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Activated charcoal both reduces primary drug absorption and enhances drug elimination. However, the two mechanisms of action overlap and are indistinguishable from each other. In order to estimate the extend of enhanced elimination, we summarized the effect of activated charcoal on intravenously administered drugs, where reduced drug exposure can be attributed to enhanced elimination. We performed a meta-analysis of randomized controlled studies evaluating the effect of orally administered activated charcoal on the systemic exposure of intravenously administered drugs. We searched the bibliographic databases PubMed, Embase and Cochrane. Meta-regression analyses of selected physiochemical drug properties on the effect sizes of activated charcoal were performed. All but one of 21 included studies used multiple-dose activated charcoal (MDAC). MDAC reduced the median half-life of the intravenously administered study drugs by 45.7% (interquartile range: 15.3%-51.3%) and area under the concentration time curve by 47.0% (interquartile range: 36.4%-50.2%). MDAC significantly improved drug elimination across nine different intravenously administered drugs, but we were unable to identify factors allowing extrapolation to other drugs. The results offer a possible and plausible rationale for the previously observed effects of single-dose activated charcoal beyond the timeframe where ingested drug is present in the gastro-intestinal tract.

Background: Therapies with novel mechanisms of action against hepatitis B virus (HBV) infection are being explored with the goal of achieving a functional cure (sustained off-treatment response) without requiring lifelong therapy. We aimed to evaluate the pharmacokinetics, safety, and antiviral activity of ABI-H0731, an investigational inhibitor of the HBV core protein. Method(s): This phase 1, randomised, placebo-controlled study was done in two parts. In part 1, healthy adults without hepatitis B aged 18-65 years at one clinical research centre in New Zealand (eight participants per dose cohort) were randomly assigned (3:1) to receive single oral doses of ABI-H0731 (100, 300, 600, or 1000 mg) or matching placebo, or once-daily or twice-daily doses of ABI-H0731 800 mg or matching placebo for 7 days. In part 2, adults aged 18-65 years at clinical research centres in New Zealand, Australia, the UK, Hong Kong, Taiwan, and South Korea with chronic HBV (12 participants per dose cohort) were randomly assigned (5:1) to receive ABI-H0731 (100, 200, 300, or 400 mg) or matching placebo once daily for 28 days. In part 2, participants were required to have HBeAg-positive or HBeAg-negative chronic HBV infection, with serum HBV DNA concentrations of at least 2 x 104 IU/mL (HBeAg-positive) or 2 x 103 IU/mL (HBeAg-negative) and serum alanine aminotransferase concentrations less than seven times the upper limit of normal. Both parts used simple randomisation, with study participants, site personnel, and study monitors masked to treatment assignments. The primary study objective was dose-related safety and tolerability of ABI-H0731 in healthy volunteers and in participants with chronic HBV infection, assessed in all treated participants. Key secondary assessments included pharmacokinetic analyses and virological responses. This study is registered with ClinicalTrials.gov, identifier NCT02908191 and is completed. Finding(s): 48 [61%] of 79 healthy volunteers were enrolled in the sing

Background: Therapies with novel mechanisms of action against hepatitis B virus (HBV) infection are being explored with the goal of achieving a functional cure (sustained off-treatment response) without requiring lifelong therapy. We aimed to evaluate the pharmacokinetics, safety, and antiviral activity of ABI-H0731, an investigational inhibitor of the HBV core protein. Method(s): This phase 1, randomised, placebo-controlled study was done in two parts. In part 1, healthy adults without hepatitis B aged 18-65 years at one clinical research centre in New Zealand (eight participants per dose cohort) were randomly assigned (3:1) to receive single oral doses of ABI-H0731 (100, 300, 600, or 1000 mg) or matching placebo, or once-daily or twice-daily doses of ABI-H0731 800 mg or matching placebo for 7 days. In part 2, adults aged 18-65 years at clinical research centres in New Zealand, Australia, the UK, Hong Kong, Taiwan, and South Korea with chronic HBV (12 participants per dose cohort) were randomly assigned (5:1) to receive ABI-H0731 (100, 200, 300, or 400 mg) or matching placebo once daily for 28 days. In part 2, participants were required to have HBeAg-positive or HBeAg-negative chronic HBV infection, with serum HBV DNA concentrations of at least 2 x 104 IU/mL (HBeAg-positive) or 2 x 103 IU/mL (HBeAg-negative) and serum alanine aminotransferase concentrations less than seven times the upper limit of normal. Both parts used simple randomisation, with study participants, site personnel, and study monitors masked to treatment assignments. The primary study objective was dose-related safety and tolerability of ABI-H0731 in healthy volunteers and in participants with chronic HBV infection, assessed in all treated participants. Key secondary assessments included pharmacokinetic analyses and virological responses. This study is registered with ClinicalTrials.gov, identifier NCT02908191 and is completed. Finding(s): 48 [61%] of 79 healthy volunteers were enrolled in the sing

Congenital diaphragmatic hernia (CDH) is a birth defect characterized by failed closure of the diaphragm, allowing abdominal viscera to herniate into the thoracic cavity and subsequently impair pulmonary and vascular development. Despite improving standardized postnatal management, there remains a population of severe CDH for whom postnatal care falls short. In these severe cases, antenatal surgical intervention (fetoscopic endoluminal tracheal occlusion [FETO]) may improve survival; however, FETO increases the risk of preterm delivery, is not widely offered, and still fails in half of cases. Antenatal medical therapies that stimulate antenatal pulmonary development are therefore interesting alternatives. By presenting the animal research underpinning novel antenatal medical therapies for CDH, and considering the applications of these therapies to clinical practice, this review will explore the future of antenatal CDH management with a focus on the phosphodiesterase-5 inhibitor sildenafil.Copyright © 2018 by Thieme Medical Publishers, Inc.

