Peak Serum Concentrations Research Articles

Rectus sheath single-injection blocks: a study to quantify local anaesthetic absorption using serial ultrasound measurements and lidocaine serum concentrations.

Rectus sheath blocks are an established option for analgesia following abdominal surgery, but pharmacokinetic data are limited. This study sought to characterise the absorption of lidocaine injectate and the pharmacokinetics of lidocaine after rectus sheath injection. Bilateral rectus sheath single-injection blocks were given to 10 patients undergoing general or urological surgery. Afterwards, serial lidocaine serum levels and ultrasound measurements of the rectus sheath injectate reservoir were collected. Injectate within the rectus sheath was visible with ultrasound up to 12h after injection. However, the rate of drug absorption exceeded that of injectate disappearance. Peak serum concentration occurred within 30min with average peak concentrations of 1.65μg/ml. Lidocaine clearance was lower than reported in young healthy subjects. The body mass index positively correlated with lidocaine terminal phase half-life, and clearance negatively correlated with age. The study provides the first data describing lidocaine pharmacokinetics after rectus sheath injection. Peak serum concentrations transiently achieved systemic levels associated with pain relief after a single bolus injection. The data from this study could be used to develop a regime using single shot rectus sheath blockade with a bolus of lidocaine followed by infusion using bilateral rectus sheath catheters.

Lack of Pharmacokinetic Basis of Weight-Based Dosing and Intra-Operative Re-Dosing with Cefazolin Surgical Prophylaxis in Obese Patients: Implications for Antibiotic Stewardship.

Traditionally, there have been uniform antibiotic dosing guidelines for prophylaxis for clean-clean-contaminated surgery in both non-obese and obese adults. All other factors predisposing to surgical site infections (SSIs) being equal, over time, the preferred drug is cefazolin. The usual dose, given immediately pre-procedure, has been 1 g intravenously (IV) in non-penicillin-allergic patients, which has been highly effective, Recently, it has become common practice to use high-dose cefazolin; i.e., 3 g IV, in obese patients. This article reviews the literature on high-dose cefazolin prophylactic regimens in the obese from a pharmacokinetic (PK) point of view. There are no comparative studies to support this approach, which is based largely on the theory "more must be better." Weight-based dosing of cefazolin in the obese is flawed, because it does not take into account PK factors, which are critical in the obese. Cefazolin is a water-soluble (hydrophilic) antibiotic that does not penetrate adipose tissue regardless of IV dose. Importantly, adipose tissue is not a valid target tissue in clean-clean-contaminated SSI prophylaxis, as it does not become infected. Higher doses result in proportionately higher serum/non-adipose tissue concentrations, but adipose tissue concentrations are unaffected. Cefazolin displays time-dependent killing kinetics so that as long as serum/tissue concentrations are above the minimum inhibitory concentration (MIC) of SSI pathogens, there is no enhanced killing with higher concentrations relative to concentration-dependent antibiotics. Taking into account PK principles, a cefazolin 1 g IV bolus results in peak serum concentrations of ∼185 mcg/mL, provides at least six hours of intra-operative protection, aside from any post-antibiotic effects, and eliminates any rationale for intra-operative re-dosing for procedures lasting six hours or less. Some have argued that a cefazolin 3 g IV dose in the obese does not matter, as more must necessarily be better. However, from an antibiotic stewardship program (ASP) perspective, unneeded antibiotics are unnecessary. Moreover, the costs of cefazolin 1 g (IV push) at $0.75 versus 2 g (IV piggyback) at $ 6.83 can be significant in large centers using cefazolin prophylaxis for cardiothoracic, orthopedic, obstetric/gynecology, and bariatric surgery. Excessive antibiotics also expose the patient to potential adverse effects; i.e., Clostridium difficile. There is no dose-dependent or duration of exposure effect on resistance with one or two pre-operative or intra-operative doses. Well-done PK-based studies in obese patients clearly demonstrate the lack of benefit of using a 3-g dose or intra-operative re-dosing and show no incremental increase in adipose tissue concentrations with high doses. From an ASP point of view, antibiotic dosing recommendations should be reviewed and revised on the basis of PK principles that indicate that weight-based dosing has no basis for pre-operative prophylaxis in obese patients.

Cells released from S. epidermidis biofilms present increased antibiotic tolerance to multiple antibiotics.

