Increase In Volume Of Distribution Research Articles

Designer benzodiazepine rat pharmacokinetics: A comparison of alprazolam, flualprazolam and flubromazolam

Designer benzodiazepines, including flualprazolam and flubromazolam, are clandestinely produced to circumvent federal regulations. Although flualprazolam and flubromazolam are structurally similar to alprazolam, they do not have an approved medical indication. Flualprazolam differs from alprazolam by the addition of a single fluorine atom. Whereas, flubromazolam differs by the addition of a single fluorine atom and substitution of a bromine for a chlorine atom. The pharmacokinetics of these designer compounds have not been extensively evaluated. In the present study, we evaluated flualprazolam and flubromazolam in a rat model and compared the pharmacokinetics of both compounds to alprazolam. Twelve male, Sprague-Dawley rats were given a 2 mg/kg subcutaneous dose of alprazolam, flualprazolam and flubromazolam and plasma pharmacokinetic parameters were evaluated. Both compounds displayed significant two-fold increases in volume of distribution and clearance. Additionally, flualprazolam displayed a significant increase in half-life leading to a nearly double half-life when compared to alprazolam. The findings of this study demonstrate that fluorination of the alprazolam pharmacophore increases pharmacokinetic parameters including half-life and volume of distribution. The increase in these parameters for flualprazolam and flubromazolam leads to an overall increased exposure in the body and a potential for greater toxicity than alprazolam.

Cell Penetrating Peptides Conjugated to Anti-Carcinoembryonic Antigen "Catch-and-Release" Monoclonal Antibodies Alter Plasma and Tissue Pharmacokinetics in Colorectal Cancer Xenograft Mice.

Cell penetrating peptides conjugated to delivery vehicles, such as nanoparticles or antibodies, can enhance the cytosolic delivery of macromolecules. The present study examines the effects of conjugation to cell penetrating and endosomal escape peptides (i.e., TAT, GALA, and H6CM18) on the pharmacokinetics and distribution of an anti-carcinoembryonic antigen "catch-and-release" monoclonal antibody, 10H6, in a murine model of colorectal cancer. GALA and TAT were conjugated to 10H6 using SoluLINK technology that allowed the evaluation of peptide-to-antibody ratio by ultraviolet spectroscopy. H6CM18 was conjugated to either NHS or maleimide-modified 10H6 using an azide-modified valine-citrulline linker and copper-free click chemistry. Unmodified and peptide-conjugated 10H6 preparations were administered intravenously at 6.67 nmol/kg to mice-bearing MC38CEA+ tumors. Unconjugated 10H6 demonstrated a clearance of 19.9 ± 1.36 mL/day/kg, with an apparent volume of distribution of 62.4 ± 7.78 mL/kg. All antibody-peptide conjugates exhibited significantly decreased plasma and tissue exposure, increased plasma clearance, and increased distribution volume. Examination of tissue-to-plasma exposure ratios showed an enhanced selectivity of 10H6-TAT for the GI tract (+25%), kidney (+24%), liver (+38%), muscle (+3%), and spleen (+33%). 10H6-GALA and 10H6-H6CM18 conjugates demonstrated decreased exposure in all tissues, relative to unmodified 10H6. All conjugates demonstrated decreased tumor exposure and selectivity; however, differences in tumor selectivity between 10H6 and 10H6-H6CM18 (maleimide) were not statistically significant. Relationships between the predicted peptide conjugate isoelectric point (pI) and pharmacokinetic parameters were bell-shaped, where pI values around 6.8-7 exhibit the slowest plasma clearance and smallest distribution volume. The data and analyses presented in this work may guide future efforts to develop immunoconjugates with cell penetrating and endosomal escape peptides.

Aspirin for Primary Cardiovascular Prevention in Patients with Diabetes: Uncertainties and Opportunities.

