Maximum Drug Concentration Research Articles

Pharmacokinetics and Bioequivalence of Two Formulations of Montelukast Sodium Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

Montelukast sodium is a leukotriene type 1 receptor antagonist that can be used for the prophylaxis and treatment of asthma. However, the pharmacokinetics of montelukast sodium tablets (10mg) remain unclear in healthy Chinese subjects. Here, a single-dose randomized, open-label, 2-sequence, and 2-period crossover (7-day washout period between treatments) study was performed to compare the pharmacokinetics and bioequivalence between the test products and the reference at a single dose of 10mg among healthy Chinese subjects under fasting and fed conditions. Blood samples were collected at specified time points to analyze the plasma concentrations of montelukast by a validated liquid chromatography-tandem mass spectrometry method. The results showed that the 90% confidence interval values of the geometric mean ratio of test/reference for the maximum plasma drug concentration, area under the concentration-time curve from time 0 to the end, and area under the concentration-time curve from time 0 to infinity were within the range of 80%-125%. Moreover, both the test and reference formulations were safe and well tolerated, with no occurrence of severe adverse events. These results demonstrate that both the test montelukast sodium tablets and the reference showed similar bioequivalence, safety, and tolerability among healthy Chinese subjects under fasting and fed conditions.

DEVELOPMENT OF GABAPENTIN-LOADED SOLID LIPID NANOPARTICLE FOR ALLEVIATING SEIZURE ACTIVITY IN PICROTOXIN AND BICUCULLINE-INDUCED RATS

Objective: The current research aimed to prepare gabapentin-loaded Solid Lipid Nanoparticles (SLN) for alleviating seizure activity in picrotoxin and bicuculline-induced Wistar rats. Methods: Gabapentin-loaded SLNs were formulated using a Box-Behnken experimental design with three-level three-factor consisting of 17 experimental runs by micro-emulsification. Three independent parameters were considered in this study, namely sodium glyceryl tripalmitate (A), RPM (B), and Poloxamer-188 (C). Particle size, drug release, and Encapsulation Efficiency (EE) as dependent variables. The formulation was evaluated for drug release, EE, Attenuated Total Reflection (ATR), Differential Scanning Calorimetry (DSC), X-ray diffraction (XRD), surface morphology, particle size, zeta potential, in vivo anti-convulsion study. Results: The data collected during the experiment includes the measurements of EE (Encapsulation Efficiency), drug release at the 12th h, and particle size. It was reported that formulations containing a high concentration of Glyceryl tripalmitate (50%) had a high Encapsulation Efficiency (EE). The in vitro release results indicate that F17 demonstrated a maximum drug concentration of 99.99% within a 12 h. The optimization process was conducted using mathematical and graphical methods. From ATR spectra, it was found that there are no such major interactions between gabapentin and excipients. A significant endothermal peak was seen in the DSC investigation at 208.81 °C. X-ray diffraction revealed that gabapentin was present in the crystalline form. Drug crystals and SLN were seen to be dispersed and scattered from Scanning Electron Microscope (SEM). The optimized formulation's particle size was found to be 203.4 nm, the Polydispersity Index (PI) of 0.426, and the zeta value of 16.5 mV; indicating stability. Following a lethal and chronic dosage of picrotoxin, the gabapentin-SLN exhibited a higher anticonvulsant efficacy, according to in vivo research on rats (p<0.05). Conclusion: Compared to the Bicuculline model, the optimized SLN demonstrated superior outcomes regarding seizure initiation in the Picrotoxin-induced convulsion.

Therapeutic Drug Monitoring of Elexacaftor, Tezacaftor, and Ivacaftor in Adult People with Cystic Fibrosis.