Biofilm released cells (Brc) are thought to present an intermediary phenotype between biofilm and planktonic cells and this has the potential of affecting their antimicrobial tolerance.AimCompare the antimicrobial tolerance profiles of Brc, planktonic or biofilm cultures of S. epidermidis.MethodologyPlanktonic, biofilm cultures or Brc from 11 isolates were exposed to peak serum concentrations (PSC) of antibiotics. The antimicrobial killing effect in the three populations was determined by CFU.ResultsIncreased Brc tolerance to vancomycin, teicoplanin, rifampicin, erythromycin, and tetracycline was confirmed in model strain 9142. Furthermore, significant differences in the susceptibility of Brc to vancomycin were further found in 10 other clinical isolates.ConclusionsBrc from distinct clinical isolates presented a decreased susceptibility to most antibiotics tested and maintained that enhanced tolerance despite growing planktonically for up to 6 h. Our data suggest that Brc maintain the typical enhanced antibiotic tolerance of biofilm populations, further suggesting that addressing antimicrobial susceptibility in planktonic cultures might not reflect the full potential of biofilm-associated bacteria to survive therapy.

SAT-171 Effective Intrajejunal Wall Delivery of Recombinant Human Insulin via a Self-Deployed Ingestible Capsule in Anesthetized Swines: A Pharmacokinetic and Pharmacodynamic Study

BACKGROUND: Biotherapeutic agents must be administered parenterally to reach and maintain therapeutic blood concentrations, lowering patient compliance and complicating long-term care. We have developed an ingestible robotic pill capable of delivering a variety of drugs directly into the wall of the proximal small intestine. METHODS: This observational, pilot study was performed in 17 juvenile anesthetized pigs under a 60-80 mg/dl euglycemic glucose clamp. All animals underwent midline, abdominal laparotomies. In a TEST group of 8 pigs (mean weight = 17.4±1.2 kg), 20 IU of recombinant human insulin (RHI) were auto-injected into the jejunal wall by inserting the pill into the proximal jejunum via a 1-cm enterotomy. A CONTROL group of 9 pigs (17.0±0.4 kg) received 20 IU of RHI injected subcutaneously. In both study groups, blood samples were collected at 10-min intervals, between -20 and +420 min after RHI administration for measurements of blood concentrations of glucose, using a handheld glucometer, and serum insulin, using the ELISA method. RESULTS: The peak serum concentrations (Cmax) of RHI were 517±109 and 342±50 pM for the jejunal wall and the subcutaneous groups, respectively (ns). The area under the insulin concentration curves (83±18 and 81±10 nmol/l.min) were likewise similar in both groups. The mean time to peak serum concentration of insulin (Tmax) was 139±42 min in the jejunal wall group, shorter than in the subcutaneous group (227±24 min). CONCLUSIONS: 1) The bioactivity of RHI was preserved after its delivery into the jejunal wall, 2) the jejunal wall route provided a more rapid and physiologic uptake of insulin compared with the subcutaneous route, though the difference (p=0.097) was not statistically significant, and 3) the pharmacokinetic and pharmacodynamic profile of RHI after its jejunal wall delivery suggests that drugs such as basal insulin, currently administered parenterally, could be successfully delivered into the proximal intestinal wall via the ingestible robotic capsule.

Development and Validation of Liquid Chromatography Method for Determination of Glimepiride in Presence of (Vimto®) Soft Drinks in Rats: Application to Pharmacokinetics Studies.

Context:Diet and beverages are thought to have notable effects on drugs. Recently, this relationship has received significant consideration.Aims:To develop and validate a simple, rapid, and sensitive method for the determination of glimepiride in rat serum. This will be performed using high-performance liquid chromatography–mass spectrometry (HPLC-MS/MS). Potential pharmacokinetic interactions between glimepiride and the soft drink, Vimto, will also be investigated in the serum of experimental rats.Materials and Methods:HPLC-MS/MS was constructed and clarithromycin was used as an internal standard.Results:The method was validated in terms of linearity, precision, accuracy, stability, and system suitability parameters. The method was found to be satisfactory and suitable for the determination of glimepiride. The precision of glimepiride was high (coefficient of variation, CV% <15%), the accuracy over all 3 days of validation was within the accepted criteria. Glimepiride peak serum concentration (Cmax) was 126.01 ng/mL and was reached within 1 h (Tmax) of administration. Mean area under curve (AUC) was 964.70 ng/mL and was reached within 24 h of administration. The Vimto soft drink significantly (P < 0.050) reduced glimepiride peak serum concentration to 57.87 ng/mL and was reached within 2 h of administration. AUC was significantly reduced to 335.04 ng*h/mL (P < 0.050).Conclusion:Glimepiride pharmacokinetic parameters such as Cmax and AUC were significantly affected by the Vimto soft drink. Therefore, this study developed a simple, rapid, and sensitive method for validation and determination of the effects of soft drinks on drugs using the LC-MS/MS method.

Administration of Vancomycin at High Doses in Patients with Post Neurosurgical Meningitis: A Comprehensive Comparison between Continuous Infusion and Intermittent Infusion.

