC in all examined patients with COPD gives a possibility to consider the content of these proteins as an additional systemic marker of disease severity. The maximum endobronchial and serum concentrations of sHLA-I and sHLA-II were detected in patients with severe COPD during the exacerbation. The negative associations between the content of these molecules in EBC and serum and the parameters of lung function in patients with severe COPD were established. These findings suggest a pathogenetic role of sHLA-I and sHLA-II molecules in the mechanisms of the development and progression of local and systemic inflammation in COPD.

Randomized, double-blind, placebo-controlled, phase I study of the safety and pharmacokinetics of namilumab in healthy Japanese and Caucasian men

Namilumab is an investigational human monoclonal antibody to human granulocyte-macrophage colony-stimulating factor (GM-CSF). A phase I study of repeated namilumab dosing (150 or 300 mg subcutaneously) in non-Japanese patients with rheumatoid arthritis reported no safety concerns. The objective of this study was to report the safety (primary endpoint) and pharmacokinetic/pharmacodynamic effects of namilumab in healthy Japanese and Caucasian men aged 20-45 years (NCT02354599). 24 Japanese subjects were randomized to a single dose of namilumab (80, 150, or 300mg; n = 6/group) or placebo (n=6; 2subjects randomized/matched dose); 8 Caucasian subjects received namilumab 150mg (n=6) or placebo (n=2). Overall, 29 subjects completed the study (2 withdrew voluntarily; 1 due to a serious adverse event (AE) unrelated to treatment). Baseline demographics were similar across treatment groups; mean age and weight were higher in Caucasians. Namilumab was well tolerated, with no notable safety concerns or pharmacokinetic/pharmacodynamic differences between Japanese and Caucasian subjects. AEs were mild to moderate, with no dose-proportional increase in Japanese subjects. Area under the serum concentration-time curve from zero to infinity (AUC0-∞) and maximum serum concentration (Cmax) increased in a dose-proportional manner in Japanese subjects. AUC0-∞ was similar in Japanese (575.2µg×day/mL) and Caucasian (559.7µg×day/mL) 150-mg groups. Cmax was ~40% higher in Japanese subjects. Mean plasma total GM-CSF concentration-time profiles were similar in the Japanese and Caucasian 150-mg groups. Namilumab induced no clinically-relevant antibody response. Namilumab was well tolerated in Japanese and Caucasian subjects; namilumab 150 mg had similar pharmacokinetics in both populations, supporting further clinical development of this dose. .

Disposition kinetics, in vitro plasma protein binding and tissue residues of tilmicosin in healthy and experimentally (CRD) infected broiler chickens

Background: Several studies assayed the pharmacokinetics of tilmicosin in broilers at a dosage of (25mg/kg.b.wt.). The aim of this study was to investigate the pharmacokinetics and tissue residues of tilmicosin following single and repeated oral administrations (25mg/kg.b.wt.) once daily for 5 consecutive days in healthy and experimentally Mycoplasma gallisepticum and E. coli infected broilers.Methods: After oral administrations of tilmicosin (25 mg/kg.b.wt.) one ml blood was collected from the right wing vein and tissues samples for determination of tilmicosin concentrations and the disposition kinetics of it by the microbiological assay method using Bacillus subtilis (ATCC 6633) as a test organism.Results: In this study, the plasma concentration time graph was characteristic of a two-compartments open model. Following a single oral administration, tilmicosin was rapidly absorbed in both healthy and experimentally infected broilers with an absorption half-life of (t0.5(ab)) 0.45 and 0.52h, maximum serum concentration (Cmax) was 1.06 and 0.69μg/ml at (tmax) about 2.56 and 2.81h, (t0.5(el)) was 21.86 and 22.91h and (MRT) was 32.15 and 33.71h, respectively; indicating the slow elimination of tilmicosin in chickens. The in-vitro protein binding was 9.72±0.83%. Serum concentrations of tilmicosin following repeated oral administration once daily for five consecutive days, almost peaked 2h after each dose with lower significant values recorded in experimentally infected broiler chickens than in healthy ones.Conclusions: This study showed that tilmicosin was cleared rapidly from tissues. The highest residue values were recorded in the lung followed by liver and kidneys while the lowest values were recorded in spleen, fat and thigh muscles. Five days for withdrawal period of tilmicosin suggested in broilers.