The use of the antiplatelet agent aspirin (acetylsalicylic acid) was previously routinely recommended for the primary prevention of cardiovascular (CV) events in patients with diabetes, but recent large-scale randomized trials have failed to demonstrate a sizeable net clinical benefit with a once-daily, low-dose (81-100 mg) regimen in this population. Previous pharmacokinetic and pharmacodynamic studies have suggested that the aspirin formulation (enteric-coated) and dosing schedule (once daily) studied in randomized trials for primary prevention of CV events defining contemporary clinical practice may not leverage the full potential of the drug, particularly in patients with diabetes. Indeed, the diabetic platelets bear characteristics that increase their thrombotic potential and alter their pharmacologic response to the drug. Consequently, the appropriateness of studying a uniform aspirin regimen in landmark primary prevention trials needs to be revisited. In this review, we present the evidence showing that diabetes not only increases baseline platelet reactivity, but also alters platelet response to aspirin through different mechanisms including a faster platelet turnover rate. Obesity, which is frequently associated with diabetes, also impacts its pharmacokinetics via an increase in distribution volume. Small-scale pharmacokinetic and pharmacodynamic studies have suggested that the relative aspirin resistance phenotype observed in patients with diabetes may be reversed with a twice-daily dosing schedule, and with nonenteric-coated aspirin formulations. Properly powered randomized controlled trials investigating the efficacy and safety of aspirin dosing schedules and formulations tailored to the population of patients with diabetes are urgently required to optimize patient care.

Excessive unbound cefazolin concentrations in critically ill patients receiving veno-arterial extracorporeal membrane oxygenation (vaECMO): an observational study

The scope of extracorporeal membrane oxygenation (ECMO) is expanding, nevertheless, pharmacokinetics in patients receiving cardiorespiratory support are fairly unknown leading to unpredictable drug concentrations. Currently, there are no clear guidelines for antibiotic dosing during ECMO. This study aims to evaluate the pharmacokinetics (PK) of cefazolin in patients undergoing ECMO treatment. Total and unbound plasma cefazolin concentration of critically ill patients on veno-arterial ECMO were determined. Observed PK was compared to dose recommendations calculated by an online available, free dosing software. Concentration of cefazolin varied broadly despite same dosage in all patients. The mean total and unbound plasma concentration were high showing significantly (p = 5.8913 E−09) greater unbound fraction compared to a standard patient. Cefazolin clearance was significantly (p = 0.009) higher in patients with preserved renal function compared with CRRT. Based upon the calculated clearance, the use of dosing software would have led to lower but still sufficient concentrations of cefazolin in general. Our study shows that a “one size fits all” dosing regimen leads to excessive unbound cefazolin concentration in these patients. They exhibit high PK variability and decreased cefazolin clearance on ECMO appears to compensate for ECMO- and critical illness-related increases in volume of distribution.

Quetiapine dose optimisation during gestation: a pharmacokinetic modelling study.

The second-generation antipsychotic quetiapine has been demonstrated to undergo gestation-related changes in pharmacokinetics. This study applied pharmacokinetic modelling principles to investigate the mechanism of these changes and to propose new dosing strategies to counteract these changes. A pharmacokinetic modelling approach was implemented using virtual population groups. Changes in quetiapine trough plasma concentration during gestation were quantified across all trimesters, and dose adjustment strategies were applied to counteract these changes by targeting a therapeutic range of 50-500ng/ml throughout gestation. The application of the model during gestation predicted a decrease in trough concentration. A maximum decrease of 58% was predicted during trimester 2, and being associated with a statistically significant decrease in oral clearance at gestation week 25, 204l/h±100.8l/h compared with non-pregnant subjects, 121.9l/h±51.8l/h. A dosing optimisation strategy identified that dose increases to 500-700mg twice daily would result in 32-55% of subjects possessing trough concentration in excess of 50ng/ml. Quetiapine doses in pregnancy should be increased to 500-700mg twice daily to counteract a concomitant increase in metabolic clearance, increase in volume of distribution and decrease in plasma protein binding.

Особенности фармакокинетики антибактериальных антибиотиков при беременности

Представлена современная информация о фармакокинетических особенностях отдельных антибактериальных антибиотиков у беременных, включающая увеличение объема распределения, почечного клиренса и снижение степени связывания с белками крови. Показано, что существует прямая зависимость между антибактериальной активностью препарата и степенью его связывания с белками: чем больше препарата находится в связанном состоянии, тем меньше его антибактериальная активность. Приведены особенности фармакокинетики пенициллинов, цефалоспоринов, аминогликозидов, макролидов у беременных, которые предопределяют необходимость изменения режима дозирования этих препаратов. Рассмотрены аспекты безопасности применения антибиотиков для плода.