Poor penetration of vancomycin into Central Nervous System (CNS) can lead to treatment failure. The aim of this study was to evaluate and compare CSF concentration and serum pharmacokinetics of high dose vancomycin by continuous infusion vs. intermittent infusion in post neurosurgical meningitis patients. Twenty patients were divided into two groups. Patients in intermittent infusion group received vancomycin as a loading dose of 25 mg/kg over two hours, followed by 25 mg/kg over two hours every 12 h. In the Continuous Infusion group, patients received vancomycin as a loading dose of 25 mg/kg over two hours, followed by 50 mg/kg/day by continuous infusion. In the intermittent infusion group, mean ± SD of serum trough, peak and CSF concentrations were 17.49 ± 2.46 mg/L, 41.33 ± 2.73 mg/L, and 4.83 ± 1.05 mg/L, respectively. Mean of CSF/trough% ratio was 27.39 ± 2.43%. A positive linear correlation was found between the serum trough levels and CSF levels (r = 0.970, P < 0.001). In continuous infusion group, mean ± SD of serum and CSF concentrations were 24.76 ± 2.02 mg/L and 6.20 ± 1.31 mg/L respectively. Mean ± SD of CSF/serum% ratio was 24.84% ± 3.54%. The serum and CSF levels revealed positive linear correlation (r = 0.902, P < 0.001). The mean of CSF concentration in CI group was 6.20 ± 1.31 mg/L which was significantly higher than II group (4.83 ± 1.05 mg/L, P < 0.019). CSF/serum ratio did not show any significant difference between the two groups. Continuous infusion of vancomycin makes it possible to achieve faster and constant target level in serum but did not have any significant effect on the penetration (CSF/Serum ratio) of vancomycin in to the CNS.

The Benefit of Therapeutic Drug Monitoring of Vancomycin in a Respiratory ICU; A Patient with Acute Kidney Injury: A Case Report

Introduction: Vancomycin damage to the kidney is one of the severe adverse reactions. The primary objective of this study was to discuss how the clinical pharmacists should deal with the results of therapeutic drug monitoring (TDM) for Vancomycin. Case Presentation: A case of severe acute kidney injury in a 60-year-old woman receiving Vancomycin as empirical therapy is reported here. The patient was admitted to the respiratory intensive care unit (RICU) of the First Affiliated Hospital of Bengbu Medical College, China, on 15 Oct 2015. On Day 7, the steady-state serum trough concentration and peak concentration of Vancomycin were 102.2 and 111.9 μg/mL, respectively. Clinical pharmacists immediately contacted the clinicians and advised them to discontinue Vancomycin therapy as soon as possible, and the proposal was adopted. On Day 8, serum creatinine (SCr) increased to 719 μmol/L, and creatinine clearance rate (CrCl) decreased to 6 mL/min; then, the patient was given dialysis treatment. After she underwent dialysis treatment, SCr decreased to 330 μmol/L and CrCl increased to 14 mL/min on Day 19; then, the patient was discharged after she accepted the doctor’s advice to start a home-dialysis program outside the hospital. Conclusions: In this case, clinical pharmacists contacted the doctor to avoid further aggravated renal damage timely when they found a significant increase in Vancomycin concentrations. It indicates that the Vancomycin level can be used as an indirect marker of renal function as increased Vancomycin level results from and contributes to acute kidney injury.

Clinical Pharmacokinetic and Pharmacodynamic Overview of Nilotinib, a Selective Tyrosine Kinase Inhibitor.

Nilotinib, an oral inhibitor of the tyrosine kinase activity of Abelson protein, is approved for the treatment of patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase and patients with CML in chronic phase or accelerated phase resistant or intolerant to prior therapies. This review describes the pharmacokinetic and pharmacodynamic data of nilotinib in patients with CML and in healthy volunteers. Nilotinib is rapidly absorbed, with a peak serum concentration approximately 3 hours after dosing. The area under the plasma drug concentration-time curve over 24 hours and the peak serum concentration of nilotinib were dose proportional from 50-400 mg once daily. The metabolism of nilotinib is primarily via hepatic cytochrome P450 (CYP) 3A4 according to in vitro studies. In the clinical setting, exposure to nilotinib was significantly reduced by the induction of CYP3A4 with rifampicin and significantly increased by the inhibition of CYP3A with ketoconazole. Additionally, nilotinib is a competitive inhibitor of CYP3A4/5, CYP2C8, CYP2C9, CYP2D6, and uridine diphosphate glucuronosyltransferase 1A1. The bioavailability of nilotinib is increased by up to 82% when given with a high-fat meal compared with fasted state. There is a positive correlation between the occurrences of all-grade total bilirubin elevations and the steady-state nilotinib trough concentrations. Fredericia method corrected QT interval change from baseline was observed to have a correlation with nilotinib exposure. No significant relationship between nilotinib exposure and major molecular response at 12 months was seen at therapeutic doses of nilotinib 300-400 mg, probably due to the narrow range of the doses investigated.