Background: Phenobarbitone (PB) is the first-line anti-convulsant for neonatal seizures. The use of peritoneal dialysis (PD) to enhance drug elimination in cases of neonatal PB overdose has not been reported. Objective(s): To report a case of neonatal severe PB toxicity and review the elimination of PB by PD. Method(s): Assessment of PD drug clearance. Result(s): A neonate with prolonged seizures was administered PB. Encephalopathy and myocardial failure developed, which were initially suspected to be secondary to hypoxia. At 42 h of age, the serum PB concentration was in the toxic range at 131 mg/L. Despite supportive care, the infant's condition deteriorated with escalating inotropes and the need for CPR. Enhanced PB elimination via multiple-dose activated charcoal and exchange transfusion were considered too risky. Hourly PD cycles via Tenckhoff catheter were commenced, based on reports suggesting that PD enhances PB clearance. The clinical state of the infant then improved. PD administration was continued for 60 h, recovering 20% of the estimated total PB body load. The infant survived and there were no PD complications. Conclusion(s): PD increased PB clearance in this neonate, correlating with clinical recovery. Where other techniques are not possible, PD may have a role to play in enhancing PB elimination.Copyright © 2017 S. Karger AG, Basel.

Congenital diaphragmatic hernia (CDH) is a birth defect characterized by failed closure of the diaphragm, allowing abdominal viscera to herniate into the thoracic cavity and subsequently impair pulmonary and vascular development. Despite improving standardized postnatal management, there remains a population of severe CDH for whom postnatal care falls short. In these severe cases, antenatal surgical intervention (fetoscopic endoluminal tracheal occlusion [FETO]) may improve survival; however, FETO increases the risk of preterm delivery, is not widely offered, and still fails in half of cases. Antenatal medical therapies that stimulate antenatal pulmonary development are therefore interesting alternatives. By presenting the animal research underpinning novel antenatal medical therapies for CDH, and considering the applications of these therapies to clinical practice, this review will explore the future of antenatal CDH management with a focus on the phosphodiesterase-5 inhibitor sildenafil.Copyright © 2018 by Thieme Medical Publishers, Inc.

Background: Chemotherapy for colorectal, head and neck, and breast cancer continues to rely heavily on 5-fluorouracil and its oral prodrug capecitabine. Associations of serious fluoropyrimidine adverse effects have focused on inherited deficiency of the catabolic enzyme, dihydropyrimidine dehydrogenase. However, abnormal dihydropyrimidine dehydrogenase activity accounts for only about one-third of observed toxicity cases. Thus, the cause of most fluorouracil toxicity cases remains unexplained. Method(s): For this small cohort study, thymine (THY) 250 mg was administered orally to 6 patients who had experienced severe toxicity during treatment with 5FU or capecitabine. Plasma and urine were analyzed for THY and its catabolites dihydrothymine (DHT) and bureidoisobutyrate. Result(s): Of the 6 patients, 2 had decreased THY elimination and raised urinary THY recovery consistent with inherited partial dihydropyrimidine dehydrogenase deficiency, confirmed by DPYD sequencing. Unexpectedly, 3 patients displayed grossly raised plasma THY concentrations but normal elimination profiles (compared with a normal range for healthy volunteers previously published by the authors). DPYD and DPYS sequencing of these 3 patients did not reveal any significant loss-of-activity allelic variants. The authors labeled the phenotype in these 3 patients as "enhanced thymine absorption". Only 1 of the 6 cases of toxicity had a normal postdose plasma profile for THY and its catabolites. Postdose urine collections from all 6 patients had THY/DHT urinary ratios above 4.0, clearly separated from the ratios in healthy subjects that were all below 3.0. Conclusion(s): This small cohort provided evidence for a hypothesis that fluorouracil toxicity cases may include a previously undescribed pyrimidine absorption variant, "enhanced thymine absorption," and elevated THY/DHT ratios in urine may predict fluorouracil toxicity. A prospective study is currently being conducted.Copyright © 2018 Wolters Kluwer He

Background: Phenobarbitone (PB) is the first-line anti-convulsant for neonatal seizures. The use of peritoneal dialysis (PD) to enhance drug elimination in cases of neonatal PB overdose has not been reported. Objective(s): To report a case of neonatal severe PB toxicity and review the elimination of PB by PD. Method(s): Assessment of PD drug clearance. Result(s): A neonate with prolonged seizures was administered PB. Encephalopathy and myocardial failure developed, which were initially suspected to be secondary to hypoxia. At 42 h of age, the serum PB concentration was in the toxic range at 131 mg/L. Despite supportive care, the infant's condition deteriorated with escalating inotropes and the need for CPR. Enhanced PB elimination via multiple-dose activated charcoal and exchange transfusion were considered too risky. Hourly PD cycles via Tenckhoff catheter were commenced, based on reports suggesting that PD enhances PB clearance. The clinical state of the infant then improved. PD administration was continued for 60 h, recovering 20% of the estimated total PB body load. The infant survived and there were no PD complications. Conclusion(s): PD increased PB clearance in this neonate, correlating with clinical recovery. Where other techniques are not possible, PD may have a role to play in enhancing PB elimination.Copyright © 2017 S. Karger AG, Basel.