In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease.

BackgroundLiver disease (LD) prolongs mirtazapine half‐life in humans, but it is unknown if this occurs in cats with LD and healthy cats.Hypothesis/ObjectivesTo determine pharmacokinetics of administered orally mirtazapine in vivo and in vitro (liver microsomes) in cats with LD and healthy cats.AnimalsEleven LD and 11 age‐matched control cats.MethodsCase‐control study. Serum was obtained 1 and 4 hours (22 cats) and 24 hours (14 cats) after oral administration of 1.88 mg mirtazapine. Mirtazapine concentrations were measured by liquid chromatography with tandem mass spectrometry. Drug exposure and half‐life were predicted using limited sampling modeling and estimated using noncompartmental methods. in vitro mirtazapine pharmacokinetics were assessed using liver microsomes from 3 LD cats and 4 cats without LD.ResultsThere was a significant difference in time to maximum serum concentration between LD cats and control cats (median [range]: 4 [1‐4] hours versus 1 [1‐4] hours; P = .03). The calculated half‐life of LD cats was significantly prolonged compared to controls (median [range]: 13.8 [7.9‐61.4] hours versus 7.4 [6.7‐9.1] hours; P < .002). Mirtazapine half‐life was correlated with ALT (P = .002; r = .76), ALP (P < .0001; r = .89), and total bilirubin (P = .0008; r = .81). The rate of loss of mirtazapine was significantly different between microsomes of LD cats (–0.0022 min−1, CI: −0.0050 to 0.00054 min−1) and cats without LD (0.01849 min−1, CI: −0.025 to −0.012 min−1; P = .002).Conclusions and Clinical ImportanceCats with LD might require less frequent administration of mirtazapine than normal cats.

Preclinical and Clinical Pharmacology of Hydrocodone for Chronic Pain: A Mini Review.

Hydrocodone is one of the most prescribed oral analgesic drugs and it is one of the most abused drugs in general population. It is a mu-opioid agonist predominantly metabolized to the O-demethylated product hydromorphone and to the N-demethylated product norhydrocodone. The purpose of the study is to summarize the preclinical and clinical characteristics of hydrocodone. Pharmacokinetic aspect (terminal half-life, maximum serum concentration, and time to maximum serum concentration) of hydrocodone and the influence of metabolic genetic polymorphism in analgesic response to hydrocodone are also illustrated and commented. Literature on experimental preclinical pharmacology investigating analgesic activity in laboratory animals is furtherly discussed. Moreover, the authors discuss and comment on the updated data regarding safety profile and effectiveness of hydrocodone in the treatment of chronic pain. A bibliographic research was carried out (from February 01, 2018 to August 28, 2018) independently by two researchers (blinded to the authors and initially on results) in the major scientific databases and research engines of peer-reviewed literature on life sciences and biomedical topics, starting from January 1990 to August 2018. Analysis of results of clinical studies suggests that abuse-deterrent extended-release (ER) hydrocodone formulations can be effective and they are well tolerated in the treatment of chronic low back pain. Weaker is the evidence of the analgesic effectiveness of ER hydrocodone on other chronic pain syndromes and non-cancer non-neuropathic chronic pain. In these conditions, hydrocodone showed to have positive effects in non-controlled open studies and needs to be further studied to assess the real strength of results.