Amikacin Pharmacokinetics in Terminal Stage of Hematological Malignancy.

The influence of cancer cachexia on the pharmacokinetics of and kidney injury caused by amikacin remains unclear. This study investigated whether the pharmacokinetics of amikacin and the risk of kidney injury are altered with the progression of cancer cachexia. A retrospective analysis was conducted using therapeutic drug monitoring data obtained from 52 cancer patients who received amikacin intravenously for infection(s). The patients were classified into 2 groups based on the status of cachexia using a consensus definition: noncachexia group (n = 31) and cachexia group (n = 21). Differences in amikacin pharmacokinetics and occurrence of kidney injury were compared between the 2 groups. Amikacin pharmacokinetics was calculated based on a 1-compartment model using peak and trough concentrations measured clinically for therapeutic drug monitoring. In addition, intrapatient analysis was conducted based on patients who received amikacin treatments more than once during the study period to examine the alteration in amikacin pharmacokinetics with the progression of cancer cachexia. Systemic clearance of amikacin [median (range)] was significantly (P < 0.05) lower in the cachexia group [37.3 (11.2-87.3) (mL/min)] than in the noncachexia group [52.0 (19.1-133.4) (mL/min)]. In contrast, volume of distribution was significantly (P < 0.05) increased in the cachexia group [0.47 (0.20-1.45) L/kg] compared with the noncachexia group [0.32 (0.21-1.00) L/kg]. There was no difference in the occurrence of kidney injuries between the 2 groups. In an intrapatient analysis of the longitudinal alteration of amikacin pharmacokinetics, an approximately 50% reduction in clearance and 30% increase in volume of distribution were observed as cancer cachexia progressed. The present study suggests that progression of cancer cachexia may reduce amikacin clearance and increase the volume of distribution, but cancer cachexia does not increase amikacin-induced kidney injury.

A pharmacokinetic assessment of optimal dosing, preparation, and chronotherapy of aspirin in pregnancy

The benefit of aspirin in preventing preeclampsia is well established; however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing, and preparation of aspirin. We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid, in pregnant women and nonpregnant women, and to examine the effect of dose (100 mg vs 150 mg), preparation (enteric coated vs non-enteric-coated), and chronotherapy of aspirin (morning vs evening) between the 2 groups. Twelve high-risk pregnant women and 3 nonpregnant women were enrolled in this study. Pregnant women were in 1 of 4 groups (100 mg enteric coated, 100 mg non-enteric-coated, 150 mg non-enteric-coated morning dosing, and 150 mg non-enteric-coated evening dosing), whereas nonpregnant women undertook each of the 4 dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (before ingestion) and at 1, 2, 4, 6, 12, and 24 hours after ingestion of aspirin. Plasma obtained was analyzed for salicylic acid levels by means of liquid chromatography-mass spectrometry. Pharmacokinetic values of area under the curve from time point 0 to 24 hours point of maximum concentration, time of maximum concentration, volume of distribution, clearance, and elimination half-life were analyzed for statistical significance with SPSS v25 software. Pregnant women had a 40% ± 4% reduction in area under the curve from time point 0 to 24 hours (P < .01) and 29% ± 3% reduction in point of maximum concentration (P < .01) with a 44% ± 8% increase in clearance (P < .01) in comparison to that in nonpregnant women when 100 mg aspirin was administered. The reduction in the area under the curve from time point 0 to 24 hours, however, was minimized with the use of 150 mg aspirin in pregnant women, with which the area under the curve from time point 0 to 24 hours was closer to that achieved with the use of 100 mg aspirin in nonpregnant women. There was a 4-hour delay (P < .01) in the time of maximum concentration, a 47% ± 3% reduction in point of maximum concentration (P < .01) and a 48% ± 1% increase in volume of distribution (P < .01) with the use of 100 mg enteric-coated aspirin compared to non-enteric-coated aspirin, with no difference in the overall area under the curve. There was no difference in the pharmacokinetics of aspirin between morning and evening dosing. There is a reduction in the total drug metabolite concentration of aspirin in pregnancy, and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy, with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric-coated and non-enteric-coated aspirin and between morning and evening dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings.