Elexacaftor, tezacaftor, and ivacaftor (ETI) have significantly improved lung function in people with cystic fibrosis (pwCF). Despite exceptional improvements in most cases, treatment-related inter-subject variability and drug-drug interactions that complicate modulator therapy have been reported. This retrospective analysis presents data on the serum concentration of ETI in our pwCF with full or reduced dosage from August 2021 to December 2023 via routine therapeutic drug monitoring (TDM). The data were compared with the maximum drug concentrations (Cmax) from the pharmaceutical company's summary of product characteristics. A total of 786 blood samples from 155 pwCF (41% female, 59% male) were analyzed. The examinations were divided into four groups: full dose within the given tmax (38.5% of all measurements), full dose outside the tmax (29%), reduced dose within the tmax (19.2%), and reduced dose outside the tmax (13.2%). In pwCF receiving the full dose and blood taken within the tmax, 45.3% of serum concentrations of elexacaftor, 51.1% of serum concentrations of ivacaftor, and 8.9% of serum concentrations of tezacaftor were found to be above the Cmax, respectively. For those on reduced doses within the tmax, 24.5% had a serum concentration of elexacaftor, 23.2% had a serum concentration of ivacaftor, and 2.5% had a serum concentration of tezacaftor above the Cmax, respectively. Many pwCF under ETI therapy have Cmax values for elexacaftor and ivacaftor above the recommended range, even on reduced doses or before the tmax was reached. This highlights the value of a TDM program. Further pharmacokinetic studies are necessary.

Assessment of basic pharmacokinetic parameters of dapagliflozin in TTS formulations in male minipigs

Given the extended time over which diabetes treatment is administered, the transdermal delivery system is anticipated to be a more suitable option for older individuals who may experience difficulty swallowing. The continuous delivery of dapagliflozin and more stable plasma levels are anticipated to reduce the incidence of side effects and the frequency of dosing. The objectives of the study were to determine the safety and plasma pharmacokinetics of dapagliflozin in male minipigs following application of the ointment and skin patch. In the initial phase of the study, the potential for transdermal permeation of dapagliflozin from ointment and transdermal patch to blood plasma of 15 male Göttingen minipigs was investigated. In the subsequent phase, the efficacy of utilising patches of varying strengths and sizes was assessed. The LC/MS method was employed to quantify the concentration of the active substance. The transportation of the studied API to the general circulation and accumulation in tissues were confirmed. The maximum drug concentration (122.99 ng/mL) in plasma was observed on the fourth day of application. The highest calculated Cmax was 131.91 ng/mL with a mean AUC0-last of 6620.7 ng h/mL. Following transdermal administration, dapagliflozin is excreted in the urine. The trend between urinary dapagliflozin 3-O-glucuronide levels and urinary glucose excretion was also observed. The transdermal patch has been demonstrated to be an effective drug delivery system for dapagliflozin.

Comparative Bioequivalence Studies of doxysam and doxycycline (Pfizer) by reversed phase HPLC.

Isocratic high performance liquid chromatography on reversed phase a (150x 4.6 mm I.D), 5 ?m ?-Bondapak RP-8 column (with acidic mobile phase allow the separation of doxcycycline hydrochloride with low detection limit of 0.2 µg/ml detected by UV set at 226 nm. The method was validated for Doxycycline between 0.156- to 5 µg/ml. The concentration of doxycycline was assessed in two single dose randomized crossover studies with intervals of one week between two period. In sera of 20 adults healthy male volunteers with average age of (42 + 10) year, body weight 48-85 kg, body height of (160-185cm) after a single dose of doxycycline hydrochoride 100 mg in form of capsules were orally administrated for both formulations. The blood samples (2ml) were drawn concomitantly from 0.5 – 24 hours. µg The pharmacokinetics parameter were obtained from the mean serum concentration measured at various sampling times for both formulations. The maximum peak concentration (Cmax) of doxycycline reference drug from Pfizer In serum was (3.1 +0.094 µg /ml) attained in 2 hrs. While the maximum concentration (Cmax) of test drug doxysam (2.8 +0.098 µg /ml) attained in about 2 hrs, both drug have long elimination time with half time of approximately (13 hrs.) Both test and reference drug were show no significant difference in pharmacokinetics parameters, so they were considered to be bioequivalent.

Novel Patient-Friendly Orodispersible Formulation of Ivermectin is Associated With Enhanced Palatability, Controlled Absorption, and Less Variability: High Potential for Pediatric Use.