The safety and efficacy of drugs depend upon appropriate dosing of drugs made possible by understanding the dispositional profile a drug will follow. A drug’s disposition includes its absorption from an administration site, its distribution throughout the body, and its elimination from the body, characterized by metabolism and excretion. Disposition is often mediated by drug metabolizing enzymes and drug transporters. Alterations in the expression or activity of metabolizing enzymes and transporters can therefore affect the safety or efficacy of a drug and it is necessary to characterize their impact on every drug. The Biopharmaceutics Drug Disposition Classification System (BDDCS) uses the extent of metabolism and solubility of drugs to predict drug disposition, including when transporters and metabolizing enzymes are clinically relevant. Here, we utilized observations from this system to predict the three major routes of drug elimination (metabolism, renal excretion of unchanged drug, and biliary excretion of unchanged drug). These predictions were made by integrating in vitro measurements of permeability rate to predict the extent of metabolism with an in silico logistic regression model we developed that uses calculated polarizability and predicted metabolic stability to predict when poorly metabolized compounds will be eliminated in the urine or the bile. This approach correctly identified 72 ± 9%, 85 ± 2%, and 73 ± 2% of extensively metabolized, biliarily eliminated, and renally eliminated drugs, respectively. We discuss the physiological context through which permeability, polarizability, and metabolic stability may inform the major elimination route. We further developed a model predicting BDDCS class using commercially available in silico models of permeability rate to predict the extent of metabolism and dose number to predict the solubility class. This approach correctly identified 54.1%, 57.8%, 69.3%, and 45.2% of class 1, 2, 3, and 4 drugs, respectively

Introduction: Apixaban is a novel oral anticoagulation agent that exerts its effect through direct factor Xa inhibition. We present a case of multi-drug overdose including apixaban with associated apixaban concentrations. Case: A 53 year-old man presented to our metropolitan hospital following a deliberate self-poisoning with 200 mg apixaban, 35 mg ramipril, 105 mg bisoprolol, 280 mg atorvastatin, 6 mg colchicine, 37.4 mg magnesium, 4 x 500 mg paracetamol/9.5 mg codeine/5 mg phenylephrine and alcohol. He developed hypotension that was treated with noradrenaline. His initial and peak apixaban concentration was 1022.6 ng/ml and was associated with only minor bleeding from his femoral central line insertion site, which improved with local compression. Vitamin K 10 mg (at 9 h post-ingestion) and Prothrombinex-VF 2000 units (at 13 h post-ingestion) were also administered without any observed effect on coagulation studies. Apixaban elimination appeared to display first-order kinetics with an elimination half-life of 7.4 h. His plasma apixaban concentration was within the therapeutic dose range 10 h post-ingestion and he recovered uneventfully. Conclusion(s): A case of apixaban overdose with associated apixaban concentrations is presented. There was rapid resolution of anticoagulation with no demonstrable benefit of currently available clotting factor replacement.Copyright © 2016 Informa UK Limited, trading as Taylor & Francis Group.

In the absence of specific data to guide optimal dosing, this study aimed to describe the pharmacokinetics of ceftriaxone in severely septic Australian Indigenous patients and to assess achievement of the pharmacodynamic target of the regimens prescribed. A pharmacokinetic study was conducted in a remote hospital intensive care unit in patients receiving ceftriaxone dosing of 1g every 12h (q12h). Serial blood and urine samples were collected over one dosing interval on two consecutive days. Samples were assayed using a validated chromatography method for total and unbound concentrations. Concentration-time data collected were analysed with a non-compartmental approach. A total of 100 plasma samples were collected from five subjects. Ceftriaxone clearance, volume of distribution at steady-state, elimination half-life and elimination rate constant estimates were 0.9 (0.6-1.5) L/h, 11.2 (7.6-13.4) L, 9.5 (3.2-10.2) h and 0.07 (0.07-0.21) h-1, respectively. The unbound fraction of ceftriaxone ranged between 14% and 43%, with a higher unbound fraction present at higher total concentrations. The unbound concentrations at 720min from the initiation of infusion for the first and second dosing intervals were 7.2 (4.8-10.7) mg/L and 7.8 (4.7-12.1) mg/L respectively, which exceeds the minimum inhibitory concentration of all typical target pathogens. In conclusion, the regimen of ceftriaxone 1g q12h is adequate for critically ill Australian Indigenous patients with severe sepsis caused by non-resistant pathogens.Copyright © 2016

Paracetamol overdose is one of the commonest pharmaceutical poisonings in the world. For nearly four decades, intravenous acetylcysteine regimens have been used to treat most patients successfully and prevent or mitigate hepatotoxicity. However, the rate of occurrence of adverse reactions to acetylcysteine is quite high, and there is a potential for these to be reduced. Recent studies show that distributing the loading-dose of acetylcysteine over the first few hours of treatment may decrease the incidence of adverse reactions. In addition, varying the duration of acetylcysteine administration may potentially benefit certain cohorts of poisoned patients, depending on their risk of developing hepatotoxicity.Copyright © 2016 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine

