Response surface analyses of antihypertensive effects of angiotensin receptor blockers and amlodipine or hydrochlorothiazide combination therapy in patients with essential hypertension.

While previous studies have examined the dose-response characteristics of certain antihypertensive drugs alone or in combination, response surface analysis for combination therapies involving angiotensin receptor blockers (ARBs) and either amlodipine (AML) or hydrochlorothiazide (HCT) has not been explored, particularly in the context of low-dose combinations. The objectives of present study were to generate useful dose-response information for the combination of ARB/AML or ARB/HCT and to predict the blood pressure lowering effects of combination therapies compared to monotherapies. We reviewed the New Drug Application data of combination drugs of ARB/AML and ARB/HCT. Data on systolic blood pressure (SBP), from studies conducted using a factorial dose-response design over a period of 8-12 weeks, were used. The placebo-subtracted SBP change was used for analysis. Response surface analyses of the collected data were conducted using a polynomial regression model. For ARB/AML combination, the quadratic polynomial regression model containing two linear terms, two quadratic terms, and one interaction term was best fitted to the naïve pooled data. Meanwhile, for ARB/HCT combination, the best-fitted model was a quadratic model that included two linear terms and two quadratic terms. The 1/2-dose combination of these medications, compared to each monotherapy, resulted in predicted SBP reductions that were 8-30% greater. The ratio of the estimated antihypertensive effects of the combination to the expected additive effects of each component ranged from 82% to 100% of the expected effect. These results can provide a rationale for developing lower-dose combinations of ARB/AML or ARB/HCT and assist in designing clinical trials.

Patch test reactions in patients with the additional diagnosis of vitiligo.

BACKGROUND: Melanocytes involved in vitiligo may have inherent aberrations that make them vulnerable to extracellular insult. Allergic contact dermatitis (ACD) has been implicated in the development and progression of vitiligo. This study was conducted to investigate the association between ACD and vitiligo. METHODS: A total of 125 patients with vitiligo, who showed lesions in particular locations, onset at an older age, and/or pre-existing inflammation or pruritus, were included. Patch tests were performed using a Korean standard series. In order to investigate the association between avoidance of allergen and clinical improvement, 43 vitiligo patients who showed positive reactions to the patch test completed a questionnaire administered by telephone and self-assessed the status of their condition using a 10-point scale. RESULTS: A total of 98 (78.4%) of 125 patients with vitiligo showed positive patch test reactions to at least one antigen. Although a limited number of contact allergens may have specific predilection sites, a significant association (P = 0.002, odds ratio 3.06) was found between lesions distributed on the scalp and/or hairline and a positive patch test reaction to paraphenylenediamine (PPD). A positive correlation (P = 0.03) was also detected between avoidance of allergen and improvement of vitiligo lesions. CONCLUSIONS: Causative allergens of ACD may play a role in the development and/or aggravation of vitiligo.

Study to establish Ojeok-San (Five Accumulation Powder: wu ji san) administration criteria and a questionnaire to evaluate the holistic effects of Ojeok-San on patients with low back pain.

OBJECTIVES: The study objectives were to establish ojeok-san (Five Accumulation Powder: wu ji san) administration criteria and a questionnaire to evaluate the holistic effects of ojeok-san on patients with low back pain (LBP). METHODS: Texts and literatures, recommended by specialists, were searched to gather ojeok-san-related symptoms. Then, the opinions of Oriental medicine doctors (OMDs) practicing in Seoul were surveyed to ask which symptoms they consider the most in clinical practice. Based on the survey, selection of potential items for the questionnaire was made. The final version was established based on the results of the survey and Delphi process of musculoskeletal diseases specialists. In order to evaluate the reliability and validity of the newly developed assessment tool (Ojeok-san Low Back Questionnaire: OLQ), patients with chronic LBP were recruited. OLQ and other tools such as visual analogue scale, numeric rating scale, Roland-Morris Disability Questionnaire, Modified-Modified Schober test, and 36-Item Short Form Health Survey were applied to the subjects in a 2-week interval. Test-retest reliability, internal consistency, and convergent and discrimination validity were assessed. RESULTS: A total of 90 potential items were generated by the research team. One hundred and two (102) OMDs fully replied to the survey. Based on the survey results, 34 items were initially selected as potential items. Through Delphi method of experts, 10 top items, rated more than 5 points on a scale of 10, were finally established. The 10 items were each established as a response scale of 0-10 (0 as no symptom and 10 as the most excessive form of symptom). Based on the above stages, an initial OLQ was established and used in the evaluation phase. The validity and reliability of OLQ assessment results showed high test-retest reliability, intraclass correlation coefficient, and internal consistency. CONCLUSIONS: The newly developed Ojeok-san administration criteria and questionnaire may be a promising tool for future Oriental medicine clinical study protocols.

