Clinical Therapeutics (CLIN THER)

Publications in this journal

• Article: Velásquez JL, Becerra PF, Faure A, et.Al. Clinical experience in México with a New oral rehydration solution with lower osmolality, Clin Ther.Vol 12. Suppl.. A. 1990

  Velásquez JL, Becerra PF, Faure A
  Clinical Therapeutics 01/2010; 12(Suppl).
• Article: Modelling the cost-effectiveness of prothrombin complex concentrate compared to fresh frozen plasma in emergency warfarin reversal in the UK

  JF Guest, HG Watson, S Limaye
  Clinical Therapeutics 01/2010; 32(14):2478-2493..
• Article: Bioavailability and bioequivalence of two oral formulations of alendronate sodium 70 mg: an open-label, randomized, two-period crossover comparison in healthy Korean adult male volunteers.

  Si-Youn Rhim, Jin-Hee Park, Yoo-Sin Park, Min-Ho Lee, Dong-Sun Kim, Leslie M Shaw, Seok-Chul Yang, Ju-Seop Kang
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  ABSTRACT: Alendronate sodium is a Bisphosphonate drug used to treat and prevent osteoporosis and several other bone diseases. A new formulation has been developed and is currently awaiting regulatory approval, pending findings on bioequivalence. The aims of the present study were to compare the bioavailability and pharmacokinetic (PK) properties, and to determine the bioequivalence, of a test and reference formulation of alendronate sodium 70 mg in a healthy Korean adult male population. This open-label, randomized, 2-sequence, 2-period crossover study was carried out at Hanyang University Medical Center (Seoul, Republic of Korea). Healthy Korean adult male volunteers were randomly assigned to receive a single 70-mg dose of the test or reference formulation of alendronate sodium, administered with 240 mL of water, followed by a 7-day washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Serial blood samples were collected and adverse events were monitored by a clinical investigator via observation, personal interview, and vital signs (blood pressure, heart rate, and body temperature) over a 7-hour period (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours) after drug administration. Plasma alendronate sodium concentrations were determined using a validated high-performance liquid chromatographic-postcolumn fluorescence derivatization method, with visible detection in the range of 2 to 100 ng/mL and lower limit of quantification set at 2 ng/mL. PK properties, including AUC(0-t), AUC(0-infinity), C(max), T(max), t(1/2), and the elimination constant (k(e)), were determined using non-compartmental analysis. The formulations were considered bioequivalent if the 90% CI ratios for C(max) and AUC were within the predetermined interval of 80% to 125%, the regulatory definition set by the US Food and Drug Administration (FDA). Twenty-three healthy male volunteers (mean [SD] age, 23.5 [2.0] years [range, 19-28 years]; height, 175.9 [5.4] cm [range, 162.0-185.0 cm]; and weight, 71.2 [9.5] kg [range, 61-96 kg]) were included in the study. No period or sequence effects were detected. The 90% CIs for the corresponding ratios of AUC(0-t), AUC(0-infinity) and C(max) were 84.97 to 114.47, 86.09 to 115.59, and 82.37 to 110.71, respectively. Additionally, the mean (range) of T(max) was 1.09 hours (0.5-2.0 hours), and the mean (SD) of t(1/2) and k(e) were 2.04 (0.97) hours and 0.34 (0.71) hour, respectively. The values for the test and reference formulations were within the FDA bioequivalence definition interval of 80% to 125%. No adverse events were reported in this study. Single doses of these formulations of alendronate sodium 70 mg met the criteria for bio-equivalence. No statistically significant differences in AUC(0-t), AUC(0-infinity), and C(max) were found in this healthy Korean adult male population.
  Clinical Therapeutics 06/2009; 31(5):1037-45.
• Article: Results of a model analysis to estimate cost utility and value of information for intravenous immunoglobulin in Canadian adults with chronic immune thrombocytopenic purpura.