Ivermectin has been used since the 1980s as an anthelmintic and antiectoparasite agent worldwide. Currently, the only available oral formulation is tablets designed for adult patients. A patient-friendly orodispersible tablet formulation designed for pediatric use (CHILD-IVITAB) has been developed and is entering early phase clinical trials. To inform the pediatric program of CHILD-IVITAB, 16 healthy adults were enrolled in a phase I, single-center, open-label, randomized, 2-period, crossover, single-dose trial which aimed to compare palatability, tolerability, and bioavailability and pharmacokinetics of CHILD-IVITAB and their variability against the marketed ivermectin tablets (STROMECTOL) at a single dose of 12 mg in a fasting state. Palatability with CHILD-IVITAB was considerably enhanced as compared to STROMECTOL. Both ivermectin formulations were well tolerated and safe. Relative bioavailability of CHILD-IVITAB compared to STROMECTOL was estimated as the ratios of geometric means for Cmax, AUC 0-∞, and AUC0-last, which were 1.52 [90% CI: 1.13-2.04], 1.27 [0.99-1.62], and 1.29 [1.00-1.66], respectively. Maximum drug concentrations occurred earlier with the CHILD-IVITAB formulation, with a median Tmax at 3.0 h [range 2.0-4.0 h] versus 4.0 h [range 2.0-5.0 h] with STROMECTOL (P =.004). With CHILD-IVITAB, variability in exposure was cut in half (coefficient of variation: 37% vs 70%) compared to STROMECTOL. Consistent with a more controlled absorption process, CHILD-IVITAB was associated with reduced variability in drug exposure as compared to STROMECTOL. Together with a favorable palatability and tolerability profile, these findings motivate for further clinical studies to evaluate benefits of such a patient-friendly ODT formulation in pediatric patients with a parasitic disease, including infants and young children <15 kg.

Ocular pharmacokinetics of acetazolamide from intravitreal implants by high-performance liquid chromatography coupled to tandem mass spectrometry

Glaucoma, a leading cause of irreversible blindness, affects about 70 million people globally. Its treatment focuses on reducing intraocular pressure. Acetazolamide, a potent anti-glaucoma drug, is currently used only systemically due to low solubility and permeation, which cause severe side effects. Developing topical medications with acetazolamide requires robust analytical methods for its detection in biological samples. In this context, this study aimed to develop a method to quantify acetazolamide in rabbit vitreous humor samples. The method involved a simple, fast, inexpensive, and environmentally friendly protein precipitation step for sample preparation, needing just 50 μL of sample and 200 μL of organic solvent, with adequate recovery. This was combined with high-performance liquid chromatography coupled to tandem mass spectrometry, enabling highly sensitive (LOQ of 5 ng/mL) quantification within only 5 min. The method proved to be selective, precise, and accurate, with well-fitted analytical curves, with no carryover, and no matrix effect impacting reliability. The method was successfully applied to analyze vitreous humor samples from rabbits in pharmacokinetic studies, monitoring drug release from intravitreal implants. Results showed a controlled release profile, with a maximum drug concentration (Cmax) of 426.01 ± 64.57 ng/mL, time to reach Cmax (Tmax) of 28 days, and area under the curve (AUC0–42 and AUC0-∞) of 7722.66 ± 1125.96 ng days/mL and 8998.11 ± 1311.92 ng days/mL, respectively. The device demonstrated significantly slower elimination, ensuring therapeutic levels for an extended period when compared to intravitreal injection.

Effect of Levobupivacaine Hydrochloride-Loaded Nanospheres on Delayed Cerebral Vasospasm Following Subarachnoid Hemorrhage in Rabbits

