Systemic absorption of epinephrine compared between the intranasal and intramuscular routes of administration in healthy adults.

BACKGROUND: Epinephrine 5 mg administered via the intranasal (IN) route was shown to be bioequivalent to epinephrine 0.3 mg administered via the intramuscular (IM) route in our preliminary study. OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of IN and IM epinephrine absorption in a larger group of healthy adults (n = 12). METHODS: Each subject was administered IN saline, IN epinephrine (5 mg), and IM epinephrine (0.3 mg) on 3 separate days. Plasma epinephrine levels were determined using liquid chromatography-tandem mass spectrometry. RESULTS: IN epinephrine administration showed significant systemic absorption compared to IN saline control with the areas under the curve (AUC0-180 min) of 4.4 (4.9) ± 4.0 and 0.2 (0.5) ± 0.3 ng.min/mL, respectively; the values are mean (median) ± standard deviation. IN epinephrine absorption was about 0.5-fold that of IM epinephrine (AUC0-180 min 10.0 (9.2) ± 8.6 ng.min/mL), but the difference was not statistically significant (p = 0.16). The mean peak epinephrine concentration and the time to reach it were also not significantly different between the IN and IM routes. The corresponding values were 120 pg/mL and 41 min for IN, and 209 pg/mL and 41 min for IM, respectively. CONCLUSIONS: The systemic absorption of IN epinephrine 5 mg was significantly different from the control IN saline and about 0.5-fold that of IM epinephrine 0.3 mg. Although epinephrine administration via the less invasive IN route is safe and feasible, further investigations are necessary to achieve an adequate and consistent systemic absorption comparable to that of the conventional IM injection.

Comparative Fasting Bioavailability of 2 Cilostazol Formulations in Healthy Thai Volunteers: An Open-Label, Single-Dose, Randomized, 2-Way Crossover Study.

OBJECTIVE: To evaluate the bioequivalence of50 mg cilostazol tablets manufactured locally (Citazol®) and originally (Pletaal®) in healthy Thai volunteers. MATERIAL AND METHOD: An open-label, single dose, randomized, two-period, two-sequence, crossover study in 30 healthy volunteers. Each volunteer received a 50 mg cilostazol tablet of bothformulations with a washoutperiodofat least 14 days. Blood samples were obtained atpre-dose and over 48 hours after dosing. Cilostazolplasma concentrations were quantified by using liquid chromatography with tandem mass spectrometry (LC-MS/MS). RESULTS: The 30 volunteers completed the entire study. The geometric mean ratios (GAM) (test/reference) between the two formulations of cilostazol were 112.38% (101.70%-124.19%) for Cmax; 103.66% (96.06%-111.86%) for AUC0-48; and 95.14% (86.12%-105.12%)forAUC0-∞. There was no statistical difference ofthe Tmax between the twoformulations (p>0.05). No serious adverse events related to the studied drugs were found. CONCLUSION: No significant difference in the analyzed pharmacokineticparameters was found between the twoformulations of 50 mg cilostazol tablets. Therefore, it can be concluded that these two cilostazol tablet formulations were considered bioequivalent.

Plasma concentrations of bupivacaine after spinal anesthesia with single shot femoral nerve block in total knee arthroplasty.

BACKGROUND: Femoral nerve block is commonly established for postoperative analgesia in total knee arthroplasty but no evidence of plasma bupivacaine level has been reported. OBJECTIVE: Determine the plasma concentrations of bupivacaine in patients who had single-injection of femoral nerve block. MATERIAL AND METHOD: A prospective observational study was undertaken with 25 patients scheduled for unilateral total knee arthroplasty under spinal anesthesia and single shot femoral nerve block with 20 mL of 0.5% bupivacaine. Venous blood samples were collected at 0, 5, 10, 15, 30, 60, 90, and 120 minutes after femoral nerve block. Plasma bupivacaine levels were analyzed by high performance liquid chromatography with tandem mass spectrometry. RESULTS: Four males and 21 females, ASA I-II were enrolled in the present study. Mean age, body mass index, and serum albumin level were 69.9 +/- 5.95 years, 27 +/- 3.67 kg/m2, and 4.46 +/- 0.26 mg/dL, respectively. The median of peak plasma concentration was 538.35 ng/mL (min = 176.30, max = 1,383.99) at 60 minutes after femoral nerve block, while the maximal plasma concentration of bupivacaine was 1,883.39 ng/mL at 10 minutes. None showed signs or symptoms of bupivacaine toxicity. CONCLUSION: Peak plasma concentrations of bupivacaine were demonstrated at 60 minutes after a single shot femoral nerve block, and no signs or symptoms of bupivacaine toxicity were observed Therefore, single shot femoral nerve block with 20 mL of 0.5% bupivacaine is safe.