  Feng Xie, Gord Blackhouse, Nazila Assasi, Kaitryn Campbell, Mitchell Levin, Jim Bowen, Jean-Eric Tarride, David Pi, Ron Goeree
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  ABSTRACT: The aim of this work was to estimate the cost-effectiveness of intravenous immunoglobulin (IVIg) compared with oral prednisone as a treatment for Canadian adults with persistent chronic immune thrombocytopenic purpura (ITP). The lifetime costs and effectiveness of IVIg and prednisone were estimated from the perspective of a publicly funded health care system in Canada, using a Markov model that was developed based on a systematic clinical and economic review and recommendations of clinical experts in Canada. Transition probabilities (ie, point estimates and 95% CIs) were estimated from the studies identified in a systematic literature review using a random-effect meta-analysis; point estimates were weighted-mean values from the meta-analysis. No published studies directly estimate the utility weight for patients with relapsed or refractory ITP; therefore, a value of 0.76 was used, based on the mean of the utilities for thrombocytopenia without major bleeding or hemorrhagic stroke. Costs and incremental cost-effectiveness ratios were reported as year-2007 Can $. The incremental costs and quality-adjusted life-years (QALYs) of IVIg versus prednisone were Can $8080 and 0.0071, respectively, resulting in an incremental cost-effectiveness ratio of Can $1.13 million/ QALY in the base-case analysis. The probability of IVIg being cost-effective was 0 if the maximum willingness-to-pay (WTP) value for an additional QALY was below Can $40,000. The probability that IVIg would be cost-effective was only 20%, even if the WTP increased to Can $100,000. The expected value of perfect information (EVPI) and expected value of partial perfect information (EVPPI) were 0 if the WTP was less than Can $30,000. If WTP increased to Can $100,000, the EVPI was Can $1700, and the EVPPI was Can $1010 for utility weights of relapse/refractory states, Can $136 for initial response rates of the treatments, and Can $6 for first-year relapse rates for the treatments. Based on the current available clinical evidence, this model analysis of hypothetical patients suggests that IVIg may not be a cost-effective option for adults with persistent chronic ITP in Canada.
  Clinical Therapeutics 06/2009; 31(5):1082-91; discussion 1066-8.
• Article: Pharmacokinetic, tolerability, and bioequivalence comparison of three different intravenous formulations of recombinant human erythropoietin in healthy Korean adult male volunteers: an open-label, randomized-sequence, three-treatment, three-way crossover study.

  Sang-Heon Cho, Hyeong-Seok Lim, Jong-Lyul Ghim, Sangmin Choe, Un-Jib Kim, Jin Ah Jung, Kyun-Seop Bae
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  ABSTRACT: Existing formulations of recombinant human erythropoietin (rhEPO) in Korea contain human serum albumin. To avoid the potential risk of infection by human serum albumin, a new albumin-free rhEPO has been developed. Objective: This study was conducted to characterize and compare the pharmacokinetic and safety profiles and the bioequivalence of a newly developed albumin-free rhEPO (Aropotin [TS Corporation, Seoul, South Korea]) with 2 existing rhEPO formulations (Espogen [LG Life Sciences, Seoul, South Korea]; Recormon [Roche, Basel, Switzerland]) with albumin in healthy Korean subjects. This was an open-label, randomized-sequence, 3-treatment, 3-way crossover study in which healthy, nonobese (+/-20% of ideal weight), male volunteers between the ages of 19 and 50 years were assigned to 1 of 2 dose levels (50 IU/kg or 100 IU/kg) of 3 formulations. Blood was collected over 32 hours and plasma rhEPO concentrations were determined using a validated enzyme immunoassay. There was a 14-day washout between periods. The pharmacokinetic parameters of the 3 formulations were compared using the bioequivalence criteria of the US Food and Drug Administration, which requires that the 90% CIs of the geometric mean ratios for AUC(0-t), AUC(0-infinity), and C(max) fall within 0.80 to 1.25. Tolerability was evaluated by physical examination with measurements of vital signs, clinical laboratory tests, and electrocardiogram. Subjects were followed up for 2 weeks after the last administration of study drug. Twelve Korean male volunteers were enrolled and completed the study. Six subjects (mean [SD] age, 22.0 [1.7] years; weight, 63.3 [6.2] kg; height, 172.3 [3.5] cm) received a single 50 IU/kg IV bolus dose of study drug and the remaining 6 subjects (mean [SD] age, 23.7 [1.5] years; weight, 66.3 [4.8] kg; height, 174 [4.7] cm) received 100 IU/kg. After a single 50 IU/kg dose, the geometric mean ratio (90% CI) for Aropotin/Espogen was 1.04 (0.91-1.19) IU/L/h for AUC(0-t) and 1.02 (0.89-1.17) IU/L for C(max). The geometric mean ratio (90% CI) for Aropotin/Recormon was 1.01 (0.88-1.15) IU/L/h for AUC(0-t) and 1.01 (0.89-1.16) IU/L for C(max). After a single 100-IU/kg dose, the geometric mean ratio (90% CI) for Aropotin/ Espogen was 0.98 (0.86-1.13) IU/L/h for AUC(0-t) and 0.99 (0.87-1.13) IU/L for C(max). The geometric mean ratio (90% CI) for Aropotin/Recormon was 0.99 (0.861.14) IU/L/h for AUC(0-t) and 0.96 (0.84-1.10) IU/L for C(max). The most frequent adverse events (AEs) were 3 occurrences of elevated serum creatine phosphokinase and serum lactate dehydrogenase levels in the Recormon 100-IU/kg group (n = 3), 3 events of elevated serum lactate dehydrogenase levels in the Espogen 100-IU/kg group (n = 3), and 4 events of elevated serum total bilirubin levels in the Aropotin 100-IU/kg group (n = 3). All formulations were well tolerated with no serious AEs. The new formulation of rhEPO met the regulatory criteria for bioequivalence in these healthy Korean adult male volunteers. All formulations were generally well tolerated.
  Clinical Therapeutics 06/2009; 31(5):1046-53.
• Article: Connecting drug safety and effectiveness research to public values.