Combination of glucosamine improved therapeutic effect of low-dose cyclosporin A in patients with atopic dermatitis: a pilot study.

Both glucosamine and cyclosporin have been reported to show immunomodulatory effect with inhibition of each different key transcription factor for cytokine gene expression and T-cell function. The overall purpose of this pilot study was to assess the feasibility of the combination of cyclosporin with glucosamine for the treatment of patients with atopic dermatitis. Twelve patients more than 12 years old who required systemic cyclosporin were included in the study. Two of them dropped out due to violation of medication schedule. The single (S) and combination (C) regimens were crossed over every 2 weeks without a washout period between the cross-over for 6 months. Five patients were randomly assigned to the S regimen first (SC sequence), whereas the other five were given the C first (CS sequence). The change of SCORAD index was analyzed as the primary efficacy end-point by general linear model and piecewise linear mixed model. The SCORAD index was reduced with both SC and CS sequence regimens. In particular, index reduction with the C was more than that associated with S regimen; this difference increased as time lapsed. The glucosamine combination was predicted to cause an additive decrease in the mean percent change of the SCORAD index (~6%), with decreasing interleukin (IL)-4 and IL-5 cytokine levels but without increasing treatment-related adverse events. This study suggests that the C would produce better clinical outcomes than the S regimen in patients with atopic dermatitis, although confirmatory clinical trials are warranted to determine the effect of combination.

Placental transfer of clarithromycin in human pregnancies with preterm premature rupture of membranes.

AIM: The aim of this study was to evaluate the transplacental transfer of clarithromycin, which was used in the treatment of preterm premature rupture of membranes (PPROM) in human pregnancies, by comparing umbilical cord and maternal serum clarithromycin concentrations. METHODS: Singleton pregnant women with PPROM (<34 weeks) were prospectively enrolled between April 2009 and January 2011. The diagnosis of PPROM was made with vaginal pooling, leakage, nitrazine, and Amnisure tests. The women were managed expectantly with bed rest, corticosteroids, and a triple antibiotic combination including ceftriaxone, clindamycin, and clarithromycin. Amniocentesis was offered, and culture for aerobe/anaerobe and mycoplasma was performed. After delivery, blood was drawn from the mother's antecubital and umbilical cord veins. Clarithromycin concentrations were measured using liquid chromatography-tandem mass spectrometry. The percentage and correlation between cord and maternal serum clarithromycin concentrations were calculated. Logistic regression analysis was performed to investigate the factors related to the cord and maternal serum clarithromycin concentration percentage. RESULTS: A total of 34 cord-maternal serum pairs were included in the final analysis. The mean cord-maternal serum clarithromycin concentration percentage was 7.93±0.9%. There was a good correlation between cord serum and maternal serum clarithromycin concentration (r=0.795, P<0.001). The cord-maternal serum clarithromycin concentration percentage significantly increased according to advancing gestation (P<0.001). CONCLUSIONS: Our data showed that the mean placental transfer of clarithromycin is approximately 8% and dependent on gestational age.

The effect of corneal anterior surface eccentricity on astigmatism after cataract surgery.

BACKGROUND AND OBJECTIVE: To evaluate the effect of cornea eccentricity on induced astigmatism after cataract surgery. PATIENTS AND METHODS: The study included 125 eyes of 87 patients. Preoperative corneal astigmatism, pachymetry, and eccentricity were measured. During cataract surgery, the location of the main incision (2.8-mm clear corneal) was selected to be either superior, superior-nasal, superior-temporal, nasal, or temporal to decrease the preexisting corneal astigmatism. Aspheric intraocular lenses were implanted. Keratometry and manifest refraction were recorded 6 months after surgery. Astigmatism was calculated using vector subtraction software. RESULTS: Three parameters significantly affected postoperative astigmatism: preoperative amount of corneal astigmatism, eccentricity of anterior cornea, and location of the main incision. The mean surgically induced astigmatism (SIA) was calculated to be: superior = 0.82 diopters (D), superior-nasal = 0.50 D, superior-temporal = 0.63 D, temporal = 0.45 D, and nasal = 0.55 D. Superior incision induced the greatest SIA and temporal incision induced the smallest SIA. The eccentricity of anterior cornea showed significantly positive correlation with the amount of SIA (P < .001). The preoperative corneal cylinder power showed significantly positive correlation with the amount of SIA (P < .001). CONCLUSION: Postoperative astigmatism was affected by various factors in cataract surgery. The greatest postoperative astigmatism is expected in corneas with high anterior eccentricity, high preoperative corneal astigmatism, and superior location of the main incision.