Introduction: Apixaban is a novel oral anticoagulation agent that exerts its effect through direct factor Xa inhibition. We present a case of multi-drug overdose including apixaban with associated apixaban concentrations. Case: A 53 year-old man presented to our metropolitan hospital following a deliberate self-poisoning with 200 mg apixaban, 35 mg ramipril, 105 mg bisoprolol, 280 mg atorvastatin, 6 mg colchicine, 37.4 mg magnesium, 4 x 500 mg paracetamol/9.5 mg codeine/5 mg phenylephrine and alcohol. He developed hypotension that was treated with noradrenaline. His initial and peak apixaban concentration was 1022.6 ng/ml and was associated with only minor bleeding from his femoral central line insertion site, which improved with local compression. Vitamin K 10 mg (at 9 h post-ingestion) and Prothrombinex-VF 2000 units (at 13 h post-ingestion) were also administered without any observed effect on coagulation studies. Apixaban elimination appeared to display first-order kinetics with an elimination half-life of 7.4 h. His plasma apixaban concentration was within the therapeutic dose range 10 h post-ingestion and he recovered uneventfully. Conclusion(s): A case of apixaban overdose with associated apixaban concentrations is presented. There was rapid resolution of anticoagulation with no demonstrable benefit of currently available clotting factor replacement.Copyright © 2016 Informa UK Limited, trading as Taylor & Francis Group.

In the absence of specific data to guide optimal dosing, this study aimed to describe the pharmacokinetics of ceftriaxone in severely septic Australian Indigenous patients and to assess achievement of the pharmacodynamic target of the regimens prescribed. A pharmacokinetic study was conducted in a remote hospital intensive care unit in patients receiving ceftriaxone dosing of 1g every 12h (q12h). Serial blood and urine samples were collected over one dosing interval on two consecutive days. Samples were assayed using a validated chromatography method for total and unbound concentrations. Concentration-time data collected were analysed with a non-compartmental approach. A total of 100 plasma samples were collected from five subjects. Ceftriaxone clearance, volume of distribution at steady-state, elimination half-life and elimination rate constant estimates were 0.9 (0.6-1.5) L/h, 11.2 (7.6-13.4) L, 9.5 (3.2-10.2) h and 0.07 (0.07-0.21) h-1, respectively. The unbound fraction of ceftriaxone ranged between 14% and 43%, with a higher unbound fraction present at higher total concentrations. The unbound concentrations at 720min from the initiation of infusion for the first and second dosing intervals were 7.2 (4.8-10.7) mg/L and 7.8 (4.7-12.1) mg/L respectively, which exceeds the minimum inhibitory concentration of all typical target pathogens. In conclusion, the regimen of ceftriaxone 1g q12h is adequate for critically ill Australian Indigenous patients with severe sepsis caused by non-resistant pathogens.Copyright © 2016

Paracetamol overdose is one of the commonest pharmaceutical poisonings in the world. For nearly four decades, intravenous acetylcysteine regimens have been used to treat most patients successfully and prevent or mitigate hepatotoxicity. However, the rate of occurrence of adverse reactions to acetylcysteine is quite high, and there is a potential for these to be reduced. Recent studies show that distributing the loading-dose of acetylcysteine over the first few hours of treatment may decrease the incidence of adverse reactions. In addition, varying the duration of acetylcysteine administration may potentially benefit certain cohorts of poisoned patients, depending on their risk of developing hepatotoxicity.Copyright © 2016 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine

The safety and efficacy of drugs depend upon appropriate dosing of drugs made possible by understanding the dispositional profile a drug will follow. A drug’s disposition includes its absorption from an administration site, its distribution throughout the body, and its elimination from the body, characterized by metabolism and excretion. Disposition is often mediated by drug metabolizing enzymes and drug transporters. Alterations in the expression or activity of metabolizing enzymes and transporters can therefore affect the safety or efficacy of a drug and it is necessary to characterize their impact on every drug. The Biopharmaceutics Drug Disposition Classification System (BDDCS) uses the extent of metabolism and solubility of drugs to predict drug disposition, including when transporters and metabolizing enzymes are clinically relevant. Here, we utilized observations from this system to predict the three major routes of drug elimination (metabolism, renal excretion of unchanged drug, and biliary excretion of unchanged drug). These predictions were made by integrating in vitro measurements of permeability rate to predict the extent of metabolism with an in silico logistic regression model we developed that uses calculated polarizability and predicted metabolic stability to predict when poorly metabolized compounds will be eliminated in the urine or the bile. This approach correctly identified 72 ± 9%, 85 ± 2%, and 73 ± 2% of extensively metabolized, biliarily eliminated, and renally eliminated drugs, respectively. We discuss the physiological context through which permeability, polarizability, and metabolic stability may inform the major elimination route. We further developed a model predicting BDDCS class using commercially available in silico models of permeability rate to predict the extent of metabolism and dose number to predict the solubility class. This approach correctly identified 54.1%, 57.8%, 69.3%, and 45.2% of class 1, 2, 3, and 4 drugs, respectively