  Colleen J Metge
  Clinical Therapeutics 06/2009; 31(5):1066-8.
• Article: Re: trial comparing insulin detemir with insulin glargine.

  Sanne Swinnen, Frits Holleman
  Clinical Therapeutics 06/2009; 31(5):1124-5; author reply 1125-6.
• Article: Efficacy of clodronate, pamidronate, and zoledronate in reducing morbidity and mortality in cancer patients with bone metastasis: a meta-analysis of randomized clinical trials.

  Márcio Machado, Lorena Souza Cruz, Gabriela Tannus, Marcelo Fonseca
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  ABSTRACT: Complications from skeletal-related events (SREs) constitute a challenge in the care of patients with metastatic bone disease (MBD) that originated from any type of malignancy. The purpose of this article was to compare the efficacy of clodronate, pamidronate, and zoledronate with that of placebo in reducing morbidity and overall mortality in cancer patients with MBD. MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched (from inception to January 2009) to retrieve randomized clinical trials that evaluated the bisphosphonates of interest. The search included articles published in English, French, Italian, Portugese, and Spanish. Patients with a definite (ie, biopsy-proven) diagnosis of MBD were included in the analysis. We extracted and combined data from studies that reported the number of patients with SREs and mortality data. A random-effects, meta-analytic model was applied in all calculations. The Jadad scale was used to assess the quality of study reporting. The literature search identified 62 potential full-text studies; 44 of these studies were excluded and 18 were evaluated. The mean (SD) quality of reporting of the included studies was 57.8% (22.6%), or 2.89/5 (1.1/5). Each of the 3 drugs was found to be more effective than placebo in preventing all SREs in cancer patients with MBD. The relative risk of developing SREs was 0.70 (95% CI, 0.61-0.81; N = 1211) for zoledronate, 0.81 (95% CI, 0.73-0.91; N = 2251) for pamidronate, and 0.87 (95% CI, 0.75-1.00; N = 681) for clodronate. However, no clear advantage of one drug over the others was observed (CIs overlapped substantially). None of the bisphosphonates was more beneficial than placebo in reducing the number of deaths in the course of the trials (P = NS). Clodronate, pamidronate, and zoled-ronate were associated with reductions in morbidity in cancer patients with MBD with regard to preventing SREs, but were not associated with a reduction in overall mortality.
  Clinical Therapeutics 06/2009; 31(5):962-79.
• Article: Effect of multidrug resistance gene-1 (ABCB1) polymorphisms on the single-dose pharmacokinetics of cloxacillin in healthy adult Chinese men.

  Ophelia Q P Yin, Brian Tomlinson, Moses S S Chow
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  ABSTRACT: Plasma concentrations of cloxacillin have been found to vary as much as 20-fold among individuals receiving the same oral dose. There is evidence that cloxacillin may be a substrate for P-glycoprotein, suggesting that polymorphisms in the ABCB1 gene may be a contributing factor to the observed variability in plasma cloxacillin concentrations. This study investigated the effect of ABCB1 polymorphisms on the pharmacokinetic profile of cloxacillin in healthy subjects. A single oral dose of cloxacillin 500 mg was administered to healthy Chinese male subjects under fasting conditions. Serial blood and urine samples were collected for up to 6 hours after administration. A high-performance liquid chromatography method was used to determine plasma cloxacillin pharmacokinetics and urinary excretion. A polymerase chain reaction technique was used for genotyping of 3 single nucleotide polymorphisms (SNPs) of the ABCB1 gene: exon 12 C1236T, exon 21 G2677T/A, and exon 26 C3435T. Cloxacillin pharmacokinetic parameters and urinary excretion were then compared according to genotype and haplotype groups. The study included 18 healthy Chinese male subjects who ranged in age from 21 to 26 years, had a mean weight ranging from 55.6 to 70.6 kg, and had normal renal function at baseline (mean [SD] serum creatinine, 93.4 [11.0] micromol/L). Plasma concentrations of cloxacillin were generally lower in the group carrying the 1236CC genotype (n = 3) compared with those carrying the 1236CT genotype (n = 9) or the 1236TT genotype (n = 6). Compared with the other groups, carriers of the 1236CC genotype had a significantly lower mean Cmax (-53%; P = 0.013) and AUC(0-infinity) (-40%; P = 0.044), and a significantly higher mean apparent oral clearance (35%; P = 0.013). They also had significantly lower urinary excretion of cloxacillin over 6 hours (-52%; P = 0.027). There were no significant differences in cloxacillin t(1/2) or renal clearance between the 3 C1236T genotypes, nor was the G2677T or C3435T SNP associated with any significant changes in the cloxacillin pharmacokinetic profile. Among subjects with 1 of the 3 major haplotype pairs, those carrying the CGC/CGC pair had a significantly lower C(max) (P = 0.017), AUC (P = 0.032), and urinary excretion of cloxacillin (P = 0.026) compared with those carrying the CGC/TGC and TTT/TTT pairs. In this small population of healthy Chinese men, the C1236T variant of ABCB1 appeared to be an important contributor to interindi-vidual differences in plasma cloxacillin exposure, most likely through an effect on oral absorption rather than on disposition. Studies of multiple doses in larger sample sizes are needed to confirm these findings.
  Clinical Therapeutics 06/2009; 31(5):999-1006.
• Article: Fatal acute hepatitis after sequential treatment with levofloxacin, doxycycline, and naproxen in a patient presenting with acute Mycoplasma pneumoniae infection.