Implementation of a two-point pharmacokinetic AUC-based vancomycin therapeutic drug monitoring approach in patients with methicillin-resistant Staphylococcus aureus bacteraemia

Limited evidence exists evaluating pharmacokinetic thresholds for vancomycin efficacy and nephrotoxicity using non-Bayesian methods. The objective of this study was to evaluate the 24-h steady-state vancomycin area under the concentration-time curve (AUC24) thresholds for efficacy and nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus bacteraemia (MRSA-B) after implementing two-point pharmacokinetic therapeutic drug monitoring. A single-centre, retrospective cohort study was performed including adult patients admitted between 1 June 2016 and 1 January 2018 with MRSA-B treated with vancomycin for ≥72 h. The AUC24 was calculated using peak and trough vancomycin serum concentrations. Clinical success was defined as defervescence and blood culture sterilisation by Day 7. Nephrotoxicity was defined as an increase in serum creatinine of >0.5 mg/dL (or ≥50%) from baseline. Classification and regression tree (CART) analyses were performed to identify AUC24 thresholds for efficacy and nephrotoxicity. Forty-six patients were included in the study. Clinical success and nephrotoxicity were observed in 81.8% and 13.0%, respectively. The CART-derived vancomycin AUC24 thresholds for clinical success and nephrotoxicity were ≥297 mg·h/L and ≥710 mg·h/L, respectively. Patients with an AUC24 ≥297 mg·h/L had a >2.7-fold increase in clinical success compared with those who did not (89.5% vs. 33.3%, respectively; P = 0.01), and patients with an AUC24 ≥710 mg·h/L had a >7-fold increase in nephrotoxicity compared with those with an AUC24 <710 mg·h/L (66.7% vs. 9.3%, respectively; P = 0.04). This study supports current recommendations to target vancomycin AUC24 values of 400-600 mg·h/L when calculated using two-point pharmacokinetics, although a wider range may exist.

Predictors of insufficient peak amikacin concentration in critically ill patients on extracorporeal membrane oxygenation

BackgroundAmikacin infusion requires targeting a peak serum concentration (Cmax) 8–10 times the minimal inhibitory concentration, corresponding to a Cmax of 60–80 mg/L for the least susceptible bacteria to theoretically prevent therapeutic failure. Because drug pharmacokinetics on extracorporeal membrane oxygenation (ECMO) are challenging, we undertook this study to assess the frequency of insufficient amikacin Cmax in critically ill patients on ECMO and to identify relative risk factors.MethodsThis was a prospective, observational, monocentric study in a university hospital. Patients on ECMO who received an amikacin loading dose for suspected Gram-negative infections were included. The amikacin loading dose of 25 mg/kg total body weight was administered intravenously and Cmax was measured 30 min after the end of the infusion. Independent predicators of Cmax < 60 mg/L after the first amikacin infusion were identified with mixed-model multivariable analyses. Various dosing simulations were performed to assess the probability of reaching 60 mg/L < Cmax < 80 mg/L.ResultsA total of 106 patients on venoarterial ECMO (VA-ECMO) (68%) or venovenous-ECMO (32%) were included. At inclusion, their median (1st; 3rd quartile) Sequential Organ-Failure Assessment score was 15 (12; 18) and 54 patients (51%) were on renal replacement therapy. Overall ICU mortality was 54%. Cmax was < 60 mg/L in 41 patients (39%). Independent risk factors for amikacin under-dosing were body mass index (BMI) < 22 kg/m2 and a positive 24-h fluid balance. Using dosing simulation, increasing the amikacin dosing regimen to 30 mg/kg and 35 mg/kg of body weight when the 24-h fluid balance is positive and the BMI is ≥ 22 kg/m2 or < 22 kg/m2 (Table 3), respectively, would have potentially led to the therapeutic target being reached in 42% of patients while reducing under-dosing to 23% of patients.ConclusionsECMO-treated patients were under-dosed for amikacin in one third of cases. Increasing the dose to 35 mg/kg of body weight in low-BMI patients and those with positive 24-h fluid balance on ECMO to reach adequate targeted concentrations should be investigated.

The effects of respiratory inhaled drugs on the prevention of acute mountain sickness