The fluoropyrimidine drugs 5-fluorouracil and its oral prodrug capecitabine remain first line therapy for solid tumours of the neck, breast and colon. However, significant and unpredictable toxicity affects about 10-25% of patients depending upon the mode of 5-fluorouracil delivery. The pharmacokinetics of thymine (5-methyluracil) may provide an approach for screening for 5-fluorouracil toxicity, based on the rationale that thymine is a close structural analogue of 5-fluorouracil and is catabolized by the same enzymatic pathway. Oral thymine loading tests were performed on 12 healthy volunteers. Each subject was given a single oral dose of 250 mg thymine in capsule form. Blood, urine and saliva samples were collected pre-dose and up to 5 h post-dose. Concentrations of thymine, and its catabolites dihydrothymine and s-ureidoisobutyrate were analysed by HPLC-tandem mass spectrometry in plasma, urine and saliva. The pharmacokinetic data of healthy volunteers were analysed assuming a non-compartmental model. Thymine peaked quickly (30-45 min) in plasma to a maximum concentration of 170 +/- 185 mug/L (mean +/- SD). Clearance was high (mean 57.9 L/h/kg) exceeding normal human liver blood flow, suggesting low systemic bioavailability; urinary recovery of the thymine dose was low (< 1%). Apparent formation rate-limited kinetics were observed for dihydrothymine, and the plasma concentration of dihydrothymine was consistently 10-fold higher than that of thymine. Plasma s-ureidoisobutyrate concentrations, on the other hand, were similar to that of thymine. Genotyping confirmed that pathological mutations of the DPYD gene were absent. The urinary excretion ratio of thymine/dihydrothymine was informative of the maximum concentration. Saliva thymine was highly variable. These data are potentially useful as a basis for developing of a screening procedure to prospectively identify patients who are at risk of toxicity from fluoropyrimidine drugs.Copyright © 2015 Published by Elsevie

The fluoropyrimidine drugs 5-fluorouracil and its oral prodrug capecitabine remain first line therapy for solid tumours of the neck, breast and colon. However, significant and unpredictable toxicity affects about 10-25% of patients depending upon the mode of 5-fluorouracil delivery. The pharmacokinetics of thymine (5-methyluracil) may provide an approach for screening for 5-fluorouracil toxicity, based on the rationale that thymine is a close structural analogue of 5-fluorouracil and is catabolized by the same enzymatic pathway. Oral thymine loading tests were performed on 12 healthy volunteers. Each subject was given a single oral dose of 250 mg thymine in capsule form. Blood, urine and saliva samples were collected pre-dose and up to 5 h post-dose. Concentrations of thymine, and its catabolites dihydrothymine and s-ureidoisobutyrate were analysed by HPLC-tandem mass spectrometry in plasma, urine and saliva. The pharmacokinetic data of healthy volunteers were analysed assuming a non-compartmental model. Thymine peaked quickly (30-45 min) in plasma to a maximum concentration of 170 +/- 185 mug/L (mean +/- SD). Clearance was high (mean 57.9 L/h/kg) exceeding normal human liver blood flow, suggesting low systemic bioavailability; urinary recovery of the thymine dose was low (< 1%). Apparent formation rate-limited kinetics were observed for dihydrothymine, and the plasma concentration of dihydrothymine was consistently 10-fold higher than that of thymine. Plasma s-ureidoisobutyrate concentrations, on the other hand, were similar to that of thymine. Genotyping confirmed that pathological mutations of the DPYD gene were absent. The urinary excretion ratio of thymine/dihydrothymine was informative of the maximum concentration. Saliva thymine was highly variable. These data are potentially useful as a basis for developing of a screening procedure to prospectively identify patients who are at risk of toxicity from fluoropyrimidine drugs.Copyright © 2015 Published by Elsevie

A comparative study of the pharmacokinetics of levofloxacin and triazavirine as well as 2-memyltMo-6-nitro-l,2,4-triazolo[5,l-ñ]-l,2,4-triazine-7(4r)-ide (3S)-(-)-9-fluoro-2,3-dmydro-3-memyl-10-(4-memylpiperazm-l-yl)-7-oxo-7H-pyri e]-l,4-benzoxazine-6-carboxylic acid (conjugate 2) obtained by conjugation of triazavirine and levofloxacin, representing a new class of pharmacological agents, was carried out in experiments on rats. It is established that conjugate 2 in comparison to individual levofloxacin and triazavirine has a higher relative bioavailability and lower rate of elimination, which can lead to improved effectiveness of therapy at reduced dose and frequency of drug administration.

The Biopharmaceutics Drug Disposition Classification System (BDDCS) can be utilized to predict drug disposition, including interactions with other drugs and transporter or metabolizing enzyme effects based on the extent of metabolism and solubility of a drug. However, defining the extent of metabolism relies upon clinical data. Drugs exhibiting high passive intestinal permeability rates are extensively metabolized. Therefore, we aimed to determine if in vitro measures of permeability rate or in silico permeability rate predictions could predict the extent of metabolism, to determine a reference compound representing the permeability rate above which compounds would be expected to be extensively metabolized, and to predict the major route of elimination of compounds in a two-tier approach utilizing permeability rate and a previously published model predicting the major route of elimination of parent drug. Twenty-two in vitro permeability rate measurement data sets in Caco-2 and MDCK cell lines and PAMPA were collected from the literature, while in silico permeability rate predictions were calculated using ADMET Predictor or VolSurf+. The potential for permeability rate to differentiate between extensively and poorly metabolized compounds was analyzed with receiver operating characteristic curves. Compounds that yielded the highest sensitivity-specificity average were selected as permeability rate reference standards. The major route of elimination of poorly permeable drugs was predicted by our previously published model, and the accuracies and predictive values were calculated. The areas under the receiver operating curves were >0.90 for in vitro measures of permeability rate and >0.80 for the VolSurf+ model of permeability rate, indicating they were able to predict the extent of metabolism of compounds. Labetalol and zidovudine predicted greater than 80% of extensively metabolized drugs correctly and greater than 80% of poorly metabolized drugs correctly in Ca