  Miguel F Carrascosa, María Isabel Lucena, Raúl J Andrade, José Ramón S Caviedes, Antonio C Lavín, Juan C Mones, Andrea P Rivero, Vicente B Serrano
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  ABSTRACT: The diagnosis of drug-induced liver injury relies on comprehensive clinical assessments due to the absence of an established biomarker or pathognomonic features of liver histology. However, prompt recognition of a culprit drug as the cause of liver injury is the most important aspect in the management of hepatotoxicity. A 63-year-old white male (85 kg) was admitted because of community-acquired pneumonia with associated pericarditis and subclinical hepatitis, subsequently related to acute Mycoplasma pneumoniae infection (diagnostic positive immuno-globulin M enzyme immunoassay, on hospital days 5 and 20). The patient had received cisplatin and radiotherapy from March to May 2006, as treatment for pharyngolaryngeal squamous cell carcinoma T3N0M0 without subsequent evidence of localized or meta-static recurrent disease (last oncologic consultation, May 17, 2007). He reported alcohol ingestion until March 2006 but no known liver disease, blood transfusion, or exposure to mushrooms or industrial cleaning solvents. Results of serologic tests for viral and nonviral infectious hepatitis, iron and copper studies, and tests for autoantibodies were normal or negative. The patient became initially asymptomatic and fever disappeared following sequential treatment with levo-floxacin (500 mg BID), doxycycline (100 mg BID), and naproxen (500 mg TID). However, on hospital day 10 jaundice and a significant elevation (alanine aminotransferase, 1577 U/L; aspartate amino-transferase, 1754 U/L; alkaline phosphatase, 189 U/L) of serum transaminases appeared. Despite the discontinuation of all medication, the patient gradually deteriorated and died 27 days after admission due to acute fulminant hepatic failure. Autopsy revealed massive hepatic necrosis, inflammatory changes with presence of eosinophils, and cholestasis. An objective causality assessment scale (Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method scale) suggested that each of the 3 drugs could "probably" (score = 6) be related to the patient's fulminant hepatitis. The Naranjo Adverse Drug Reactions Probability Scale assessment for the same drugs indicated a "possible" causal relation (score = 2). We report a case of lethal hepatitis possibly/probably associated with levofloxacin, doxy-cycline, and naproxen in a patient with acute M pneumoniae infection.
  Clinical Therapeutics 06/2009; 31(5):1014-9.
• Article: Cost-effectiveness of pegfilgrastim versus filgrastim primary prophylaxis in women with early-stage breast cancer receiving chemotherapy in the United States.

  Gary H Lyman, Anjana Lalla, Richard L Barron, Robert W Dubois
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  ABSTRACT: Prophylaxis with granulocyte colony-stimulating factor reduces the risk for febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy. We estimated the incremental cost-effectiveness of primary prophylaxis (starting in cycle 1 of chemotherapy) with pegfilgrastim versus filgrastim in women with early-stage breast cancer receiving myelosuppressive chemotherapy in the United States. A decision-analytic model was constructed from a health payer's perspective with a lifetime study horizon. The model considered direct medical costs and outcomes related to reduced FN and potential survival benefits due to reduced FN-related mortality and on-time receipt of full-dose chemotherapy. Sensitivity analyses were conducted. Pegfilgrastim was cost-saving and more effective (ie, dominant strategy) than 11-day filgrastim. The incremental cost-effectiveness ratio (ICER) for pegfilgrastim versus 6-day filgrastim was $12,904 per FN episode avoided. Adding the survival benefit due to reduced FN mortality and receipt of optimal chemotherapy dose yielded an ICER of $31,511 per quality-adjusted life year (QALY) gained and $14,415 per QALY gained, respectively. The most influential factors included inpatient FN case-fatality rate, cost of pegfilgrastim and filgrastim, baseline probability of FN, relative risk for FN between filgrastim and pegfil-grastim, and cost of administration of filgrastim. Pegfilgrastim was cost-saving compared with 11-day filgrastim and cost-effective compared with 6-day filgrastim from a health payer's perspective for the primary prophylaxis of FN in these women with early-stage breast cancer receiving myelosuppressive chemotherapy.
  Clinical Therapeutics 06/2009; 31(5):1092-104.
• Article: Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies.