Vancomycin Removal During High-Volume Peritoneal Dialysis in Acute Kidney Injury Patients: A Prospective Cohort Clinical Study

IntroductionVancomycin pharmacokinetic data in patients with acute kidney injury (AKI) on high-volume peritoneal dialysis (HVPD) are lacking. The aims were to study the pharmacokinetics of i.v. vancomycin in patients with AKI treated by HVPD who received an i.v. dose of vancomycin (15–20 mg/kg), to determine the vancomycin removal, and to establish vancomycin dosing and evaluation pharmacokinetics target attainment achievement for the empirical treatment of patients with AKI treated by HVPD.MethodsVancomycin was administered 1 hour before dialysis start. Samples of all dialysate were collected for a 24-hour period. Blood samples were collected after 1, 2, 4, and 24 hours of therapy. Vancomycin concentrations were determined using a liquid chromatographic (high-performance liquid chromatography)–fluorescence method. Pharmacokinetic calculations were completed assuming a 1-compartment model.ResultsTen patients completed the study. The mean vancomycin dose administered was 18.0 ± 2.95 mg/kg (14.7–21.8 mg/kg) on the day of study (first day) and the mean percentage of vancomycin removal by HVPD was 21.7% ± 2.2% (16%–29%). Peritoneal clearance was 8.1 ± 2.2 ml/min (5.3–12 ml/min). The serum vancomycin half-life was 71.2 ± 24.7 hours (42–110 hours) during HVPD session, the maximum serum concentration was 26.2 ± 3.5 mg/l, which occurred 1 hour after vancomycin administration and HVPD start. Area under the curve (AUC)0–24/minimum inhibitory concentration (MIC) ratio ≥400 was achieved in all patients when MIC = 1 mg/l was considered.ConclusionHVPD removes considerable amounts of vancomycin in septic patients with AKI. Administration of 18 mg/kg vancomycin each 48 to 72 hours in patients with AKI undergoing HVPD was required to reach and maintain therapeutic concentrations.

INTRANASAL DELIVERY OF ARTEMETHER FOR THE TREATMENT OF CEREBRAL MALARIA

Objective: Nasal delivery provides a route of entry of drug to the brain that circumvents the obstacle for blood-brain barrier allowing direct drug delivery to the central nervous system via olfactory neurons. The objective of work was to prepare solid lipid nanoparticles of antimalarial drug artemether for brain delivery through olfactory delivery route for treatment of cerebral malaria.Methods: Artemether containing solid lipid nanoparticles were prepared with soya lecithin and poloxamer 407 with a hot homogenization method followed by solvent injection technique. The prepared solid lipid nanoparticles were characterized by their shape, particle size, zeta potential, encapsulation efficiency total drug content and drug release study.Results: These solid lipid nanoparticles were observed spherical in shape in scanning electron microscopy, the optimized size was found to be 211.6 nm (Polydispersity Index PI&lt;0.415), with −27mV zeta potential value. The maximum % yield of the formulation was found to be found 49%. The maximum entrapment efficiency was 82% (w/w), and optimized formulation showed 98.07±1.521% drug release form formulation. In vivo studied were conducted on wistar rats after administration of artemether containing solid lipid nanoparticles intranasally and compared with plain artemether solution administered orally. The results of optimized formulation showed the value of biological half-life (T1/2) was 4.95 h, maximum serum concentration Cmax was 644.60ng/ml, time for drug to reach peak plasma concentration Tmax was 1 h volume of distribution (Vd) was 2.7l/kg, body clearance (Cl) was 0.37 lh/kg and Area under curve [AUC]0∞ was 3970.5 nghr/ml for formulation.Conclusion: The results revealed that the brain: plasma concentration ratio was higher after intranasal administration of solid lipid nanoparticles (SLNs) of artemether than the oral route. In conclusion, the intranasal administration of lipid nanoparticles of artemether could provide complete protection against cerebral malaria.