Purpose: The objective of this study was to conduct a randomised phase II study in second-line metastatic colorectal cancer with the purpose of confirming preliminary clinical data indicating that the formulation of irinotecan with the drug carrier, hyaluronan (HA) reduced toxicity of the drug. Method(s): Irinotecan-naive patients were randomized to receive either irinotecan (350 mg/m2) or HA-Irinotecan (HA 1,000 mg/m2 and irinotecan at 350 mg/m2) every 3 weeks for a maximum of eight cycles. Result(s): Seventy-six patients (41 HA-Irinotecan and 35 irinotecan-alone) were enrolled. There was no significant difference in any individual, or overall, grade 3 or 4 toxicity. There was a trend for increased diarrhea in the HA-Irinotecan-treated patients (20 versus 9%; P = 21), potentially explained by a disproportionate number of baseline toxicity-associated risk factors in this treatment group. The median number of cycles completed was six for HA-Irinotecan patients and two for irinotecan-alone patients (P = 0.005). When compared to the control arm, HA-Irinotecan patients had a significantly longer median progression-free survival of 5.2 versus 2.4 months (P = 0.017) and time to treatment failure (4 vs. 1.8 months; P = 0.007). Median overall survival was 10.1 months for HA-Irinotecan compared to 8.0 months for irinotecan patients (P = 0.196). Conclusion(s): Further studies are required to define the safety of the formulation of irinotecan with HA. While this study was not adequately powered to demonstrate survival differences, these phase II data indicated HA-Irinotecan to be a promising therapy demonstrating improved efficacy compared to irinotecan-alone. © 2010 Springer-Verlag.

The morbidity, mortality and economic burden of chronic kidney disease (CKD) and associated anaemia are substantial. With the increasing numbers of patients who are likely to be affected in the future, approaches are required to improve anaemia management without increasing the burden on health-care professionals. A multidisciplinary approach to treatment, where early initiation of erythropoiesis-stimulating agents (ESA) is encouraged, may improve patient outcomes. Recent studies also suggest that the early use of iron therapy in patients with CKD not on dialysis may be associated with beneficial effects on haemoglobin levels. Another strategy to reduce the burden on health-care providers is to simplify anaemia management by extending the administration interval of ESA. Indeed, recent studies have explored the efficacy of extending the administration interval of ESA in clinical practice in CKD patients on dialysis and not on dialysis. The ability to maintain haemoglobin levels within guideline ranges at extended administration intervals may improve patient care and reduce the workload of health-care providers. © 2006 The Author.

Purpose: The objective of this study was to conduct a randomised phase II study in second-line metastatic colorectal cancer with the purpose of confirming preliminary clinical data indicating that the formulation of irinotecan with the drug carrier, hyaluronan (HA) reduced toxicity of the drug. Method(s): Irinotecan-naive patients were randomized to receive either irinotecan (350 mg/m2) or HA-Irinotecan (HA 1,000 mg/m2 and irinotecan at 350 mg/m2) every 3 weeks for a maximum of eight cycles. Result(s): Seventy-six patients (41 HA-Irinotecan and 35 irinotecan-alone) were enrolled. There was no significant difference in any individual, or overall, grade 3 or 4 toxicity. There was a trend for increased diarrhea in the HA-Irinotecan-treated patients (20 versus 9%; P = 21), potentially explained by a disproportionate number of baseline toxicity-associated risk factors in this treatment group. The median number of cycles completed was six for HA-Irinotecan patients and two for irinotecan-alone patients (P = 0.005). When compared to the control arm, HA-Irinotecan patients had a significantly longer median progression-free survival of 5.2 versus 2.4 months (P = 0.017) and time to treatment failure (4 vs. 1.8 months; P = 0.007). Median overall survival was 10.1 months for HA-Irinotecan compared to 8.0 months for irinotecan patients (P = 0.196). Conclusion(s): Further studies are required to define the safety of the formulation of irinotecan with HA. While this study was not adequately powered to demonstrate survival differences, these phase II data indicated HA-Irinotecan to be a promising therapy demonstrating improved efficacy compared to irinotecan-alone. © 2010 Springer-Verlag.

The morbidity, mortality and economic burden of chronic kidney disease (CKD) and associated anaemia are substantial. With the increasing numbers of patients who are likely to be affected in the future, approaches are required to improve anaemia management without increasing the burden on health-care professionals. A multidisciplinary approach to treatment, where early initiation of erythropoiesis-stimulating agents (ESA) is encouraged, may improve patient outcomes. Recent studies also suggest that the early use of iron therapy in patients with CKD not on dialysis may be associated with beneficial effects on haemoglobin levels. Another strategy to reduce the burden on health-care providers is to simplify anaemia management by extending the administration interval of ESA. Indeed, recent studies have explored the efficacy of extending the administration interval of ESA in clinical practice in CKD patients on dialysis and not on dialysis. The ability to maintain haemoglobin levels within guideline ranges at extended administration intervals may improve patient care and reduce the workload of health-care providers. © 2006 The Author.