  Daphne D Williams, Bin Peng, Christine K Bailey, Mary B Wire, Yanli Deng, Jung Wook Park, David A Collins, Shiva G Kapsi, Julian M Jenkins
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  ABSTRACT: Eltrombopag is the first orally self-administered, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura. The aim of these studies was to assess the effect of food and antacids on the pharmacokinetic and safety profiles of eltrombopag. Two independent, single-dose, open-label, randomized-sequence, crossover studies of oral eltrombopag were conducted in healthy adult volunteers. The first study (study A) compared eltrombopag 50 mg (tablets or capsules) administered in the fasted state or tablets with a high-fat, high-calcium breakfast. The second study (study B) investigated eltrombopag tablets (75 mg) administered in the fasted state; immediately after a low-fat, low-calcium meal or a high-fat, low-calcium meal; 1 hour before a high-fat, low-calcium meal; or with an antacid containing aluminum hydroxide and magnesium carbonate. Vital signs were recorded and electrocardiogram and clinical laboratory tests were performed at screening, within 24 hours before and within 48 hours after each dose of study medication. Symptom assessment was performed and adverse events (AEs) were assessed previous to study drug administration through follow-up in terms of severity and relationship to study medication. In study A, 18 male subjects (mean age, 23.0 years; weight, 70.3 kg; white race, 94.4%) who received a high-fat, high-calcium breakfast had reduced bioavailability of eltrombopag in terms of AUC(0-infinity)) by 59% (geometric mean ratio [GMR], 0.41; 90% CI, 0.36-0.46) and C(max) by 65% (GMR, 0.35; 90% CI, 0.30-0.41) compared with subjects in a fasted state. In study B, the bioavailability in 26 subjects (14 male, 12 female; mean age, 35.6 years; weight, 76.0 kg; white race, 65.4%) was not significantly changed when administered with food that was low in calcium, despite the fat content (GMRs ranged from 0.87-1.03 for AUC(0-infinity) and 0.85-1.01 for C(max) across the 3 studied meals). Mean plasma AUC(0-infinity)) and C(max) values decreased by approximately 70% (GMR, 0.30; 90% CI, 0.24-0.36 for AUC(0-infinity)) and 0.24-0.38 for C(max)) when administered with a metal cation-containing antacid. No serious AEs were reported and all AEs were rated as mild to moderate in intensity. The most frequently reported AE was headache (study A, 6.3%; study B, 12.0%-29.2%). Concomitant administration of eltrombopag with high-calcium food or an antacid containing aluminum and magnesium was associated with significantly reduced systemic exposure, whereas low-calcium meals were not. A single dose of eltrombopag was generally well tolerated in these healthy volunteers.
  Clinical Therapeutics 05/2009; 31(4):764-76.
• Article: Gastroprotective drugs in Australia: utilization patterns between 1997 and 2006 in relation to NSAID prescribing.

  Nadia Barozzi, Susan E Tett
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  ABSTRACT: In Australia, the prescribing of proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H(2)RAs) for defined gastrointestinal disorders is approved for subsidy by the universal Australian Pharmaceutical Benefits Scheme. These agents also may be used with NSAIDs, but this prescribing is not approved for subsidy. PPI prescribing increased in Australia between 1997 and 2006, and some authorities are concerned that this increase may be due to prescriptions outside the approved indications. The aims of this study were to quantify gastroprotective drug consumption in Australia between 1997 and 2006 and to investigate the relationship over time between this prescribing and NSAID prescribing. Data from concession beneficiaries (seniors and welfare recipients) were included. Data on PPIs, H(2)RAs, NSAIDs, and cyclooxygenase (COX)-2 inhibitors dispensed between 1997 and 2006 were gathered from Medicare Australia and are expressed as defined daily doses (DDDs) per 1000 concession beneficiaries per day (CBPDs). Gastroprotective drugs were defined using the World Health Organization Anatomical Therapeutic Chemical classification of 2006. Drug utilization 90% and expenditures in Australian dollars (AUD $, not normalized to an index year) were calculated. H(2)RA prescribing was stable between 1997 and 2001, at approximately 60 DDDs/1000 CBPDs. Dispensation of H(2)RAs began to decrease in 2001 to 20 DDDs/ 1000 CBPDs in 2006. PPI consumption increased consistently, with a sharp change beginning in 2001 (from about 45 to 140 DDDs/1000 CBPDs between 2001 and 2006). The government expenditure for PPIs per concession beneficiary per year also increased from about AUD $26 in 1997 to almost AUD $74 in 2006, whereas the expenditure for H2RAs decreased from about AUD $24 to about AUD $5. Nonselective NSAID prescribing decreased with the introduction of COX-2 inhibitors in 2000. COX-2 inhibitors increased the overall consumption of total NSAIDs in the first 4 years (2000-2003) after their introduction. The prescribing of H(2)RAs decreased, whereas the prescribing of PPIs increased, between 1997 and 2006 in this population of concession beneficiaries in Australia. During the same period, nonselective NSAID prescribing decreased while COX-2 inhibitor prescribing increased.
  Clinical Therapeutics 05/2009; 31(4):849-61.
• Article: The financial implications for Medicare of greater use of peritoneal dialysis.