Pharmacokinetics and Tissue Residues of Tilmicosin in Normal and Experimentally Mycoplasma Gallisepticum-Infected Broiler Chickens

The present study was conducted to investigate the pharmacokinetics of tilmicosin (25 mg/kg b.wt.) following single and repeated oral administration (once daily for three consecutive days) as well as tissue residues in normal and experimentally Mycoplasma gallisepticum-infected broiler chickens. Following single administration of tilmicosin in normal chickens, the drug reached its maximum serum concentrations (Cmax) after 2.45±0.01 h of administration with value of 0.97±0.04 µg/ml. Absorption half-life (t0.5ab) of tilmicosin was 0.89±0.02 h and the elimination half-life (t0.5el) was 14.73 ±1.24 h. The repeated oral administration of tilmicosin in normal and Mycoplasma gallisepticum- infected chickens revealed a lower significant serum tilmicosin concentration after all times of sampling in infected chickens compared to those of normal chickens. Tilmicosin residues was assayed in lung, kidney, liver, heart, breast muscle, thigh muscle, fat and skin after 24, 48, 72, 96, 120 and 144 h post last dose. The results showed that the highest residue values were recorded in lung followed by liver and kidneys while the lowest values were recorded in heart. Tilmicosin residues were not detected in all tested tissues except in lung till 5th day after sessation of drug administration. However, all the tested tissues were free from tilmicosin residues after 5th day after sessation of tilmicosin administration and this suggest a withdrawal period of five days for tilmicosin in broiler chickens. In conclusion, timicosin has rapid absorption, long elimination half-life, rapid and extensive penetration from blood into tissues especially lungs. Additionally, timicosin had a short

Can toxicokinetics of (synthetic) cannabinoids in pigs after pulmonary administration be upscaled to humans by allometric techniques?

Being advertised and distributed as attractive substitutes of cannabis, synthetic cannabinoids (SC) are gaining increasing relevance in forensic and clinical toxicology. As no data from controlled human studies are available, SC are sold and consumed without the knowledge of their toxicokinetic (TK) and toxicodynamic properties. Hence, animal models coupled with mathematical approaches should be used to ascertain those properties. Therefore, a controlled pig TK study allowing for extrapolation to human data was performed. For this purpose, eleven pigs received a single pulmonary dose of 200 µg/kg body weight each of Δ9-tetrahydrocannabinol (THC), 4-ethylnaphthalene-1-yl-(1-pentylindole-3-yl)methanone (JWH-210) as well as 2-(4-methoxyphenyl)-1-(1-pentyl-indole-3-yl)methanone (RCS-4) via an ultrasonic nebulizer. Blood and urine samples were repeatedly drawn over 8 h. Serum-concentration-time profiles of the parent compounds were determined using LC-MS/MS. Urine specimens were analyzed by LC-HR-MS/MS in order to elucidate the main metabolites. Maximum serum concentrations were reached 10–15 min after beginning of nebulization and amounted to 66 ± 36 ng/mL for THC, 41 ± 11 ng/mL for JWH-210, and 34 ± 8.9 ng/mL for RCS-4. The serum-concentration-time profiles of THC, JWH-210, and RCS-4 were best described by three-compartment models with first order absorption and elimination processes. Absorption from the lungs to serum was modeled by first-order processes. The determination of the bioavailability yielded 23.0%, 24.2%, and 45.7% for THC, JWH-210, and RCS-4, respectively. Furthermore, the developed THC model was upscaled to humans using allometric scaling techniques. A successful prediction of human concentration-time profiles could be done. Also the metabolic patterns were in good agreement with human data. In conclusion, these findings are the first reported regarding the TK properties of SC after pulmonary administration to pigs. The presented method of TK serves as an appropriate predictor of human TK of cannabinoids.