Background:Acute mountain sickness (AMS) is common in high-altitude travelers, and may lead to life-threatening high-altitude cerebral edema (HACE) or high-altitude pulmonary edema (HAPE). The inhaled drugs have a much lower peak serum concentrations and a shorter half-life period than oral drugs, which give them a special character, greater local effects in the lung. Meanwhile, short-term administration of inhaled drugs results in almost no adverse reactions.Methods:We chose inhaled ipratropium bromide/salbutamol sulfate (combivent, COM), budesonide (pulmicortrespules, BUD), and salbutamol sulfate (ventolin, VEN) in our study to investigate their prophylactic efficacy against AMS. Since COM is a compound drug of ipratropium bromide and salbutamol sulfate, to verify which part of COM plays a role in the prevention of AMS, we also tested VEN in our experiment.Results:In our study, Lake Louise scores (LLS) in the COM (1.14 ± 0.89 vs 1.91 ± 1.23, P < .05) and BUD (1.35 ± 0.94 vs 1.91 ± 1.23, P < .05) groups were both significantly lower than the placebo group at 72 hours. There were no significant differences in LLS scores among the 4 groups at 120 hours. The incidence of AMS in the COM group was significantly reduced at 72 hours (16.7% in COM group vs 43.4% in placebo group, P < .05) after exposure to high-altitude. There were no significant differences in AMS incidences at 120 hours among the 4 groups.Conclusion:The prophylactic use of COM could prevent AMS in young Chinese male at 72 hours after high-altitude exposure. BUD also could reduce LLS but not prevent AMS at 72 hours. Ipratropium bromide maybe the effective drug in COM work on the prevention of AMS alone.

Pharmacokinetics, Metabolism, and Biodistribution of a Liver‐Targeted siRNA Therapeutic in Preclinical Species

Almost twenty years ago, small interfering RNA (siRNA) was first demonstrated as a tool to silence gene expression in vitro. Today siRNA is part of an emerging drug class of RNA interference‐based therapeutics undergoing development against formerly undruggable targets. siRNA is a double‐stranded molecule typically 21–23 nucleotides in length. Upon uptake into the cell, the siRNA duplex is loaded into a multi‐protein RNA‐induced silencing complex (RISC). One strand, referred to as the sense strand, of the siRNA duplex is degraded while the remaining strand, the antisense strand, guides RISC to a target mRNA sequence for cleavage, subsequently decreasing the expression of the corresponding protein. The primary objective of this work was to determine an extensive pharmacokinetic profile of a liver‐targeting siRNA construct in preclinical species. To aid in measuring low levels of siRNA drug, an ultrasensitive hybridization‐ligation enzyme‐linked immunosorbent assay was developed utilizing locked nucleic acid probes for the quantitation of the sense and antisense strands across multiple biological matrices. Following a single subcutaneous injection of siRNA (0.1, 1 or 10 mg/kg) in non‐human primates (NHP), we observed peak serum concentrations of sense and antisense strands to occur as soon as 1–2 hours post‐dose from which circulating siRNA levels then declined, but were detected out to 7 days post‐dose. In addition to this work, we aimed to gain a better understanding of siRNA tissue distribution, specifically to the liver and kidneys, as well as the metabolism of the molecule that may occur in vivo potentially compromising drug efficacy. Interestingly, we observed a similar accumulation of both sense and antisense strands in the liver, whereas, the sense strand reached concentrations three orders of magnitude greater than the antisense strand in the kidneys, suggesting denaturation of the siRNA duplex. We also confirmed siRNA loading of RISC via immunoprecipitation from the liver homogenate and observed comparable loading levels of both sense and antisense strands. Further, these liver homogenates were then analyzed for metabolite formation using high‐resolution liquid chromatography‐tandem mass spectrometry. Metabolite profiling was performed on the antisense strand of the siRNA duplex as this is the pharmacologically active component of the molecule. We were excited to observe that the full‐length antisense strand was the predominant analyte detected (71.3% of total drug and metabolites) in liver homogenate followed by six metabolites of lesser abundance that resulted from single nucleotide cleaving at the 3′ end, n‐1 (21.5%), n‐2 (1%), n‐3 (0.6%), n‐4 (1.5%), n‐5 (2.8%) and n‐6 (1.5%). Concurrent to this work, efforts are underway to develop a fluorescent‐based in situ hybridization to investigate intra‐ and extra‐hepatic distribution of the siRNA construct at the cellular level. Through the described studies, we have successfully achieved a more complete understanding of the absorption, distribution, metabolism and excretion properties of an siRNA therapeutic in preclinical species which will inform clinical translation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Anti‐Methamphetamine Antibody Gene Therapy Ameliorates Methamphetamine‐induced Locomotor Effects in Mice for 8 Months after a Single Treatment