This research was aimed to analyze the mechanism of action of levobupivacaine hydrochloride-loaded nanospheres on delayed cerebral vasospasm following subarachnoid hemorrhage (SAH). Levobupivacaine hydrochloride-loaded nanospheres (LevoBPV Hcl/PLGA) were prepared using the solvent evaporation methodology, with the raw material as a control. The blood drug concentrations were detected by HPLC after subcutaneous and subarachnoid administration in experimental rabbits. Forty New Zealand white rabbits were randomly assigned into Sham group, SAH group, LevoBPV Hcl group (10 mg/kg), and LevoBPV Hcl/PLGA group (10 mg/kg), with 10 rabbits in each group. The SAH model was induced using the double blood injection methodology combined with internal carotid artery ligation. Brain tissue samples were collected on day 7 for pathological characterization, determination of neuronal apoptosis, and measurement of basilar artery diameter and area. The levels of oxidative stress factors (superoxide (SOD), malondiadehyde (MDA), glutathione peroxidase (GSH-Px)) and vasoconstrictor factors (nitric oxide (NO), endothelin-1 (ET-1)) in the cerebrospinal fluid (CSF) were detected using assay kits. The results revealed that the drug loading capacity of LevoBPV Hcl/PLGA was 29.13%, encapsulation efficiency was 87.09%, and the average particle size was 81.43 μm. Under the same dosage, both subcutaneous and subarachnoid administration of LevoBPV Hcl/PLGA exhibited two concentration peaks in the blood drug concentration, with lower concentration values versus LevoBPV Hcl group, and a longer average residence time than LevoBPV Hcl group (P &lt; 0.05). Relative to Sham group, SAH group exhibited decreased diameter and area of the basilar artery, reduced neuronal density, increased neuronal apoptosis rate, decreased levels of SOD, GSH-Px, and NO in the CSF, and increased levels of MDA and ET-1 (P &lt; 0.05). Moreover, LevoBPV Hcl group and LevoBPV Hcl/PLGA group showed increased diameter and area of the basilar artery, higher neuronal density, reduced neuronal apoptosis rate, elevated levels of SOD, GSH-Px, and NO in the CSF, and decreased levels of MDA and ET-1 versus SAH group (P &lt; 0.05). The LevoBPV Hcl/PLGA group exhibited increased diameter and area of the basilar artery, higher neuronal density, reduced neuronal apoptosis rate, elevated levels of SOD, GSH-Px, and NO in the CSF, and decreased levels of MDA and ET-1 versus LevoBPV Hcl group (P &lt; 0.05). In short, LevoBPV HCl-loaded nanospheres can prolong the in vivo residence time of subcutaneous and subarachnoid administration, reduce the maximum blood drug concentration, and enhance drug safety. Furthermore, these nanospheres can inhibit neuronal apoptosis following SAH, regulate oxidative stress and vasoconstrictor factor expression, thereby suppressing the occurrence of delayed cerebral vasospasm and alleviating brain tissue damage.

Pharmacokinetic Profile and Comparative Bioavailability of an Oral Fixed-Dose Combination of Metformin and Acetylsalicylic Acid (Aspirin).

Patients with diabetes face a 2-4-fold greater cardiovascular risk compared to those without diabetes. Both metformin and acetylsalicylic acid (aspirin) treatment have demonstrated a significant reduction in this risk. This single-center, open-label, sequence randomized, 2×2 crossover, single-dose clinical trial evaluated the pharmacokinetics profile and comparative bioavailability of a novel oral fixed-dose combination (FDC) of metformin/acetylsalicylic acid (500/100mg tablet) versus the reference mono-drugs administered concomitantly, metformin 500mg tablet and acetylsalicylic acid 100mg tablet, in 22 healthy Mexican adult volunteers under fasting conditions. Blood samples were collected predose and at specified intervals across a 24-hour period following administration and were analyzed for metformin and salicylic acid using high-performance liquid chromatography coupled with tandem mass spectrometry. Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC0 -t), and (area under the plasma drug concentration-time cruve from 0 up to infinity (AUC0 ∞) data were within the range of 80%-125%. The results obtained from the present clinical study demonstrate the comparative bioavailability of the FDC when compared with the coadministration of reference mono-drugs. There were no adverse events or adverse reactions reported throughout the study.

Pharmacokinetic and toxicological assessment of a solid self-microemulsifying drug delivery system (S-SMEDDS) of kaempferia parviflora in rats