  Nancy Neil, Steven Guest, Leslie Wong, Gary Inglese, Samir K Bhattacharyya, Todd Gehr, David R Walker, Thomas Golper
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  ABSTRACT: Although annual per-person health care costs for patients with end-stage renal disease (ESRD) on in-center hemodialysis greatly exceed those for patients on peritoneal dialysis (PD), which is a home dialysis therapy, current use of PD remains low. In April 2008, the Centers for Medicare & Medicaid Services issued a new Dialysis Conditions of Coverage final rule underscoring its intent to promote use of home dialysis whenever appropriate. The objectives of this paper were to provide context for the use of in-home versus in-center dialysis, to describe factors that influence patterns of dialysis utilization in the United States, and to explore the magnitude of the potential savings that might result from broader use of home dialysis therapies. A 5-year budget-impact analysis was performed using data from the 2007 Annual Data Report of the United States Renal Data System. Scenarios were developed in which the PD share of total dialysis was varied to estimate the impact on total Medicare dialysis costs. This study took the perspective of Medicare, the main payer for dialysis in the United States. If the PD share of total dialysis were to decrease from the current 8% to 5%, Medicare spending for dialysis would increase by an additional $401 million over a 5-year period. Alternatively, if the PD share of total dialysis were to increase to 15%, Medicare could realize potential savings of >$1.1 billion over 5 years. Similar to the conclusion articulated in the Dialysis Conditions of Coverage final rule, increasing clinically appropriate use of PD would be associated with considerable savings to Medicare and to the taxpayers who fund Medicare. These savings could be used to offset part of the financial burden of ESRD care on Medicare and to help legislators meet ever-tightening budgetary constraints.
  Clinical Therapeutics 05/2009; 31(4):880-8.
• Article: N-of-1 double-blind, randomized controlled trial of tramadol to treat chronic cough.

  Priscila Gebrim Louly, Patrícia Medeiros-Souza, Leopoldo Santos-Neto
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  ABSTRACT: Chronic cough caused by interstitial pneumopathy can present a therapeutic dilemma, and the use of tramadol in the treatment of this symptom might be an alternative to improve the quality of life in patients. The present study describes a patient with rheumatoid arthritis and interstitial lung disease lasting 11 years who developed dry cough secondary to interstitial pneumopathy but was nonresponsive to several treatments (codeine 20 mg q6h; clobutinol 240 mg/d; and dextromethorphan 10 mg q4h). The purpose of this study was to investigate, for an individual patient, the effectiveness of tramadol 50 mg compared with placebo, and whether tramadol provided any antitussive benefit. This was an N-of-1 double-blind, randomized controlled trial of tramadol against placebo. Treatment was administered in 3 pairs, each consisting of 2 periods in which either tramadol 50 mg BID or placebo was administered for 6 days, followed by a 2-day washout period, and then the administration of the alternate for 6 days. A 2-day washout period was also carried out after pairs 1 and 2. Per pair, the sequence of treatments was randomized. Outcome measures were: the intensity of daytime and nighttime cough, assessed by a visual analog scale (VAS) ranging from 0 to 5 (0 = no cough, 5 = distressing cough); and the patient's perception regarding her health state (better, same, or worse). A 55-year-old black woman (height, 153 cm; weight, 71 kg) was in the study. In all treatment pairs, cough intensity, as reported by the patient using the VAS, was significantly lower with tramadol compared with placebo (P < 0.001), both in the daytime (2 vs 5, respectively) and at nighttime (1 vs 4). Regarding the patient's health state, in all periods in which tramadol was administered, the patient reported feeling better than when placebo was administered. At the begin- ning of pair 2, the use of rescue tramadol 50 mg (un-blinded) was permitted due to cough intensity. In the remaining treatment periods in which placebo was administered, rescue tramadol was administered, whereas rescue tramadol was not needed during the periods in which tramadol was administered. Tramadol appeared to be effective in controlling cough in this patient. Because no similar report was found in the literature, further studies assessing the efficacy of tramadol as an antitussive agent are warranted.
  Clinical Therapeutics 05/2009; 31(5):1007-13.
• Article: Results of a retrospective, observational pilot study using electronic medical records to assess the prevalence and characteristics of patients with resistant hypertension in an ambulatory care setting.