There currently are no FDA‐approved pharmacological treatments to aid in treatment of methamphetamine (METH) substance use disorders. To address this, our laboratory has combined short chain variable fragments (scFvs) derived from antibodies with high binding affinity to METH with adeno‐associated viruses (AAV) to develop a long‐lasting potential therapy. These first generation gene therapies showed expression of the anti‐METH scFvs for at least 212 days but achieved an average serum concentration of less than 70.0 μg/ml in mice. We hypothesized that incorporating a constant region (Fc) derived from an IgG antibody would extend serum half‐life and increase circulating concentrations of the anti‐METH antibody fragment, thus providing greater levels of protection against METH in mice. To test this hypothesis, we cloned an anti‐METH scFv‐Fc encoding DNA sequence into custom expression plasmids and packaged into AAV serotype 8 viral vectors to make AAV‐7F9‐Fc. To test this new gene therapy, BALB/C mice were administered 1×1012 vector copies per mouse of either the AAV‐7F9‐Fc or empty AAV8 vector. Mice were allowed to reach peak AAV‐7F9‐Fc expression (~28 days, as determined by ELISA) before testing in locomotor studies. Locomotor activity was used to measure protection from the stimulant effects of METH. Briefly, after a 30‐minute baseline activity was recorded, mice were administered saline, 0.56, 1.0, 3.0, or 5.56 mg/kg METH sc, and locomotor activity was measured for 90 minutes. METH was administered consecutively with a two‐day washout period in between doses. This regimen was also performed on separate mice 7–8 months after administration of AAV‐7F9‐Fc therapy to test duration of protection. Our results show that by incorporating an IgG Fc moiety into the anti‐METH constructs, the average expression increased by over 30 fold compared to a our first generation scFvs to a peak serum concentration of 5.227.7 μg/ml, and mean of 2,116.1 μg/ml, and persisted over 239 days. The AAV‐7F9‐Fc mice showed significantly less locomotor activity (p &lt; 0.05) than empty AAV8 treated mice at the 1.0 and 3.0 mg/kg METH doses. Furthermore, the AAV‐7F9‐Fc treated mice showed no significant activity differences from baseline at any of the METH doses administered. In a separate, long‐term study, 7–8 months after AAV‐7F9‐Fc treatment, mice showed significantly lower levels of locomotor activity at 0.56 and 1.0 mg/kg sc METH doses than the sham treated group. These data suggest our AAV‐7F9‐Fc can protect against stimulant effects of METH, and that the duration of action is at least 8 months in mice. Overall, these data suggest that 1) the addition of the IgG Fc region into the AAV‐scFv constructs resulted in dramatically higher anti‐METH antibody circulating concentrations than our first generation anti‐METH scFvs and 2) this higher antibody titer was able to provide protection against METH stimulant effects at low to moderate doses for at least 8 months in mice.Support or Funding InformationSupported by NIDA R01 DA036600 &amp; NIGMS T32 GM106999This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Corticosteroid and Cortisol Serum Levels Following Intra‐articular Triamcinolone Acetonide Lumbar Facet Joint Injections

Facet joint steroid injections are used to treat chronic low back pain. However, little is known about the systemic absorption and serum levels of steroids following intra-articular facet joint injections. The primary objective of this preliminary study was to investigate the pharmacokinetics of triamcinolone acetonide following fluoroscopically guided intra-articular lumbar facet joint injections in a cohort of patients with chronic low back pain. A secondary aim was to investigate the effects of triamcinolone on serum cortisol levels following lumbar facet joint injections. The study cohort included 5 patients undergoing fluoroscopically guided intra-articular lumbar facet joint injections at a pain medicine specialty clinic. Blood was collected prior to the injections and on days 1, 2, 4, 6, 8, 14, 21, 28, 35, and 42 following the injections. The terminal elimination half-life of triamcinolone in a noncompartmental analysis was 213 hours. The peak median triamcinolone concentration of 3.6 ng/mL was detected within 24 hours after the injections. Serum cortisol levels were < 30 ng/mL for an average of 4.4 days. The maximum effect of triamcinolone on cortisol suppression was observed with triamcinolone serum levels of > 1.9 ng/mL. The peak serum concentration of triamcinolone following intra-articular facet joint injections occurred within 24 hours. The median terminal elimination half-life was 213 hours, but baseline cortisol levels were suppressed for an average of 4.4 days. Clinically, the prolonged half-life and endocrine effects of triamcinolone could increase the risk for serious drug-drug interactions in patients taking medications that inhibit corticosteroid metabolism.

Optimizing Amikacin Dosage in Pediatrics Based on Population Pharmacokinetic/Pharmacodynamic Modeling

Our objective was to determine the population pharmacokinetic parameters of amikacin in pediatric patients to contribute to the future development of a revised optimum dose and population-specific dosing regimens. We performed a retrospective chart review in non-critical pediatric patients (aged 1-12years) who received amikacin for suspected or proven Gram-negative infection at a university hospital. The population pharmacokinetic models were developed using Monolix 4.4. Pharmacokinetic/pharmacodynamic (PK/PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. The analysis included 134 amikacin plasma concentrations from 67 patients with a mean ± standard deviation age of 4.1 ± 3.9years and bodyweight of 15 ± 8.4kg. The patients received an amikacin total daily dose (TDD) of 23 ± 7.3mg/kg, which resulted in peak and trough concentrations of 20.65 ± 7.6 and 2.4 ± 1.7mg/l, respectively. The estimated pharmacokinetic parameters for amikacin were 1.2l/h and 6.5l for total body clearance (CL) and the volume of distribution (V), respectively. Dosing simulations showed that the standard dosing regimen (15mg/kg/day) of amikacin achieved the PK/PD target of peak serum concentration (Cpeak)/minimum inhibitory concentration (MIC) ≥ 8 for an MIC of 2mg/l; higher doses were required to achieve higher MIC values. The simulation results indicated that amikacin 20mg/kg once daily provided a higher probability of target attainment with lower toxicity than dosing three times daily. In addition, combination therapy is recommended for pathogens with an MIC of ≥ 8mg/l.