Kaempferia parviflora (KP), renowned as an alternative medicine, has gained widespread acclaim for its efficacy in male sexual enhancement and anti-inflammatory applications. However, methoxyflavones, its primary compound, poses challenges due to inherent low water solubility and limited oral absorption. This study aims to develop a novel solid self-microemulsifying drug delivery system for KP (KPS-SMEDDS) and to investigate the pharmacokinetic profile and acute toxicity. The liquid self-microemulsifying drug delivery system for KP (KPL-SMEDDS) was formed by combining Neobee® M − 5 (90 %) with a mixture of surfactant (10 %) consisting of Kolliphor® EL and polyethylene glycol 400 in a ratio of 1:2. Consequently, the KPL-SMEDDS was transformed into a powdered form by employing Sipernat® 22S as an absorbent in a 1:1 ratio. The developed formulations were subsequently evaluated for their physicochemical properties, in vitro dissolution tests, and in vivo oral absorption in rats by using methoxyflavones as the markers for quantitation. The findings demonstrated that the use of KPL-SMEDDS and KPS-SMEDDS improved the dissolution rate of methoxyflavones in 0.1 N HCl in comparison to KP powder. Comparative analysis revealed that the KPS-SMEDDS exhibited a significantly higher maximum drug concentration (Cmax) and area under the curve (AUC) values in comparison to the conventional KP extract. Notably, the KPS-SMEDDS formulation at an oral dose of 250 mg/kg remarkably increased the bioavailability of polymethoxyflavones up to 2.7- to 3-fold. Furthermore, acute oral toxicity assessment revealed no statistically significant alterations in clinical observations or biochemical parameters. These compelling findings underlined the potential of the KPS-SMEDDS formulation to augment the absorption and bioavailability of methoxyflavones, establishing its safety as an oral supplement.

Effect of Hepatic Impairment on Trofinetide Exposures Using an In Silico Physiologically Based Pharmacokinetic Model.

Trofinetide is the first drug to be approved for the treatment of Rett syndrome. Hepatic impairment is not expected to affect the pharmacokinetic (PK) profile of trofinetide because of predominant renal excretion. This study was conducted to help understand the potential impact of any hepatic impairment on trofinetide PK. This study used physiologically based PK modeling to estimate trofinetide exposure (maximum drug concentration and area under the concentration-time curve from time zero to infinity) in virtual patients with mild, moderate, and severe hepatic impairment (per Child-Pugh classification) compared with virtual healthy subjects following a 12 g oral trofinetide dose. In individual deterministic simulations for matched individuals and stochastic simulations at the population level (100 virtual individuals simulated per population), as anticipated, predicted plasma exposures were similar for healthy subjects and for patients with mild, moderate, and severe hepatic impairment. However, predicted blood concentration exposures slightly increased with increasing severity of hepatic impairment because of change in hematocrit levels. This study indicates that hepatic impairment is not expected to have a clinically relevant effect on exposure to trofinetide.

Pharmacokinetics of nalbuphine administered intravenously and subcutaneously in goats (Capra aegagrus hircus).

The purpose of this study was to evaluate the pharmacokinetics (PK) of intravenously (IV) and subcutaneously (SC) administered nalbuphine in domestic goats. Nalbuphine hydrochloride was administered at 0.8 mg/kg for both IV and SC routes in six goats with a minimum of 10-day washout period between sample collection phases. Eighteen plasma samples were collected over a 36-hour period, analyzed using reverse phase high-performance liquid chromatography (HPLC). Plasma data were analyzed using compartmental and noncompartmental approaches. Following IV nalbuphine administration, elimination half-life, area under the plasma concentration time curve from time 0 to infinity (AUC0 - ∞), concentration at time zero (C0), and total body clearance were 120.4 ± 39.1 (min-1 ± SD), 17311.01 ± 7227.32 (min·ng·mL-1 ± SD), 675.6 ± 337.13 (ng·mL-1 ± SD), and 44.5 ± 13.8 (mL·min-1·kg-1 ± SD), respectively. After SC nalbuphine administration, elimination half-life, area under the plasma concentration time curve from time 0 to infinity (AUC0 - ∞), and maximum plasma drug concentration were 129 ± 52.9 (min-1 ± SD), 20826.5 ± 14376.2 (min·ng·mL-1), and 368.03 ± 503.78 (ng·mL-1). Calculated bioavailability for the SC route was 138 ± 126 (% ± SD). Nalbuphine in goats is characterized by rapid elimination and high subcutaneous bioavailability and may be a safe analgesic opioid option in goats in the future.