Ceftaroline for Suspected or Confirmed Invasive Methicillin-Resistant Staphylococcus aureus: A Pharmacokinetic Case Series.

To describe the ceftaroline pharmacokinetics in critically ill children treated for suspected or confirmed methicillin-resistant Staphylococcus aureus infections, including blood stream infection and describe the microbiological and clinical outcomes. Retrospective electronic medical record review. Free-standing tertiary/quaternary pediatric children's hospital. Critically ill children receiving ceftaroline monotherapy or combination therapy for suspected or confirmed methicillin-resistant S. aureus infections in the PICU. None. Seven patients, three females (43%), and four males (57%), accounted for 33 ceftaroline samples for therapeutic drug management. A median of four samples for therapeutic drug management was collected per patient (range, 2-9 samples). The median age was 7 years (range, 1-13 yr) with a median weight of 25.5 kg (range, 12.6-40.1 kg). Six of seven patients (86%) demonstrated an increase in volume of distribution, five of seven patients (71%) demonstrated an increase in clearance, and 100% of patients demonstrated a shorter half-life estimate as compared with the package insert estimate. Six of seven patients (85.7%) had documented methicillin-resistant S. aureus growth from a normally sterile site with five of six (83.3%) having documented BSI, allowing six total patients to be evaluated for the secondary objective of microbiological and clinical response. All six patients achieved a positive microbiological and clinical response for a response rate of 100%. These data suggest the pharmacokinetics of ceftaroline in PICU patients is different than healthy pediatric and adult patients, most notably a faster clearance and larger volume of distribution. A higher mg/kg dose and a more frequent dosing interval for ceftaroline may be needed in PICU patients to provide appropriate pharmacodynamic exposures. Larger pharmacokinetic, pharmacodynamic, and interventional treatment trials in the PICU population are warranted.

Adequate anti-infective treatment : Importance of individual dosing and application

Sepsis-induced changes in pharmacokinetic parameters are a well-known problem in intensive care medicine. Dosing of antibiotics in this setting is therefore challenging. Alterations to the substance-specific kinetics of anti-infective substances have an effect on the distribution and excretion processes in the body. Increased clearance and an increased distribution volume (Vd) and particularly compromized organ function with reduced antibiotic elimination are often encountered in patients with sepsis. Renal replacement treatment, which is frequently used in intensive care medicine, represents a substantial intervention in this system. Current international guidelines recommend individualized dosing strategies and adaptation of doses according to measured serum levels and pharmacokinetic/pharmacodynamic (PK/PD) parameters as concepts to optimize anti-infective therapy in the critically ill. Likewise, the recommendation to adjust the administration form of beta-lactam antibiotics to prolonged or continuous infusion can be found increasingly more often in the literature. This article reviews the background of the individual dosing in intensive care patients and their applicability to the clinical routine.

Conformationally Constrained Cinnolinone Nucleoside Analogues as Siderophore Biosynthesis Inhibitors for Tuberculosis.

5'-O-[N-(Salicyl)sulfamoyl]adenosine (Sal-AMS, 1) is a nucleoside antibiotic that inhibits incorporation of salicylate into siderophores required for bacterial iron acquisition and has potent activity against Mycobacterium tuberculosis (Mtb). Cinnolone analogues exemplified by 5 were designed to replace the acidic acyl-sulfamate functional group of 1 (pKa = 3) by a more stable sulfonamide linkage (pKa = 6.0) in an attempt to address potential metabolic liabilities and improve membrane permeability. We showed 5 potently inhibited the mycobacterial salicylate ligase MbtA (apparent Ki = 12 nM), blocked production of the salicylate-capped siderophores in whole-cell Mtb, and exhibited excellent antimycobacterial activity under iron-deficient conditions (minimum inhibitor concentration, MIC = 2.3 μM). To provide additional confirmation of the mechanism of action, we demonstrated the whole-cell activity of 5 could be fully antagonized by the addition of exogenous salicylate to the growth medium. Although the total polar surface area (tPSA) of 5 still exceeds the nominal threshold value (140 Å) typically required for oral bioavailability, we were pleasantly surprised to observe introduction of the less acidic and conformationally constrained cinnolone moiety conferred improved drug disposition properties as evidenced by the 7-fold increase in volume of distribution in Sprague-Dawley rats.