Antibacterial activity of amoxicillin in vitro and its oral bioavailability in broiler chickens under the influence of 3 water sanitizers

The interaction of 3 water sanitizers (sodium hypochlorite, iodine-polyvinylpyrrolidone, and citrate) utilized in poultry production on antibacterial activity and bioavailability of amoxicillin trihydrate (AMX) were studied. Sanitizers were mixed with AMX in prepared water, the resulting substances were regarded as amoxicillin-sanitizer products (ASP). First, the in vitro antibacterial activity of each ASP was compared to that of AMX. Then, pharmacokinetics (PK) of ASP and AMX diluted in prepared water, were carried out in broiler-chickens. Amoxicillin or ASP (20mg/kg) from different concentrations of sanitizers was directly placed into the chicken's crop and blood samples were taken. Basic PK parameters were obtained. Serum activity/concentrations of AMX were assessed by agar diffusion and corroborated with high performance liquid chromatography. Results show that ASP of AMX/sodium hypochlorite decrease both, the antimicrobial activity of in vitro AMX and its relative bioavailability (Fr) assessed with the maximum serum concentration (Cmax), the area under the concentration-time curve, and the mean residence time (MRT) (3.80μg/mL, 2.70μg/mL·h, and 0.59h, respectively), compared to the AMX administered alone (12.54μg/mL, 44.02μg/mL·h, and MRT 2.78h). ASP from amoxicillin/ionophore, reduced the Cmax (10.62μg/mL), Fr (94.67%), and MRT (2.07h), at the highest tested concentrations. In contrast, the 2 highest concentrations of the citrate sanitizer increased the Cmax (15.07 and 15.47μg/mL), Fr (119 and 132%), and MRT (3.32 and 4.06h) and their in vitro antimicrobial activity. Interactions between the tested water sanitizers and AMX modify the Cmax, Fr, MRT of the latter, altering the PK/pharmacodymanic ratios for a time-dependent antibiotic. Results also reveal that the use of amoxicillin trihydrate administered through the drinking water does not meet the required PK/pharmacodymanic ratios. Thus, it is here postulated that this antibiotic should be administered at least twice a day and that its interaction with water sanitizers should be considered.

Disposition Kinetics of Cefepime in Healthy and Experimentally Salmonella Typhimurium Infected Broiler Chicken

Cefepime is a broad-spectrum semi synthetic β-lactamase resistant fourth generation cephalosporin. Looking to potential for clinical use, pharmacokinetics of cefepime following single intravenous and intramuscular (IM) dose (100mg/kg b. wt.) in healthy and experimentally Salmonella typhimurium infected broiler chickens were determined. Cefepime concentration in plasma samples was determined by reverse-phase high performance liquid chromatography with mobile phase. The mobile phase was a mixture of 10mM phosphate buffer (pH 7): Methanol; 75:25 was always freshly prepared. Flow rates were 1 ml/min. UV detection was performed at 256 nm, injection volume was 20 µl. After a single intravenous injection, cefepime reached its maximum serum concentrations of 4.28 ± 0.37μg/ml in normal chickens, while in the infected chickens, the maximum serum concentration was 2.62 ± 0.72 μg/ml. Cefepime was eliminated after intravenous injection with half-life (t1/2 β) of 4.608 ± 0.145 h in normal which significantly longer than 4.19 ± 0.158 h in infected chickens. The mean residence time (MRT) was 6.51 ± 0.189h in normal vs 5.86±0.18 h in infected chickens. After IM administration the drug reached its maximum serum concentrations of 193.06 ± 2.27μg/ml at maximum time of 1.138 ± 0.012 h in normal, while in infected chickens the maximum serum concentrations was 132.93 ± 1.53μg/ml attained at maximum time of 1.265 ± 0.013 h. In conclusion a cefepime at dose of 100 mg/kg administered intravenously or IM at 24 h intervals may provide successful treatment of chicken infected with Salmonella typhimurium.

Pharmacokinetics of 400 mg Locally Infiltrated Ropivacaine After Total Knee Arthroplasty Without Perioperative Tourniquet Use.