Chitosan-modified dihydromyricetin liposomes promote the repair of liver injury in mice suffering from diabetes mellitus

Liver injury caused by type-II diabetes mellitus (DM) is a significant public-health concern worldwide. We used chitosan (CS) to modify dihydromyricetin (DHM)-loaded liposomes (DL) through charge interaction. The effect of CS-modified DL (CDL) on liver injury in mice suffering from DM was investigated in vivo and in vitro. CDL exhibited superior antioxidant capacity and stability. Pharmacokinetic analyses revealed a 3.23- and 1.92-fold increase in the drug concentration–time curve (953.60 ± 122.55 ng/mL/h) in the CDL-treated group as opposed to the DHM-treated group (295.15 ± 25.53 ng/mL/h) and DL-treated group (495.31 ± 65.21 ng/mL/h). The maximum drug concentration in blood (Tmax) of the CDL group saw a 2.26- and 1.21-fold increase compared with that in DHM and DL groups. We observed a 1.49- and 1.31-fold increase in the maximum drug concentration in blood (Cmax) in the CDL group compared with that in DHM and DL groups. Western blotting suggested that CDL could alleviate liver injury in mice suffering from DM by modulating inflammatory factors and the transforming growth factor-β1/Smad2/Smad3 signaling pathway. In conclusion, modification of liposomes using CS is a viable approach to address the limitations of conventional liposomes and insoluble drugs.

LC-MS/MS analysis of didehydrostemofoline from Stemona collinsiae roots extracts in rats plasma and pharmacokinetics profile after oral administration

Stemona collinsiae Craib., Stemonaceae, has been traditionally used as medicinal plants for insecticides, treatment of parasitic worms and various diseases in Southeast Asian countries. Its ethanolic root extract has been postulated for anthelminthic activities which has a potential for development for human gnathostomiasis drug. To investigate the pharmacokinetic profile, liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for the quantification of didehydrostemofoline in rats' plasma was developed and validated. The chromatographic separation was performed on a C18 column using 1 mM ammonium acetate in water and methanol (50:50, v/v). Tetrahydropalmatine was used as an internal standard. The multiple reaction monitoring mode was used for quantitative analysis. The validated method showed good sensitivity, linearity, precision, and accuracy. The results of stability showed that didehydrostemofoline was stable in the extracted samples in auto-sampler for 24 h and in the plasma samples under room temperature for 24 h, −20 °C for 1 month, and after three freeze-thaw processes. The developed method was applied to the pharmacokinetic study of didehydrostemofoline after oral administration of S. collinsiae root extract. Didehydrostemofoline was rapidly absorbed from the gastrointestinal tract. The time to peak drug concentration was 1.75 ± 0.62 h with maximum drug concentration of 1152.58 ± 271.18 ng/mL. Didehydrostemofoline was rapidly eliminated from the body with terminal half-life of 1.86 ± 0.50 h. Calculated drug clearance of didehydrostemofoline was 96.82 ± 23.51 L/h and volume of distribution was 260.40 ± 96.81 L. The present study provided useful data for understanding drug disposition in the body with dynamic time-course which could be beneficial for further clinical trials.

Oral Drug Dosing After Gastric Bypass and Diet-Induced Weight Loss: Simpler Than We Think? Lessons Learned From the COCKTAIL Study.

This article summarizes the lessons learned from the COCKTAIL study: an open, three-armed, single-center study including patients with obesity scheduled for treatment with Roux-en-Y gastric bypass (RYGB) or nonsurgical calorie restriction, and a normal- to overweight control group. The clinical implications of the results from multiple peer-reviewed articles describing the effects of RYGB, severe caloric restriction, weight loss, and type 2 diabetes on the in vivo activity and protein expression of drug-metabolizing enzymes (cytochrome P450 (CYP) 1A2, 2C9, 2C19, and 3A) and transporters (DMETs; organic anion-transporting polypeptide (OATP) 1B1 and P-glycoprotein (P-gp)) are discussed in the perspective of three clinically relevant questions: (1) How should clinicians get the dose right in patients after RYGB? (2) Will drug disposition in patients with obesity be normalized after successful weight loss? (3) Are dose adjustments needed according to obesity and diabetes status? Overall, RYGB seems to have a lower impact on drug disposition than previously assumed, but clinicians should pay close attention to drugs with a narrow therapeutic range or where a high maximum drug concentration may be problematic. Whether obesity-related alterations of DMETs normalize with substantial weight loss depends on the DMET in question. Obesity and diabetes downregulate the in vivo activity of CYP2C19 and CYP3A (only obesity) but whether substrate drugs should be dose adjusted is also dependent on other factors that influence clearance, that is, liver blood flow and protein binding. Finally, we recommend frequent and individualized follow-up due to high inter- and intraindividual variability in these patients, particularly following RYGB.