Cardiovascular disease is highly prevalent in chronic kidney disease (CKD) and is often associated with increased vascular stiffness and calcification. Recent studies have suggested a complex interaction between vascular calcification and abnormalities of bone and mineral metabolism, with an inverse relationship between arterial calcification and bone mineral density (BMD). Although osteoporosis is recognized and treated in CKD 1 to 3, the interpretation of BMD levels in the osteoporotic range is controversial in CKD 4, 5, and 5D when renal osteodystrophy is generally present. In addition, there is a paucity of data for patients with CKD mineral and bone disorder (MBD), because studies using bisphosphonates in postmenopausal and glucocorticoid- induced osteoporosis have generally excluded patients with significant CKD. For these patients, treatment of low BMD using standard therapies for osteoporosis is not without potential for harm due to the possibility of worsening low bone turnover, osteomalacia, mixed uraemic osteodystrophy, and of exacerbated hyperparathyroidism; and bisphosphonates should only be used selectively and with caution. Some experimental and clinical studies have also suggested that bisphosphonates may reduce progression of extra-osseous calcification and inhibit the development of atherosclerosis. The authors review the potential benefits and risks associated with bisphosphonate use for bone protection in CKD, and assess their effect on vascular calcification and atherosclerosis. Copyright © 2009 by the American Society of Nephrology.

Cardiovascular disease is highly prevalent in chronic kidney disease (CKD) and is often associated with increased vascular stiffness and calcification. Recent studies have suggested a complex interaction between vascular calcification and abnormalities of bone and mineral metabolism, with an inverse relationship between arterial calcification and bone mineral density (BMD). Although osteoporosis is recognized and treated in CKD 1 to 3, the interpretation of BMD levels in the osteoporotic range is controversial in CKD 4, 5, and 5D when renal osteodystrophy is generally present. In addition, there is a paucity of data for patients with CKD mineral and bone disorder (MBD), because studies using bisphosphonates in postmenopausal and glucocorticoid- induced osteoporosis have generally excluded patients with significant CKD. For these patients, treatment of low BMD using standard therapies for osteoporosis is not without potential for harm due to the possibility of worsening low bone turnover, osteomalacia, mixed uraemic osteodystrophy, and of exacerbated hyperparathyroidism; and bisphosphonates should only be used selectively and with caution. Some experimental and clinical studies have also suggested that bisphosphonates may reduce progression of extra-osseous calcification and inhibit the development of atherosclerosis. The authors review the potential benefits and risks associated with bisphosphonate use for bone protection in CKD, and assess their effect on vascular calcification and atherosclerosis. Copyright © 2009 by the American Society of Nephrology.

Background: Falls are a major health problem among the elderly, particularly in nursing homes. Abnormalities of balance and gait, psychoactive drug use, and dementia have been shown to contribute to fall risk. Methods: We conducted a systematic review of the literature to investigate which psychoactive drugs increase fall risk and what is known about the influence of these drugs on gait in nursing home residents with dementia. We included studies with a prospective cohort design on psychoactive drug use in nursing homes with dementia residents and with falls as an outcome measure. Results: Seventeen studies were included in the review. Pooled risk estimates were not calculated because there was no homogeneity across studies. We assessed the strength of evidence for psychoactive drugs as a prognostic factor for falls by defining four levels of evidence: strong, moderate, limited or inconclusive. Strong evidence was defined as consistent findings (≥80%) in at least two high quality cohorts. We found strong evidence that the use of multiple drugs (3/3 cohorts, effect sizes 1.30-1xs0.30), antidepressants (10/12 cohorts, effect sizes 1.10-7.60), and anti-anxiety drugs (2/2 cohorts, effect sizes 1.22-1.32) is associated with increased fall risk. The evidence for the association of other psychoactive drug classes with fall risk was limited or inconclusive. Conclusions: Research on the contribution of psychoactive drugs to fall risk in nursing home residents with dementia is limited. The scarce evidence shows, however, that multiple drugs, antidepressants and anti-anxiety drugs increase fall risk in nursing home populations with residents with dementia.

HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3,3-heptafluoropropane) are used to replace chlorofluorocarbons (CFCs) in refrigerant and aerosol applications, including medical use in metered-dose inhalers. Production and consumption of CFCs are being phased out under the Montreal Protocol on Substances that Deplete the Ozone Layer. The safety and pharmacokinetics of HFC 134a and HFC 227 were assessed in two separate double-blind studies. Each HFC (hydrofluorocarbon) was administered via whole-body exposure as a vapor to eight (four male and four female) healthy volunteers. Volunteers were exposed, once weekly for 1 h, first to air and then to ascending concentrations of HFC (1000, 2000, 4000, and 8000 parts per million (ppm)), interspersed with a second air exposure and two CFC 12 (dichlorodifluoromethane) exposures (1000 and 4000 ppm). Comparison of either HFC 134a or HFC 227 to CFC 12 or air gave no clinically significant results for any of the measured laboratory parameters. There were no notable adverse events, there was no evidence of effects on the central nervous system, and there were no symptoms of upper respiratory tract irritation. HFC 134a, HFC 227, and CFC 12 blood concentrations increased rapidly and in an exposure-concentration-dependent mariner, although not strictly proportionally, and approached steady state. Maximum blood concentrations (C(max)) tended to be higher in males than females; in the HFC 227 study, these were statistically significantly (P < 0.05) higher in males for each HFC 227 and CFC 12 exposure level. In the HFC 134a study, the gender difference in C(max) was only statistically significant (P < 0.05) for CFC 12 at 4000 ppm and HFC 134a at 8000 ppm. Following the end of exposure, blood concentrations declined rapidly, predominantly biphasically and independent of exposure concentration. For the HFC 134a study, the t( 1/2 )α (α elimination half-life) was short for both CFC 12 and HFC 134a (<11 min). The t( 1/2 )β (β eli