Local infiltration analgesia (LIA) with ropivacaine for total knee arthroplasty (TKA) is increasingly used. Despite the high doses of ropivacaine, LIA is considered safe, and this perception is sustained by pharmacokinetic data demonstrating that maximum concentrations of ropivacaine stay well below the toxic threshold in plasma. These pharmacokinetic studies all involve TKA procedures with the use of a tourniquet. Recently, performing TKA without the use of a tourniquet is gaining popularity, but no pharmacokinetic data exist when LIA is administered for TKA without the use of a tourniquet. The purpose of this study was to describe the pharmacokinetic profile of a single-shot ropivacaine (200 mL 0.2%) and 0.75 mg epinephrine (1000 μg/mL) when used for LIA in patients for TKA without a tourniquet. In this prospective cohort study, 20 patients treated with LIA for TKA without a tourniquet were studied. Plasma samples were taken at 20, 40, 60, 90, 120, 240, 360, 480, 600, 720, and 1440 minutes after local anesthetic infiltration, in which total and unbound ropivacaine concentrations were determined. Results are given as median (interquartile range [IQR]). Median peak ropivacaine concentration was 1.16 μg/mL (IQR, 0.46); median peak unbound ropivacaine concentration was 0.05 μg/mL (IQR, 0.02). The corresponding times to reach the maximum concentration for total and unbound ropivacaine were 360 (IQR, 240) and 360 (IQR, 360) minutes, respectively. Although great interindividual variability in ropivacaine concentration was found, both total and unbound maximum serum concentrations remained below the assumed systemic toxic thresholds in all samples. This study was registered at Netherlands Trial Registry (http://www.trialregister.nl), trial ID NTR6306.

A Phase I, Single‐Ascending‐Dose Study in Healthy Subjects to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DS‐2969b, a Novel GyrB Inhibitor

DS-2969b is a novel GyrB inhibitor in development for the treatment of Clostridium difficile infection. The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on normal gastrointestinal microbiota groups of single daily oral ascending doses of DS-2969b in healthy subjects. The study enrolled 6 sequential ascending dose cohorts (6mg, 20mg, 60mg, 200mg, 400mg, and 600mg). In each cohort, 6 subjects were administered DS-2969b and 2 subjects were administered matching placebo. DS-2969b was safe and well tolerated at all dose levels examined. All adverse events related to DS-2969b were mild to moderate in severity and predominantly related to the gastrointestinal tract. DS-2969a (free form of DS-2969b) plasma concentrations increased with increasing doses; however, both the maximum serum concentration and area under the plasma concentration-time curve generally increased less than dose proportionally. DS-2969a was predominantly eliminated in the urine, with feces as a minor route of elimination. While the overall proportion of DS-2969a eliminated in the feces was low, target fecal levels sufficient for C. difficile eradication were achieved within 24hours of administration with doses of 60mg or higher. In exploratory analyses, DS-2969b appeared to reduce bacterial counts in 8 of the 25 groups of normal intestinal microbiota examined, suggesting that DS-2969b has only a mild effect on intestinal microbiota. Data from this study support and encourage further development of DS-2969b as a novel treatment for C. difficile infection.

Randomized, controlled study of bleselumab (ASKP1240) pharmacokinetics and safety in patients with moderate-to-severe plaque psoriasis.

This study evaluated the pharmacokinetics (PK), efficacy, safety, and tolerability of bleselumab – a fully‐human anti‐CD40 monoclonal recombinant IgG4. Patients with moderate‐to‐severe psoriasis were randomized on day 1 to receive bleselumab or placebo on days 1, 15 and 29 in a dose‐escalation of bleselumab at 0.1, 0.3, 1.0 or 3.0 mg/kg. The safety‐analysis set (SAF) and full‐analysis set (FAS) included all patients who received bleselumab or placebo, and the PK‐analysis set (PKAS) included patients in the SAF with ≥1 quantifiable serum bleselumab concentration. Serial blood samples were collected after each dose, and the bleselumab serum concentration was measured. After each dose, the area‐under‐the‐concentration–time curve over 336 hours (AUC336) and the maximum serum concentration (Cmax), and dose proportionality of AUC336 and Cmax were determined. The psoriasis area and severity index (PASI) score, the physician static global assessment (PSGA) score, the percentage body surface area (%BSA) affected with psoriasis, adverse events and laboratory parameters were assessed. Sixty patients were randomized and included in the SAF/FAS (bleselumab, n = 49; placebo, n = 11); 48 formed the PKAS. Bleselumab Cmax and AUC336 were more than dose proportional in the range 0.1–3.0 mg/kg, suggesting nonlinear PK after single/multiple doses. No clinically significant infusion reactions, cytokine‐release syndrome, or thromboembolic events were reported. Bleselumab did not improve the PASI scores, PSGA scores, or %BSA versus placebo. Transient elevation of alanine aminotransferase and aspartate aminotransferase levels by >3 × upper limit of normal were observed in four (8.2%) and two (4.1%) patients, respectively, in the 1.0 or 3.0 mg/kg groups. Patients with liver function test increases had no concurrent changes in bilirubin. Bleselumab demonstrated nonlinear PK after single and multiple doses, with few adverse reactions.