  Carrie McAdam-Marx, Xiangyang Ye, Jennifer C Sung, Diana I Brixner, Kristijan H Kahler
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  ABSTRACT: Resistant hypertension, or failure to attain blood pressure (BP) goals while treated with > or = 3 antihypertensives (including a diuretic), occurred in 15% to 18% of patients in prospective cohort trials. The aims of this work were to identify the prevalence of resistant hypertension in an ambulatory care setting and to describe the characteristics of patients with resistant hypertension. Adults with hypertension were retrospectively identified in a US electronic medical record from November 1, 2002, through November 30, 2005. Antihypertensive treatment and BP values were assessed to identify those with BP > or = 140/90 mm Hg (>130/80 mm Hg for those with diabetes mellitus or kidney disease). Patients treated with > or = 3 agents (including a thiazide) who had > or = 1 BP level above target were classified as having resistant hypertension. Baseline characteristics were compared between those with and those without resistant hypertension. Of 29,474 study patients aged > or = 18 years, 21,460 (72.8%) had > or = 1 prescription order for an antihypertensive and 19,202 (65.1%) had a follow-up BP level above target. The analysis found that 2670 patients (9.1% overall or 12.4% of those who were treated) were classified as having resistant hypertension. Relative to those without resistant hypertension, a greater proportion of those with resistant hypertension were female (65.6% vs 60.5%), were older (66.2 vs 63.0 years), had a higher body mass index (31.6 vs 30.4 kg/m(2)), had higher baseline BP levels (148/81 vs 138/80 mm Hg), and had higher rates of diabetes mellitus (35.2% vs 20.1%) or kidney disease (4.9% vs 2.7%) than those without resistant hypertension (all comparisons, P < 0.001). This retrospective, observational pilot study of usual community practice supports the findings from prospective trials that resistant hypertension is an important clinical problem. More effective management is needed to enable patients with, or at risk for, resistant hypertension to achieve BP goals.
  Clinical Therapeutics 05/2009; 31(5):1116-23.
• Article: Modified visual analog scale symptom-intensity and overall-bother measures for the assessment of symptoms in studies of pharmacologic stress agents.

  Gale Harding, Karin Coyne, Richard J Barrett, Glenn C Pixton
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  ABSTRACT: Drugs used to induce stress for cardiac imaging studies often cause discomfort. Patient-reported intensity of discomfort should be considered when comparing such agents. The purpose of this study was to assess the psychometric properties of a modified visual analog scale (VAS) symptom-intensity measure and an overall-bother measure adapted to assess patient-reported intensity of the adverse events (AEs) associated with pharmacologic stress testing with adenosine, a pharmacologic stress myocardial perfusion imaging (PS-MPI) agent. Data were based on 2 complementary, open-label, multicenter, naturalistic, observational studies among patients completing a PS-MPI procedure. Content, concurrent, and discriminant validity was examined by correlating modified VAS symptom-intensity scores obtained from patients with investigator-rated intensity at time of event, overall bother, and patient-reported measures obtained during a structured interview. Test-retest reliability of the overall-bother measure was examined using 1- and 2-hour assessments, and concurrent validity was assessed by correlating counts of symptoms and other patient-reported measures. Responsiveness was examined by calculating change scores of the VAS symptom-intensity measures from baseline to 1 hour among patients who reported symptoms during the 1-hour monitoring period after PS infusion. Low to moderate correlation was defined as a coefficient between 0.3 and 0.5. A total of 324 patients enrolled in the 2 studies. Content validity of the VAS symptom-intensity and overall-bother measures was established, with nearly all patients reporting that they were a useful way to rate symptom intensity and overall bother. VAS ratings were moderately to highly correlated with physician-rated AE intensity, and patient-reported assessments of symptom intensity, discomfort, and concern (r(s) = 0.21 r(s) = 0.84). Findings to support discriminant validity were inconclusive because of small sample size. Responsiveness was demonstrated with VAS symptom-intensity change scores ranging from 2.8 for headache to 4.9 for chest pain; effect sizes for these differences were large, ranging from 1.6 to 7.3, respectively. Findings support the validity, reliability, and responsiveness of the modified VAS symptom-intensity measure, and the reliability and validity of the overall-bother measure for use in patients completing PS procedures.
  Clinical Therapeutics 05/2009; 31(4):889-901.
• Article: Effect of a local heating device on insulin and glucose pharmacokinetic profiles in an open-label, randomized, two-period, one-way crossover study in patients with type 1 diabetes using continuous subcutaneous insulin infusion.