We report the first toxicokinetic studies of (±)-sarin. The toxicokinetics of the stereoisomers of this nerve agent were studied in anesthetized, atropinized, and restrained guinea pigs after intravenous bolus administration of a dose corresponding to 0.8 LD50 and after nose-only exposure to vapor concentrations yielding 0.4 and 0.8 LCt50 in an 8-min exposure time. During exposure the respiratory minute volume and frequency were monitored. Blood samples were taken for gas chromatographic analysis of the nerve agent stereoisomers and for measurement of the activity of blood acetylcholinesterase (ACHE). In all experiments, the concentration of (+)-sarin was below the detection limit <5 pg/ml). The concentration-time profile of the toxic isomer, i.e., (-)-sarin, after an intravenous bolus was adequately described with a two-exponential equation. (-)-Sarin is distributed ca. 10-fold faster than C(-)P(-)-soman, whereas its elimination proceeds almost 10-fold slower. During nose-only exposure to 0.4 and 0.8 LCt50 of (±)-sarin in 8 min, (-)-sarin appeared to be rapidly absorbed. The blood AChE activity decreased during the exposure period to ca. 15 and 70% of control activity, respectively. There were no effects on the respiratory parameters. A significant nonlinearity of the toxico-kinetics with dose was observed for the respiratory experiments. © 2000 Academic Press.

The non-distressing [N-15]methacetin liver function test was modified and applied to newborn healthy infants in order to measure both the total [N-15]methacetin metabolites excreted in the urine (total elimination capacity) and the proportion of glucuronated metabolite. By studying pre-and full-term normotrophic neonates 3-168 days old, the age-dependent maturation of the two developing liver function processes can be compared on the basis of either postnatal or postmenstrual age. When solely considering postnatal age, no significant differences between the pre-and full-term infants were observed in the development of the total elimination capacity. However, when postmenstrual age was considered, it became apparent that this development starts earlier in pre-term infants and continues at the same rate as their full-term counterparts, up to the postmenstrual age of approximately 280 days. This increase subsequently diminishes in the pre-terms. In the same study group, the proportion of glucuronidation, another indicator of the hepatic detoxification system, appears to develop at a lower rate in pre-term than in full-term infants. When postmenstrual age is taken into consideration, glucuronidation development is also observed to begin earlier in pre-term infants and the slower maturation is more pronounced. Although these results are not generally applicable, they contribute to a better interpretation of the [N-15]methacetin liver function test-for instance when estimating effects due to environmental exposure or accurately calculating age-related drug dosage for neonates.

Three new nonquaternary oximes have been evaluated with respect to their antidotal activities against organophosphate poisoning. The oximes 1,2,3-thiadiazole-5-carboxaldoxime (1, pKa = 7.6), 2-methyl-1,3,4-thiadiazole-5-carboxaldoxime (2, pKa = 8.4), and 3-methyl-1,2,4-thiadiazole-5-carboxaldoxime (3, pKa = 7.0) were prepared in yields of 56, 24, and 58%, respectively, by nitrosation of the corresponding methyl derivatives with isoamyl nitrite in the presence of potassium ethoxide. The new compounds are substantially more lipophilic and much less toxic than the well-known antidote P2S. They reactivate phosphylated AChE slowly. In the five animal species investigated, they disappear from the blood stream after iv administration at approximately the same rates as Obidoxime. It was shown that the disappearance of 1 from rabbit blood is not due to rapid renal excretion of the unchanged oxime, as is the case for Obidoxime and P2S. Since an unidentified derivative of 1 has been found in the urine, rapid metabolic conversion of 1 is most likely responsible. Therapeutic administration (ip) of 2-3 at 250 mg/kg, in combination with atropine, saves mice from four to five times the LD50 of sarin. Much lower doses (33-75 mg/kg) of 1 save rats and mice from five times the LD50 of sarin, whereas P2S cannot save mice from the same challenge dose. In contrast herewith, 1 does not save rats from five times the LD50 of paraoxon, whereas P2S is effective in this case. For oral prophylaxis against sarin, 1 is inferior to P2S. This inferiority may be partly ascribed to the combined effects of rapid absorption of 1 from the gastrointestinal tract and rapid elimination. Chemicals/CAS: acetylcholinesterase, 9000-81-1; atropine, 51-55-8, 55-48-1; diacetyl oxime, 57-71-6; obidoxime, 114-90-9, 7683-36-5; paraoxon, 311-45-5; sarin, 107-44-8; tri ortho cresyl phosphate, 78-30-8; Acetylcholinesterase, EC 3.1.1.7; Antidotes; Enzyme Reactivators; Organophosphorus Compounds; Oximes; Sarin, 107-44-8