High-dose amikacin for achieving serum target levels in critically ill elderly patients.

IntroductionTo achieve target concentrations, the application of higher-than-standard doses of amikacin is proposed for the treatment of sepsis due to an increase in volume of distribution and clearance, but little data are available on aminoglycoside administration in critically ill elderly patients.Patients and methodsForty critically ill elderly patients (aged over 65 years) who required amikacin therapy due to severe documented, or suspected gram-negative infections, were randomly assigned to two treatment groups. Group A (20 patients) received 15 mg/kg amikacin and Group B (20 patients) received 25 mg/kg amikacin per day as a single daily dose. All the patients were monitored for renal damage by the daily monitoring of serum creatinine. The amikacin peak (Cmax) and trough (Cmin) serum concentrations were measured on Days 3 and 7 postadministration.ResultsData from 18 patients in Group A and 15 patients in Group B were finally analyzed. On Day 3, the amikacin mean Cmax levels in the standard and high-dose treatment groups were 30.4±11 and 52.3±16.1 µg/mL (P<0.001), and the Cmin levels were 3.2±2.1 and 5.2±2.8 µg/mL, respectively (P=0.035). On Day 7, the Cmax levels in the standard and high-dose groups were 33±7.3 and 60.0±17.6 µg/mL (P=0.001), and the Cmin levels were 3.2±2.9 and 9.3±5.6 µg/mL, respectively (P=0.002). In only six (40%) of the patients in the high-dose groups and none of the patients in the standard-dose group, amikacin Cmax reached the target levels (>64 µg/mL), whereas the amikacin mean Cmin levels in the high-dose group were above the threshold of toxicity (5 µg/mL).ConclusionOur results suggest that the optimum dose of amikacin should be determined for elderly critically ill patients. It seems that higher-than-standard doses of amikacin with more extended intervals might be more appropriate than standard once-daily dosing in the elderly critically ill patients.

Abstract 2851: Cellular glutamine pool size change in response to glutaminase inhibition detected by kinetic analysis of [18F](2S,4R)4-fluoroglutamine PET