Teicoplanin dosing strategy for treatment of Staphylococcus aureus in Korean patients with neutropenic fever.

PURPOSE: The present study was conducted to determine and compare the target attainment rate (TAR) between microorganism-nonspecific (C(trough)) and microorganism- specific (AUC24/MIC) targets over two weeks of teicoplanin administration according to several dose regimens for the treatment of Staphylococcus aureus in Korean patients with neutropenic fever. MATERIALS AND METHODS: One thousand virtual concentrations were obtained for each dose using the population pharmacokinetic parameters of teicoplanin adopted from a published study. Simulation of 1,000 virtual MICs was performed using the MICs of 78 clinical isolates of S. aureus collected from a hospital in Korea. Thereafter, these simulated MICs were randomly allocated to 1,000 virtual patients in whom the TARs for AUC24/MIC>125 [or 345] and C(trough)>10 [or 20] mg/L were determined. The relationship of the maintenance dose with the steady-state TAR was predicted with respect to the AUC24/MIC>125 [or 345] using logistic analysis. RESULTS: The standard dose regimen of teicoplanin showed TARs of about 70% [or 33%] and 70% [or 20%] at steady-state in cases with AUC24/MIC>125 [or 345] and C(trough)>10 [or 20] mg/L, respectively. CONCLUSION: The current standard dose regimen was predicted to be insufficient to adequately treat S. aureus in Korean patients with neutropenic fever. To assure at least an 80% TAR in this population, dose adjustment of teicoplanin should be considered.

A population pharmacokinetic-pharmacodynamic model for simvastatin that predicts low-density lipoprotein-cholesterol reduction in patients with primary hyperlipidaemia.

Simvastatin (SV), a HMG-CoA reductase inhibitor, is widely used for the treatment of hyperlipidaemia. The objectives of the present study were to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model for simvastatin and to evaluate its usefulness in predicting the dose-response relationship of simvastatin in patients with hyperlipidaemia. The data were obtained from a drug-drug interaction study to assess the effect of aspirin on the PK of simvastatin. Twenty-seven healthy volunteers were given simvastatin 40 mg daily for 14 days in whom aspirin 100 mg q.d. was co-administered after day 8. Full PK studies were performed on days 1, 7 and 14 in addition to trough sampling on days 5, 6, 12 and 13. Low-density lipoprotein-cholesterol (LDL-C) levels were also measured serially. Then, a population PK-PD model for simvastatin and its active metabolite, simvastatin acid (SVA), was developed using mixed effect methods (NONMEM Ver. 6.2). A simple linear PK model with parent and metabolite compartments provided the best fit for the 2647 concentrations of simvastatin and simvastatin acid, and a turnover model was used to describe the change in LDL-C levels. The dose-response curve simulated from the final model and those obtained from the literature overlapped very closely. No influence of aspirin was observed in PK or PD. A simple PK-PD model developed using only 2-week study data from fewer than 30 healthy volunteers successfully predicted the dose-response relationship of simvastatin in patients when compared with published data.

Greater collagen deposition with the microneedle therapy system than with intense pulsed light.

BACKGROUND: Intense pulsed light (IPL) and the microneedle therapy system (MTS) are currently available for the treatment of scars. Greater collagen deposition has been proposed as a mechanism for the treatment of scars. OBJECTIVE: To compare the effects of IPL and MTS on collagen deposition. MATERIALS AND METHODS: Fifty-four imprinting control region mice were divided into three groups: untreated controls, treatment with IPL, and treatment with MTS. A single pass of IPL 10.5 J/cm(2) and five passes (total 15 strokes) of MTS were performed three times every 2 weeks. Four weeks after the last treatment, skin thickness measurements using a caliper, microscopic examination, Western blot analysis for type I collagen, and enzyme-linked immunosorbent assay for total collagen content were performed. RESULTS: Measured using calipers, MTS, resulted in greater skin thickness than IPL that paralleled the dermal thickness of the biopsied specimens. MTS also increased expression levels of type I collagen and total collagen content more than IPL. IPL effects were superior to control. CONCLUSION: MTS increased collagen deposition more than IPL, and MTS might be more effective than IPL for scar treatment. The authors have indicated no significant interest with commercial supporters.

Phase I study of intraperitoneal irinotecan in patients with gastric adenocarcinoma with peritoneal seeding.