Influence of chlorine, iodine, and citrate-based water sanitizers on the oral bioavailability of enrofloxacin in broiler chickens

This experiment was conducted to determine if the 3 most commonly used water sanitizers in commercial broiler chicken production affected the stability of enrofloxacin (ENR), when each was administered concurrently with ENR to broiler chickens via the drinking water. To that effect, the in vitro antibacterial activity of the solution of each ENR-sanitizer product (ESP) was compared to that of ENR alone. Also, bioavailability (F) studies of ESP were carried out in chickens and compared to the corresponding values of ENR in drinking water without sanitizer. Water sanitizers tested were iodine (as iodine-polyvinylpyrrolidone), chlorine (as sodium hypochlorite), and a citrate-based sanitizer from grapefruit extract. They were mixed with ENR in sterile de-ionized water, and the resulting substances were regarded as ESP. Then, the referred studies of ESP were carried out. Results showed that ESP of ENR/sodium hypochlorite decreased both the antimicrobial activity, as well as maximum serum concentration (Cmax) and F of ENR in chickens. ESP of ENR/citrate-based sanitizer increased both the in vitro antimicrobial activity and Cmax and F values of ENR at the 2 highest concentrations tested. ESP of ENR/iodine reduced both in vitro antimicrobial activity and Cmax values of ENR at the highest concentrations tested. This study demonstrated that interactions between water sanitizers and ENR must be considered when medicating chickens via the drinking water to meet pharmacokinetics/pharmacodynamics ratios. The use of a citrate-based sanitizer is recommended, as relative F was increased.

Impact of Novel Antidepressants on Cardiac 123I-Metaiodobenzylguanidine Uptake: Experimental Studies on SK-N-SH Cells and Healthy Rabbits

123I-metaiodobenzylguanidine (123I-MIBG) has independent prognostic value for risk stratification among heart failure patients, but the use of concomitant medication should not affect its quantitative information. We evaluated whether the 4 classes of antidepressants currently most prescribed as first-line treatment for major depressive disorder (MDD) have the potential to alter 123I-MIBG imaging results. Methods: The inhibition effect of desipramine, escitalopram, venlafaxine, and bupropion on 131I-MIBG uptake was assessed by in vitro uptake assays using human neuroblastoma SK-N-SH cells. The half-maximal inhibitory concentration of tracer uptake was determined from dose-response curves. To evaluate the effect of intravenous pretreatment with desipramine (1.5 mg/kg) and escitalopram (2.5 or 15 mg/kg) on 123I-MIBG cardiac uptake, in vivo planar 123I-MIBG scanning of healthy New Zealand White rabbits was performed. Results: The half-maximal inhibitory concentrations of desipramine, escitalopram, venlafaxine, and bupropion on 131I-MIBG cellular uptake were 11.9 nM, 7.5 μM, 4.92 μM, and 12.9 μM, respectively. At the maximum serum concentration (as derived by previous clinical trials), the inhibition rates of 131I-MIBG uptake were 90.6% for desipramine, 25.5% for venlafaxine, 11.7% for bupropion, and 0.72% for escitalopram. A low inhibition rate for escitalopram in the cell uptake study triggered investigation of an in vivo rabbit model: with a dosage considerably higher than used in clinical practice, the noninhibitory effect of escitalopram was confirmed. Furthermore, pretreatment with desipramine markedly reduced cardiac 123I-MIBG uptake. Conclusion: In the present in vitro binding assay and in vivo rabbit study, the selective serotonin reuptake inhibitor escitalopram had no major impact on neuronal cardiac 123I-MIBG uptake within therapeutic dose ranges, whereas other types of first-line antidepressants for MDD treatment led to a significant decrease. These preliminary results warrant further confirmatory clinical trials regarding the reliability of cardiac 123I-MIBG imaging, in particular, if the patient's neuropsychiatric status would not tolerate withdrawal of a potentially norepinephrine-interfering antidepressant.