Abstract INTRODUCTION Oncogene-dependent reliance on glutamine is a cancer vulnerability that can be exploited for therapeutic gain. Inhibitors of glutaminase, the enzyme that catalyzes the conversion of glutamine to glutamate, have been developed and have shown antitumor effects in several tumor models. The specific and potent glutaminase inhibitor CB-839 demonstrated marked antitumor efficacy in a triple-negative breast cancer (TNBC) cell line with inherently high glutaminase activity (HCC-1806), but not in an estrogen receptor-positive (ER+) cell line with inherently low glutaminase activity. An early phase 1 clinical trial of CB-839 in combination with paclitaxel has shown encouraging results in TNBC patients. Cell-line specific efficacy of glutaminase inhibitors supports the need for clinical biomarkers that can predict and evaluate therapeutic efficacy. As a minimally metabolized glutamine analog with similar transport properties, [18F](2S,4R)4-Fluoroglutamine ([18F]4F-Gln) is an ideal radiotracer to infer glutamine pool size through estimates of tracer distribution volume (DV). In this study, we demonstrate differences in DV of [18F]4F-Gln in two xenografts with different levels of glutaminolysis (TNBC vs. ER+) using dynamic PET imaging, as well as show the effect of anti-glutaminase therapy on [18F]4F-Gln DV. METHODS TNBC (HCC-1806) and ER+ (MCF-7) xenografts were established in athymic nu/nu mice. Mice were scanned in a dedicated animal PET scanner at baseline and after CB-839 administration. Dynamic imaging was obtained for one hour upon injection of [18F]4F-Gln (300-350 μCi) via the tail vein. Kinetic analysis was performed with PMOD. RESULTS [18F]4F-Gln uptake was largely reversible with Logan plots demonstrating late linearity and k3 in a two-compartment (trapping) model was low (less than 0.01/min in most cases). Strong correlation was seen in DV estimates by Logan plot and a single-compartmental model (R2&amp;gt;0.9), but not with estimates from a two-compartment model. MCF-7 xenografts demonstrated greater than 60% larger DV at baseline than TNBC xenografts indicative of increased cellular glutamine concentrations in MCF-7 xenografts. An increase in DV was detected in TNBC xenografts post-glutaminase inhibition (&amp;gt;30% mean change), but not in MCF-7 xenografts. CONCLUSION Estimates of [18F]4F-Gln DV offer the ability to non-invasively infer tumor glutaminolysis. Low [18F]4F-Gln uptake in highly glutaminolytic tumors and an increase in [18F]4F-Gln uptake with glutaminase inhibition is concordant with changes in cellular glutamine concentration as measured by MR spectroscopy of tumor extracts. Our studies indicate promise for the use of [18F]4F-Gln as a predictive and pharmacodynamic marker for glutaminase-targeted therapy. Supported by: Komen SAC130060, DE-SE0012476, R21-CA198563 We thank Calithera Inc. for providing CB-839 and Dr. Susan Demo for discussions. Citation Format: Austin R. Pantel, Hsiaoju Lee, Shihong Li, Robert K. Doot, Robert H. Mach, David A. Mankoff, Rong Zhou. Cellular glutamine pool size change in response to glutaminase inhibition detected by kinetic analysis of [18F](2S,4R)4-fluoroglutamine PET [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2851. doi:10.1158/1538-7445.AM2017-2851

Ex Vivo Model to Decipher the Impact of Extracorporeal Membrane Oxygenation on Beta-lactam Degradation Kinetics.

As a consequence of drug sequestration, increase in volume of distribution, or alteration of elimination, extracorporeal membrane oxygenation (ECMO) might lead to inadequate plasma concentrations of vital drugs. The aim of this experimental study was to develop an ex vivo model to better characterize the impact of ECMO procedure on beta-lactam antibiotics pharmacokinetics. Plasma concentrations of cefotaxime, ceftazidime, cefepime, piperacillin, oxacillin, amoxicillin, and ceftriaxone were measured in an ex vivo ECMO circuit primed with whole human blood and compared with controls stored in glass tubes and polyvinyl chloride tubing. Serial blood samples were collected over 48 hours, and the concentrations of beta-lactam antibiotics were quantified using a validated high-performance liquid chromatography assay. The concentrations' decay rate over time was compared between the ECMO circuits and controls using nonlinear mixed-effect modeling. Cefotaxime concentrations decreased markedly: 86% of the initial concentration remained after 4 hours and only 21% after 48 hours (P < 0.05 for the comparison in rate of decrease with both glass and polyvinyl chloride controls). There was no difference in the rate of decrease between ECMO circuit and controls for the other beta-lactam antibiotics. The average drug recoveries from the ECMO circuits at 48 hours were as follows: ceftazidime, 73%; cefepime, 67%; piperacillin, 71%; oxacillin, 46%; and amoxicillin, 72%. Concentrations of ceftriaxone remained stable throughout the 48-hour study both in ECMO circuits and in controls. Significant losses of cefotaxime were observed, whereas ceftazidime, cefepime, piperacillin, oxacillin, and amoxicillin decrease was moderate and similar to that of the control group, and ceftriaxone concentrations remained unchanged. These results are reassuring for the use of beta-lactam antibiotics in critically ill patients treated with ECMO.