Liquid chromatography–tandem mass spectrometry method for the quantification of a potent H3 receptor antagonist conessine in serum and its application to pharmacokinetic studies

Conessine, a steroidal alkaloid obtained from the bark and seeds of the plant species of Apocynaceae family, elicits a histamine antagonistic action, selectively for the H3 histaminergic receptors. This alkaloid is used mainly for the treatment of dysentery and helminthic disorders. For the quantification of conessine in serum, a liquid chromatography-tandem mass spectrometry method was developed. Chromatographic separation was achieved on a Zorbax SB-CN column (100 × 4.6 mm, 3.5 µm), and a mobile phase consisting of 90% methanol in aqueous ammonium acetate buffer (pH 3.5) with 0.1% (v/v) formic acid at an isocratic flow rate of 0.6 ml/min at 40℃ provides efficiency in separation. A volume of 40 µl was injected each time and the run time for each sample was 5 min. Phenacetin (internal standard) was added to 50 µl of serum sample prior to liquid-liquid extraction using 3% isopropanol in n-hexane. The detection was performed on a 5500 QTRAP mass spectrometer by multiple reaction monitoring mode via electrospray ionization source. The multiple reaction monitoring of conessine and IS was m/ z 357.4 to m/ z 312.1 and m/ z 180.1 to m/ z 138.1, respectively. The method that showed selectivity and linearity in the range of 1-200 ng/ml was validated in terms of sensitivity, accuracy, precision and stability. The detection and quantitation limits were recognized at 0.1 and 1 ng/ml, respectively. The intra- and inter-day precision and accuracy fulfils the acceptance criteria. Applying the method to the pharmacokinetic studies in rats, conessine showed a peak serum concentration at 2 h post oral dose with a good bioavailability of 71.28 ± 4.65%.

Prophylactic benefits of systemically delivered simvastatin treatment in a house dust mite challenged murine model of allergic asthma.

Systemically delivered statins can blunt airway inflammation in ovalbumin-challenged mice. However, in asthma clinical trials the beneficial effects of introducing oral statins are not compelling. We have invetigated this discrepancy using a clinically relevant murine model of allergic asthma, and by including a prophylactic study arm. Adult mice were: 1) challenged with house dust mite (HDM) alone or with subcutaneous (s.c.) simvastatin for two weeks; or 2) also treated with simvastatin for one week prior to HDM challenge. We assayed lung function, inflammatory cell influx and cytokine profile, goblet cell abundance, and simvastatin concentration in serum, lung lavage and tissue. Ultrahigh performance liquid chromatography-tandem mass spectrometry revealed that pharmacologically active simvastatin reached peak serum concentration after 8h, but declined rapidly. Prophylactic treatment doubled peak serum simvastatin and repeated s.c. delivery established stable serum levels, but simvastatin was undetectable in the lungs. Both simvastatin treatment arms suppressed indices of HDM-induced airway inflammation and goblet cell hyperplasia, but this was significantly greater with prophylactic therapy, in particular, inhibition of neutrophil and eosinophil influx, and cytokine accumulation. Conversely, neither acute nor prophylactic delivery of simvastatin prevented HDM challenge-induced airway hyperreactivity. Systemically administered simvastatin accumulates in the blood, but not in lung tissues, and reduces leukocyte influx and associated lung inflammation. Prophylactic therapy has the greatest anti-inflammatory effects, but as observed in human clinical trials, systemic simvastatin therapy does not prevent allergic airway hyperreactivity.

Pharmacokinetics and safety of oral glyburide in dogs with acute spinal cord injury.