  Itamar Raz, Ram Weiss, Yevgeny Yegorchikov, Gabriel Bitton, Ron Nagar, Benny Pesach
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  ABSTRACT: Reducing postprandial hyperglycemia and hypoglycemia is a major challenge in the treatment of patients with diabetes. Studies suggest that heating the insulin injection site may accelerate insulin absorption. InsuPatch (InsuLine Medical Ltd., Petach-Tikva, Israel) is a device intended to accelerate subcutaneous insulin delivery using an insulin pump by locally warming the infusion site. The aim of this study was to assess the effect of the InsuPatch device on the pharmacokinetics of short-acting insulin analogues and on postprandial glycemia. This was an open-label, randomized, 2-period, 1-way crossover study using a meal tolerance test (MTT) protocol in subjects with type 1 diabetes mellitus aged 18 to 65 years with glycosylated hemoglobin (HbA(1c)) of 6% to 12%, who were using continuous subcutaneous insulin infusion (CSII) therapy (insulin lispro or aspart). A bolus of insulin 0.15 U/kg was delivered immediately before a standardized liquid meal. The effect of the device on insulin absorption and postprandial glucose excursions was tested by measuring blood glucose and insulin concentration profiles with and without the operation of the device. Adverse events (AEs) were monitored during the 2 study visits. The infusion site was visually inspected at the end of each study. All AEs were recorded in the case-report form. The MTT protocol was performed in 17 white patients with type 1 diabetes (sex, male/female, 7/10; mean age, 31.8 years [range, 18-53 years]; mean body mass index, 25.6 kg/m(2) [range, 20.0-39.4 kg/m(2)]; and mean HbA(1c), 7.1% [range, 5.8%-9.3%]). The mean (SD) postprandial glucose excursion AUC at 120 minutes after the meal was significantly reduced in the group that used the device compared with the group that did not (104 [65] vs 155 [56] mg/dL/h; P < 0.005). Plasma insulin was measured randomly in 9 of the 17 subjects. Use of the device was associated with significant reductions in mean (SD) T(max) (45 [28] vs 78 [35] minutes) and time to half-maximum concentration (T(50%max)) (20 [11] vs 28 [10] minutes; both, P < 0.05). Insulin AUC increased significantly in the group that used the device compared with the group that did not at 30 (21 [6] vs 33 [16] mU/L/h), 60 (55 [12] vs 80 [28] mU/L/h), and 90 (93 [19] vs 118 [31] mU/L/h) minutes after administration (all, P < 0.05). Cmax also increased significantly (118 [35] vs 86 [16] mU/L [38%]; P < 0.05). In this pilot study, use of the InsuPatch was associated with significant decreases in T(max) and T(50%max) and increases in insulin AUC and C(max) of subcutaneous infused rapid-acting insulin analogues, resulting in a lower postprandial glucose excursion in these patients with type 1 diabetes mellitus treated with CSII.
  Clinical Therapeutics 05/2009; 31(5):980-7.
• Article: Retrospective claims study of fluticasone propionate/salmeterol fixed-dose combination use as initial asthma controller therapy in children despite guideline recommendations.

  Howard S Friedman, Nemr S Eid, Simone Crespi, Teresa K Wilcox, Gregory Reardon
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  ABSTRACT: According to current asthma treatment guidelines, single-entity inhaled corticosteroids (ICSs) should be used as initial controller therapy in children with mild to moderate persistent asthma. Long-acting beta(2)-agonists (LABAs) can be added to therapy for those patients whose asthma is not well controlled with a single-entity ICS. The goal of this study was to examine whether the claims history for children in a US insured population indicate proper fluticasone propionate/ salmeterol (FPS) fixed-dose combination use in accordance with recommended asthma guidelines and a US Food and Drug Administration (FDA) advisory and black box warning regarding LABA use. A comparison of study-drug charges was also conducted. Data from a US commercial insurance database were used in this retrospective study to evaluate pharmacy and medical claims for children between October 2004 and September 2006 (ie, the index period). An index date corresponding to the date of the first FPS claim was assigned to each patient. Eligible patients were aged 4 to 11 years and had >/=1 pharmacy claim for FPS during the index period. Those patients receiving 1 FPS prescription dose strength on the index date who were continuously enrolled for benefits during the preindex period (ie, the 365 days before the index date) were included in the study. Disease severity was assigned based on asthma-related pharmacy (frequency and/or incidence of oral corticosteroid, LABA, montelukast, and >365 doses of a short-acting beta(2)-agonist) and medical (asthma-related urgent care clinic or emergency department visits or hospitalizations) claim histories during the preindex period. A total of 13,306 patients between the ages of 4 and 11 years on the index date were included in the study; their mean (SD) age was 8.9 (1.9) years. The majority of the patients were male (60.7%). Of the total FPS claims, 55.2% were for patients with no evidence of pharmacy or medical claims in the 365 days before the first FPS claim that would warrant ICS/LABA combination therapy according to asthma treatment guidelines. There were no large changes in preindex ICS claims over the course of the study in response to an FDA-issued advisory and black box warning regarding the use of LABAs. Median drug charges for single-entity ICS use were $98 compared with $168 for FPS therapy. ICS/LABA combination treatment was used as initial therapy in 55.2% of children with mild to moderate asthma in this claims database population, contrary to the recommendations of current asthma treatment guidelines. The FDA advisory and black box warning for LABA use had little observed impact on the number of single-entity ICS claims.
  Clinical Therapeutics 05/2009; 31(5):1056-63.