Comparative In Vitro Killing by Pradofloxacin in Comparison to Ceftiofur, Enrofloxacin, Florfenicol, Marbofloxacin, Tildipirosin, Tilmicosin and Tulathromycin against Bovine Respiratory Bacterial Pathogens

Pradofloxacin is the newest of the veterinary fluoroquinolones to be approved for use in animals—initially companion animals and most recently food animals. It has a broad spectrum of in vitro activity, working actively against Gram-positive/negative, atypical and some anaerobic microorganisms. It simultaneously targets DNA gyrase (topoisomerase type II) and topoisomerase type IV, suggesting a lower propensity to select for antimicrobial resistance. The purpose of this study was to determine the rate and extent of bacterial killing by pradofloxacin against bovine strains of Mannheimia haemolytica and Pasteurella multocida, in comparison with several other agents (ceftiofur, enrofloxacin, florfenicol, marbofloxacin, tildipirosin, tilmicosin and tulathromycin) using four clinically relevant drug concentrations: minimum inhibitory and mutant prevention drug concentration, maximum serum and maximum tissue drug concentrations. At the maximum serum and tissue drug concentrations, pradofloxacin killed 99.99% of M. haemolytica cells following 5 min of drug exposure (versus growth to 76% kill rate for the other agents) and 94.1–98.6% of P. multocida following 60–120 min of drug exposure (versus growth to 98.6% kill rate for the other agents). Statistically significant differences in kill rates were seen between the various drugs tested depending on drug concentration and time of sampling after drug exposure.

Effects of ferrohydrodynamics on drug transport and retention in drug eluting stents

This study examines the transport of magnetized drug particles (MPs) in drug-eluting stents (DESs). The governing equations for multi-species transport in a two-domain consisting of a polymer and media are formulated and solved using the finite volume method. The effects of an external magnetic field (MF) on the distribution of different drug species are analyzed. The MF was found to increase MP concentrations in the tissue and, unexpectedly, in the polymer at the same time. This counterintuitive finding was explained by analyzing the rates of transport through the polymer topcoat and the media top-layer. It was revealed that the rates of transport into and out of the media layer initially decrease and then increase with the MF, with an intermediate regime where the dynamics resemble those without MF. The maximum averaged free drug concentration in the tissue and that of the dissolved drug in the polymer were observed to increase exponentially with the MF implying on the fact that drug delivery becomes more sensitive to the MF at its larger strength. Tracking the drug center of mass revealed a nonmonotonic variation with time consisting of two linear regimes on a time log scale. The slopes of the first regime decreases with the MF while that of the second one is unaffected by the MF. The transition time was shown to increase almost linearly with the MF. The results of this study have promising applications in palliating the tendency for low drug retention from which current DES suffers.

Comprehensive characterization of Epimedium-Rhizoma drynariae herb pair in rat plasma, urine, and feces metabolic profiles by UHPLC-Q-Orbitrap HRMS combined with diagnostic extraction strategy and multicomponent pharmacokinetic study by UHPLC-MS/MS.

Epimedium-Rhizoma drynariae (EP-RD) was a well-known herb commonly used to treat bone diseases in traditional Chinese medicine. Nevertheless, there was incomplete pharmacokinetic behavior, metabolic conversion and chemical characterization of EP-RD in vivo. Therefore, this study aimed to establish metabolic profiles combined with multicomponent pharmacokinetics to reveal the in vivo behavior of EP-RD. Firstly, the diagnostic product ions (DPIs) and neutral losses (NLs) filtering strategy combined with UHPLC-Q-Orbitrap HRMS for the in vitro chemical composition of EP-RD and metabolic profiles of plasma, urine, and feces after oral administration of EP-RD to rats were proposed to comprehensively characterize the 47 chemical compounds and the 97 exogenous in vivo (35 prototypes and 62 metabolites), and possible biotransformation pathways of EP-RD were proposed, which included phase I reactions such as hydrolysis, hydrogenation, dehydrogenation, hydroxylation, dehydroxylation, isomerization, and demethylation and phase II reactions such as glucuronidation, acetylation, methylation, and sulfation. Moreover, a UHPLC-MS/MS quantitative approach was established for the pharmacokinetic analysis of seven active components: magnoflorine, epimedin A, epimedin B, epimedin C, icariin, baohuoside II, and icariin II. Results indicated that the established method was reliably used for the quantitative study of plasma active ingredients after oral administration of EP-RD in rats. Compared to oral EP alone, the increase in area under curves and maximum plasma drug concentration (P < 0.05). This study increased the understanding of the material basis and biotransformation profiles of EP-RD in vivo, which was of great significance in exploring the pharmacological effects of EP-RD.