BackgroundGlyburide (also known as glibenclamide) is effective in reducing the severity of tissue destruction and improving functional outcome after experimental spinal cord injury in rodents and so has promise as a therapy in humans. There are many important differences between spinal cord injury in experimental animals and in human clinical cases, making it difficult to introduce new therapies into clinical practice. Spinal cord injury is also common in pet dogs and requires new effective therapies, meaning that they can act as a translational model for the human condition while also deriving direct benefits from such research. In this study we investigated the pharmacokinetics and safety of glyburide in dogs with clinical spinal cord injury.MethodsWe recruited dogs that had incurred an acute thoracolumbar spinal cord injury within the previous 72 h. These had become acutely non-ambulatory on the pelvic limbs and were admitted to our veterinary hospitals to undergo anesthesia, cross sectional diagnostic imaging, and surgical decompression. Oral glyburide was given to each dog at a dose of 75 mcg/kg. In five dogs, we measured blood glucose concentrations for 10 h after a single oral dose. In six dogs, we measured serum glyburide and glucose concentrations for 24 h and estimated pharmacokinetic parameters to estimate a suitable dose for use in a subsequent clinical trial in similarly affected dogs.ResultsNo detrimental effects of glyburide administration were detected in any participating dog. Peak serum concentrations of glyburide were attained at a mean of 13 h after dosing, and mean apparent elimination half-life was approximately 7 h. Observed mean maximum plasma concentration was 31 ng/mL. At the glyburide dose administered there was no observable association between glyburide and glucose concentrations in blood.DiscussionOur data suggest that glyburide can be safely administered to dogs that are undergoing anesthesia, imaging and surgery for treatment of their acute spinal cord injury and can attain clinically-relevant serum concentrations without developing hazardous hypoglycemia. Serum glyburide concentrations achieved in this study suggest that a loading dose of 150 mcg/kg followed by repeat doses of 75 mcg/kg at 8-hourly intervals would lead to serum glyburide concentrations of 25–50 ng/mL within an acceptably short enough period after oral administration to be appropriate for a clinical trial in canine spinal cord injury.

Validation of Cycloserine Efficacy in Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Beijing, China.

Cycloserine (Cs) is recommended by the World Health Organization as a second-line drug to treat multidrug-resistant tuberculosis (MDR-TB); however, its efficacy has never been sufficiently evaluated. To gain some insights into the value of cycloserine for MDR-TB treatment, in vitro bacteriostatic effect was determined and patient validations were performed prospectively. The in vitro activity of Cs against 104 wild-type Mycobacterium tuberculosis strains was determined, and serum Cs concentrations were measured for 73 MDR TB patients 2 h after administration. The treatment outcomes for 27 MDR-TB patients who had baseline isolates and were treated with Cs-containing regimens were followed up. The MICs for 90% of the recruited 104 wild-type strains were below 32 μg/ml. Eighteen out of 52 patients had peak serum concentrations (Cmax) below 20 μg/ml at the dosage of 500 mg daily, while 13 out of 21 patients had peak serum concentrations higher than 35 μg/ml at the dosage of 750 mg daily. The percentage of favorable treatment outcomes among patients with a Cmax/MIC ratio of ≥1 was statistically significantly higher than that among the group with a Cmax/MIC ratio of <1 (P = 0.022). The epidemiological cutoff value for Cs susceptibility testing was 32 μg/ml. A high percentage of patients receiving the recommended dosage of 10 mg/kg for Cs administration could not acquire desirable blood concentrations; therefore, adjusting the dosage according to drug concentration monitoring is necessary. The Cmax/MIC ratio might be a good indicator for predicting the treatment outcome for patients with MDR-TB or extensively drug-resistant TB (XDR-TB) who are being administered Cs-containing regimens.

Validation and Clinical Utility of the hERG IC50:Cmax Ratio to Determine the Risk of Drug-Induced Torsades de Pointes: A Meta-Analysis.

Use of the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG) to predict torsades de pointes (TdP) risk from culprit drugs is neither sensitive nor specific. The ratio of the half-maximum inhibitory concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (Cmax ) is used during drug development to screen out chemical entities likely to cause TdP. To validate the use of the hERG IC50:Cmax ratio to predict TdP risk from a culprit drug by its correlation with TdP incidence. Medline (between 1966 and March 2017) was accessed for hERG IC50 and Cmax values from the antihistamine, fluoroquinolone, and antipsychotic classes to identify cases of drug-induced TdP. Exposure to a culprit drug was estimated from annual revenues reported by the manufacturer. Inclusion criteria for TdP cases were provision of an ECG tracing that demonstrated QTc prolongation with TdP and normal serum values of potassium, calcium, and magnesium. Cases reported in patients with a prior rhythm disturbance and those involving a drug interaction were excluded. The Meta-Analysis of Observational Studies in Epidemiology checklist was used for epidemiological data extraction by two authors. Negligible risk drugs were defined by an hERG IC50:Cmax ratio that correlated with less than a 5% chance of one TdP event for every 100 million exposures (relative risk [RR] 1.0). The hERG IC50:Cmax ratio correlated with TdP risk (0.312; 95% confidence interval 0.205-0.476, p<0.0001), a ratio of 80 (RR 1.0). The RR from olanzapine is on par with loratadine; ziprasidone is comparable with ciprofloxacin. Drugs with an RR greater than 50 include astemizole, risperidone, haloperidol, and thioridazine. The hERG IC50:Cmax ratio was correlated with TdP incidence for culprit drugs. This validation provides support for the potential use of the hERG IC50:Cmax ratio for clinical decision making in instances of drug selection where TdP risk is a concern.