Increased bioavailability of tylosin phosphate as in-feed medication formulated for long-action pellets in broiler chickens

Circadian variation of serum concentrations of tylosin in broiler chickens after in-feed medication prompted a comparison study of the serum profiles of this drug after in-feed medication with standard tylosin phosphate (Tprf reference formulation group), and after in-feed medication with a sustained-release pellet formulation (Tpsr group), based on Patent No.MX/a/2012/013222 and PCT/MX2013/000137, in broiler chickens. Six hundred 4-week-old Ross broiler chickens were in-feed medicated with tylosin phosphate at an approximate dose of 25.2 mg/kg/d, based on daily feed consumption values and a final concentration of tylosin in feed of 200 mg/kg of feed. Approximately 2 to 3 mL of blood were obtained per 5 chickens every 2 h, avoiding the sampling of a bird more than once and during 72 h after making medicated feed available for the first time. Serum concentrations of tylosin were determined by HPLC. Gaussian multi-peak regressions were then fitted to serum concentration vs. time profiles. Day by d areas under the serum concentration vs. time profiles (AUC0–24), as well as overall AUC0–72, were statistically higher for the Tpsr group (P < 0.001). Also, maximum serum concentrations obtained and relative bioavailability for the Tpsr formulation were statistically higher (382.8%) as compared to the Tprf group (P < 0.01). Considering the referred improved values of AUC observed in the Tpsr formulation, as well as the fact that tylosin is a time-dependent antibacterial drug, better clinical responses are postulated with this pharmaceutical preparation intended for chickens. Tissue deposition studies for this new formulation of tylosin are required.

Anti-Rift Valley fever virus activity in vitro, pre-clinical pharmacokinetics and oral bioavailability of benzavir-2, a broad-acting antiviral compound

Rift Valley fever virus (RVFV) is a mosquito-borne hemorrhagic fever virus affecting both humans and animals with severe morbidity and mortality and is classified as a potential bioterror agent due to the possible aerosol transmission. At present there is no human vaccine or antiviral therapy available. Thus, there is a great need to develop new antivirals for treatment of RVFV infections. Benzavir-2 was previously identified as potent inhibitor of human adenovirus, herpes simplex virus type 1, and type 2. Here we assess the anti-RVFV activity of benzavir-2 together with four structural analogs and determine pre-clinical pharmacokinetic parameters of benzavir-2. In vitro, benzavir-2 efficiently inhibited RVFV infection, viral RNA production and production of progeny viruses. In vitro, benzavir-2 displayed satisfactory solubility, good permeability and metabolic stability. In mice, benzavir-2 displayed oral bioavailability with adequate maximum serum concentration. Oral administration of benzavir-2 formulated in peanut butter pellets gave high systemic exposure without any observed toxicity in mice. To summarize, our data demonstrated potent anti-RVFV activity of benzavir-2 in vitro together with a promising pre-clinical pharmacokinetic profile. This data support further exploration of the antiviral activity of benzavir-2 in in vivo efficacy models that may lead to further drug development for human use.