PURPOSE: The objectives of this phase I study were to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary efficacy of intraperitoneally administered irinotecan (CPT-11) in gastric cancer patients with peritoneal seeding. EXPERIMENTAL DESIGN: Gastric adenocarcinoma patients with surgical biopsy proven peritoneal seeding were enrolled at the time of surgery. Prior to IP chemotherapy, patients underwent palliative gastrectomy and CAPD catheter insertion in which CPT-11 was administered on postoperative day 1. The IP CPT-11 was initiated at 50 mg/m(2), which was escalated to 100, 150, 200, 250, and 300 mg/m(2). IP CPT-11 chemotherapy was repeated every 3 weeks. RESULTS: Seventeen patients received a total of 56 cycles at five different CPT-11 dose levels. The DLTs were neutropenic fever, neutropenia, and diarrhea. At the dose level 2 (100 mg/m(2)), there were one DLTs in one of the first cohort of three patients, but no DLTs at the second cohort of this level. At the dose level 5 (250 mg/m(2)), two DLTs were detected in the first two patients; thus, the accrual was stopped resulting in the recommended dose of IP CPT-11 of 200 mg/m(2). Median progression-free survival was 8.6 months (95% CI, 5.9,11.2), and median overall survival was 15.6 months (95% CI, 8.4,22.8). Pharmacokinetic results of the study showed that the C (max) of peritoneal SN-38 was achieved earlier than that of plasma SN-38. CONCLUSIONS: Intraperitoneally administered CPT-11 was feasible and tolerable. Further, phase II study of IP CPT-11 in gastric cancer patients with peritoneal seeding is warranted.

Population pharmacokinetics of CPT-11 (irinotecan) in gastric cancer patients with peritoneal seeding after its intraperitoneal administration.

PURPOSE: It is well known that CPT-11 (irinotecan) is biotransformed to its active metabolite, SN-38, by carboxylesterase in the liver and other tissues. However, little is known about its pharmacokinetics (PK) when administered intraperitoneally. The aim of our study was to develop a population pharmacokinetic model for CPT-11 and SN-38 following the intraperitoneal (IP) administration of CPT-11. METHODS: Pharmacokinetic data obtained from 16 gastric adenocarcinoma patients with peritoneal seeding were used. Administered doses ranged from 50 to 250 mg/m(2). To measure CPT-11 and SN-38 levels, we collected samples of peritoneal fluid, plasma and urine 0, 0.5, 1.5, 2, 3.5, 8, 12, 25.5, 49 and 56 h after IP infusion. Several multicompartmental pharmacokinetic models were tested for CPT-11 and SN-38 in the sampled peritoneal fluid, plasma and urine. NONMEM ver. 6 was used throughout the model-building process. RESULTS: Peak concentrations were achieved earlier for peritoneal SN-38 than for plasma SN-38. The apparent metabolic clearance of peritoneal and plasma CPT-11 to peritoneal and plasma SN-38 accounted for 0.2 and 7.3% of the total clearance of peritoneal and plasma CPT-11, respectively. The typical values of steady-state volume of distribution (Vss) (46.6 L/m(2)), inter-compartment clearance (6.70 L/h/m(2)) and clearance (16.0 L/h/m(2)) for plasma CPT-11 were estimated in a two-compartment PK model. CONCLUSIONS: Our results demonstrate that a small fraction of intraperitoneally administered CPT-11 was metabolized in situ to active SN-38 and that the Vss of plasma CPT-11 following IP administration in our patient cohort was lower than that estimated in previous reports following the intravenous administration of CPT-11.

Comparison of parametric and bootstrap method in bioequivalence test.

The estimation of 90% parametric confidence intervals (CIs) of mean AUC and Cmax ratios in bioequivalence (BE) tests are based upon the assumption that formulation effects in log-transformed data are normally distributed. To compare the parametric CIs with those obtained from nonparametric methods we performed repeated estimation of bootstrap-resampled datasets. The AUC and Cmax values from 3 archived datasets were used. BE tests on 1,000 resampled datasets from each archived dataset were performed using SAS (Enterprise Guide Ver.3). Bootstrap nonparametric 90% CIs of formulation effects were then compared with the parametric 90% CIs of the original datasets. The 90% CIs of formulation effects estimated from the 3 archived datasets were slightly different from nonparametric 90% CIs obtained from BE tests on resampled datasets. Histograms and density curves of formulation effects obtained from resampled datasets were similar to those of normal distribution. However, in 2 of 3 resampled log (AUC) datasets, the estimates of formulation effects did not follow the Gaussian distribution. Bias-corrected and accelerated (BCa) CIs, one of the nonparametric CIs of formulation effects, shifted outside the parametric 90% CIs of the archived datasets in these 2 non-normally distributed resampled log (AUC) datasets. Currently, the 80~125% rule based upon the parametric 90% CIs is widely accepted under the assumption of normally distributed formulation effects in log-transformed data. However, nonparametric CIs may be a better choice when data do not follow this assumption.