Characterization of pegylated and non-pegylated liposomal formulation for the delivery of hypoxia activated vinblastine-N-oxide for the treatment of solid tumors

Solid tumors often contain hypoxic regions which are resistant to standard chemotherapy and radiotherapy. We have developed a liposomal delivery system for a prodrug of vinblastine (CPD100) which converts to the parent compound only in the presence of lower oxygen levels. As a part of this work we have developed and optimized two formulations of CPD100: one composed of sphingomyelin/cholesterol (55/45; mol/mol) (CPD100Li) and the other composed of sphingomyelin/cholesterol/PEG (55/40/5; mol/mol) (CPD100 PEGLi). We evaluated the antiproliferative effect of CPD100 and the two formulations against A549 non-small lung cancer cell. A549 cell line showed to be sensitive to CPD100 and the two formulations displayed a higher hypoxic: air cytotoxicity ratio compared to the pro-drug. CPD100 elimination from the circulation after injection in mouse was characterized by a very short circulation time (~0.44h), lower area under the curve (AUC) (33μgh/mL) and high clearance (916mL/h/kg) and lower volume of distribution (17.4mL/kg).Total drug elimination from the circulation after the administration of liposomal formulation was characterized by prolonged circulation time (5.5h) along with increase in the AUC (56μgh/mL) for CPD100 Li and (9.5h) with AUC (170μgh/mL) for CPD100PEGLi. This was observed along with increase in volume of distribution and decrease in clearance for the liposomes. The systemic exposure of the free drug was much lower than that achieved with the liposomes. When evaluated for the efficacy in A549 xenograft model in mice, both the liposomes demonstrated excellent tumor suppression and reduction for 3months. The blood chemistry panel and the comprehensive blood analysis showed no increase or decrease in the markers and blood count. In summary, the pharmacokinetic analysis along with the efficacy data emphasis on how the delivery vehicle modifies and enhances the accumulation of the drug and at the same time the increased systemic exposure is not related to toxicity.

High prevalence of diabetes and anthropometric heterogeneity among tuberculosis patients in Pakistan

In Pakistan, the prevalence of diabetes (DM) among adults is 6.9% and expected to double by 2040. DM may facilitate transmission and halter the elimination of tuberculosis (TB). We aimed to determine the prevalence of DM among patients with TB in Pakistan, and to investigate anthropometric biochemical and haemodynamic associations between TB patients with and without DM. We conducted a cross-sectional study at Gulab Devi Chest Hospital in Lahore, Punjab. A total of 3027 newly diagnosed smear-positive TB patients ≥25 years of age were screened for DM by HbA1c regardless of previous DM history. The prevalence of screen-detected DM and known DM among the TB participants was 13.5% and 26.1%, respectively, resulting in a combined DM prevalence of 39.6%. Most participants were male (64.4%). Using bivariate analyses, participants with DM were significantly older (49.8 vs. 40.6 years) with higher haemoglobin (men, 12.1 vs. 11.8 g/dl, women 11.5 vs. 10.7 g/dl), body mass index (21.0 vs. 17.6 kg/m2 ) and waist-hip ratio (men, 0.87 vs. 0.81, women, 0.87 vs. 0.79) (all P < 0.05) than participants without DM. Stratifying by screen-detected and known DM, these differences remained significant when using multivariate analysis. We report a high prevalence of DM among patients with TB who may be anthropometrically and biochemically distinct from TB patients without DM, and this heterogeneity further transcends the different DM groups.

Comparison of two PET radioligands, [11C]FPEB and [11C]SP203, for quantification of metabotropic glutamate receptor 5 in human brain

Of the two 18F-labeled PET ligands currently available to image metabotropic glutamate receptor 5 (mGluR5), [18F]FPEB is reportedly superior because [18F]SP203 undergoes glutathionlyation, generating [18F]-fluoride ion that accumulates in brain and skull. To allow multiple PET studies on the same day with lower radiation exposure, we prepared [11C]FPEB and [11C]SP203 from [11C]hydrogen cyanide and compared their abilities to accurately quantify mGluR5 in human brain, especially as regards radiometabolite accumulation. Genomic plot was used to estimate the ratio of specific-to-nondisplaceable uptake (BPND) without using a receptor blocking drug. Both tracers quantified mGluR5; however [11C]SP203, like [18F]SP203, had radiometabolite accumulation in brain, as evidenced by increased distribution volume (VT) over the scan period. Absolute VT values were ∼30% lower for 11C-labeled compared with 18F-labeled radioligands, likely caused by the lower specific activities (and high receptor occupancies) of the 11C radioligands. The genomic plot indicated ∼60% specific binding in cerebellum, which makes it inappropriate as a reference region. Whole-body scans performed in healthy subjects demonstrated a low radiation burden typical for 11C-ligands. Thus, the evidence suggests that [11C]FPEB is superior to [11C]SP203. If prepared in higher specific activity, [11C]FPEB would presumably be as effective as [18F]FPEB for quantifying mGluR5 in human brain.