Design Optimization and Pharmacokinetic Study of Eletriptan Hydrobromide Loaded Solid Lipid Nanoparticle Nasal Gel Targeted to Brain

In the present research work, Eletriptan Hydrobromide(E-HBr)-loaded solid lipid nanoparticles (SLN’s) incorporated in a gel was prepared by emulsification solvent evaporation technique to enhance the uptake of E-HBr to brain via intra-nasal (i.n.) route and the formulations were evaluated for particle size, polydispersibility index, zeta potential, drug entrapment efficiency, in-vitro drug release, and stability of the optimized formulation. All the parameters evaluated were within the acceptable range. In-vitro drug release for the optimized gel formulation was found to be 92.45% after 12hr and was fitted to the Higuchi model with a very high correlation coefficient (R2=0.995). Pharmacokinetics studies were performed on albino male Wistar rats and the concentration of E-HBr in brain and blood plasma was measured by HPLC. The brain/blood ratio at 0.5h for E-HBr Opt.SLN’s i.n., E-HBr sol. i.n., and E-HBr sol. oral. were found to be 2.35, 1.19 and 0.80 respectively, indicating the drug transported directly from nose-to-brain, by bypassing the blood–brain barrier in the olfactory region present in the nasal cavity. The maximum concentration of drug in brain (Cmax) after i.n. administration of E-HBr-SLN gel was found to be (21465.87±1110.66ng/ml, Tmax 8.45hr) significantly higher than that achieved after oral administration (6797.23±842.86ng/ml, Tmax 7hr), and i.n. (16451.53±3792.40ng/ml, Tmax 7.69 hr) administration of E-HBr sol. The highest drug-targeting efficiency (2.35%) and direct transport percentage (66.05%) was found with E-HBr-SLN’s as compared to the other formulations. Higher DTE (%) and DTP (%) suggest, that E-HBr-SLN gel had better brain targeting efficiency as compared to other formulations.

Continuous evaluation of single-dose moxifloxacin concentrations in brain extracellular fluid, cerebrospinal fluid, and plasma: a novel porcine model.

Knowledge regarding CNS pharmacokinetics of moxifloxacin is limited, with unknown consequences for patients with meningitis caused by bacteria resistant to beta-lactams or caused by TB. (i) To develop a novel porcine model for continuous investigation of moxifloxacin concentrations within brain extracellular fluid (ECF), CSF and plasma using microdialysis, and (ii) to compare these findings to the pharmacokinetic/pharmacodynamic (PK/PD) target against TB. Six female pigs received an intravenous single dose of moxifloxacin (6 mg/kg) similar to the current oral treatment against TB. Subsequently, moxifloxacin concentrations were determined by microdialysis within five compartments: brain ECF (cortical and subcortical) and CSF (ventricular, cisternal and lumbar) for the following 8 hours. Data were compared to simultaneously obtained plasma samples. Chemical analysis was performed by high pressure liquid chromatography with mass spectrometry. The applied PK/PD target was defined as a maximum drug concentration (Cmax):MIC ratio >8. We present a novel porcine model for continuous in vivo CNS pharmacokinetics for moxifloxacin. Cmax and AUC0-8h within brain ECF were significantly lower compared to plasma and lumbar CSF, but insignificantly different compared to ventricular and cisternal CSF. Unbound Cmax:MIC ratio across all investigated compartments ranged from 1.9 to 4.3. A single dose of weight-adjusted moxifloxacin administered intravenously did not achieve adequate target site concentrations within the uninflamed porcine brain ECF and CSF to reach the applied TB CNS target.