Impact of New Scatter Correction Strategies on High-Resolution Research Tomograph Brain PET Studies.

PurposeThe aim of this study is to evaluate the impact of different scatter correction strategies on quantification of high-resolution research tomograph (HRRT) data for three tracers covering a wide range in kinetic profiles.ProceduresHealthy subjects received dynamic HRRT scans using either (R)-[11C]verapamil (n = 5), [11C]raclopride (n = 5) or [11C]flumazenil (n = 5). To reduce the effects of patient motion on scatter scaling factors, a margin in the attenuation correction factor (ACF) sinogram was applied prior to 2D or 3D single scatter simulation (SSS).ResultsSome (R)-[11C]verapamil studies showed prominent artefacts that disappeared with an ACF-margin of 10 mm or more. Use of 3D SSS for (R)-[11C]verapamil showed a statistically significant increase in volume of distribution compared with 2D SSS (p < 0.05), but not for [11C]raclopride and [11C]flumazenil studies (p > 0.05).ConclusionsWhen there is a patient motion-induced mismatch between transmission and emission scans, applying an ACF-margin resulted in more reliable scatter scaling factors but did not change (and/or deteriorate) quantification.

PK/PD of single-dose amikacin in emergency department patients with severe sepsis/shock: should we apply the ICU-based higher loading dose?

Studies in the ICU showed that a single amikacin dose of ≥25 mg/kg should be used in conditions of increased distribution volume (Vd) such as severe sepsis/shock [1]. However, no data are available for emergency department (ED) patients in the early phase of sepsis/septic shock. The purpose of this study was to determine whether a single amikacin dose of 25 versus 15 mg/kg results in PK/PD target attainment for ED patients.

Turpentine oil induced inflammation decreases absorption and increases distribution of phenacetin without altering its elimination process in rats

Plasma concentrations and pharmacokinetics of phenacetin, a CYP1A2 substrate were determined in normal and experimentally induced inflamed rats by turpentine oil to know the role of inflammation on the pharmacokinetics of phenacetin and formation of its active metabolite (paracetamol) by CYP1A2 in wistar albino rats, weighing about 200-250 g that were randomly divided into two groups consisting six in each group. Rats in group I (control) received phenacetin (150 mg kg(-1), PO) where as group II received phenacetin 12 h after induction of inflammation by turpentine oil (0.4 mL, i.m). Blood samples were collected from retro orbital plexus at pre-determined time intervals prior to and at 0.166, 0.33, 0.67, 1.5, 2, 4, 8 and 12 h post-administration of phenacetin. Plasma was separated and analyzed for phenacetin and its metabolite paracetamol by HPLC assay. Based on plasma concentrations of phenacetin and its metabolite paracetamol, the pharmacokinetic parameters were determined by compartmental methods. C(max) of phenacetin was significantly (p < 0.01) decreased to 19.50 ± 2.74 μg mL(-1) in inflamed conditions compared to 38.13 ± 2.20 μg mL(-1) obtained in normal rats. Except, for significant (p < 0.001) increase in volume of distribution at steady state (V(dss)) from 2.87 ± 0.37 to 8.03 ± 1.26 L kg(-1) and increased the rate of absorption with shorter absorption half-life (t(1/2ka)) for phenacetin in inflammation. None of the pharmacokinetic parameters of either phenacetin or its metabolite paracetamol were affected. It can be concluded that turpentine oil induced inflammation has no role on the activity of CYP1A2 in rats, as the plasma concentrations and pharmacokinetic parameters of paracetamol were found unaltered.