Bioequivalence study of 10 mg ramipril tablets in healthy Thai volunteers.

OBJECTIVE: To determine the bioequivalence of 10 mg dose of ramipril tablets between the test product (Ramtace 10 mg, Unison Laboratories, Thailand) and the reference product (Tritace 10 mg, Aventis Pharma SPA, Italy). MATERIAL AND METHOD: The present study was carried out with a single dose, 2-treatment, 2-period, 2-sequence randomized crossover design under fasting condition with a minimum of 14 days washout period in 24 healthy Thai male and female volunteers. Plasma samples for determination of ramipril and ramiprilat were obtained pre-dose and at frequent intervals for up to 72 h post dose. Ramipril and ramiprilat plasma concentrations were quantified by a validated method employing high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). All ofthe pharmacokinetic parameters were investigated using non-compartmental analysis. RESULTS: The result demonstrated the 90% confidence interval (90%CI) of the geometric mean ratio (test/reference) of C max, AUC(0-72) and AUC(0-infinity) of ramipril were 97.26% (84.50%-111.93%), 100.70% (89.47%-113.34%) and 100.29% (88.90% 113.15%), respectively. For ramiprilat, the 90% CI for C max, AUC(0-72), and AUC(0-infinity) were 108.87% (103.00%-115.07%), 104.93% (100.50%-109.55%) and 103.30% (98.03%-108.85%), respectively. CONCLUSION: the 90% confidence intervals for log-transformed geometric mean test/reference formulation ratios of primary parameters were entirely within 80.00%-125.00%. Thus, it can be concluded that the test formulation was bioequivalent to the reference formulation.

Effect of Ayurved Siriraj herbal recipe Chantaleela on platelet aggregation.

INTRODUCTION: Ayurved Siriraj Chantaleela recipe is a traditional Thai remedy consisting of eight medicinal plants, which is employed for the treatment of fever. OBJECTIVE: To investigate the effects of Ayurved Siriraj Herbal recipe Chantaleela on platelet aggregation. STUDY DESIGN: Clinical research; ex vivo with before and after study design. MATERIAL AND METHOD: Twelve healthy male and female volunteers participated in the present study. Platelet aggregation test before Chantaleela ingestion was done as a control. After administration of 750 mg Chantaleela (3 x 250 mg tablets) every 8 hours for 3 doses, platelet aggregation was measured 8 hours following the first dose using an aggregometer and microplate reader. Adrenaline (Adr) and adenosine diphosphate (ADP) were used as platelet stimulants. Platelet aggregation was measured again at 32 hours and 8-10 days after the first dose. RESULTS: All of the participants completed the present study without any adverse event. Ayurved Siriraj Chantaleela did not affect platelet aggregation; neither Adr nor ADP were used as platelet agonists in both aggregometer and microplate reader Subgroup analysis revealed no significant change in platelet aggregation after Chantaleela administration according to the control for both male and female groups. The same results were also obtained in other subgroup analysis including hyperaggregation group, hypo-normal aggregation group. CONCLUSION: From the present study, normal dose of Chantaleela for alleviation of fever does not have an effect on either platelet aggregation or platelet numbers. It may conclude that the present study supports the safety use of Chantaleela for relieving fever as platelet status does not need to be taken into consideration.

Bioequivalence study of 50 mg sertraline tablets in healthy Thai volunteers.

OBJECTIVE: To determine the bioavailability of 50 mg sertraline tablets between the test product (Zotaline, M&H Manufacturing Co., Ltd, Thailand) and the reference product (Zoloft, Pfizer Australia Pty Ltd, Australia). MATERIAL AND METHOD: An open-labeled, single dose, 2-treatment, 2-period, 2-sequence, randomized crossover study under fasting conditions with 14 days washout period was conducted in 24 healthy Thai volunteers. Blood samples were collected before dosing and at frequent intervals for up to 96 h post dose. Analysis of sertraline concentrations was performed using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. RESULTS: Twenty-four volunteers completed both treatment periods. Pharmacokinetic parameters were determined using the non-compartment model. The 90 percent confidence intervals of the geometric mean ratios (test/reference) of C(max) 104.47% (96.64%-112.93%), AUC(0-96) 108.06% (100.71%-115.94%) and AUC(0-infinity) 108.39% (100.93%-116.40%) fell within the equivalence range (80%-125%). There was no significant difference of the T(max) parameter between the two formulations (p > 0.05). No serious adverse events related to the study drugs were found. CONCLUSION: The two formulations of sertraline tablets were bio-equivalent in Thai healthy volunteers.

Bioequivalence study of 500 mg glucosamine sulfate in Thai healthy volunteers.

BACKGROUND AND OBJECTIVE: Glucosamine sulfate is widely used to relieve symptoms from osteoarthritis. The present study was conducted in order to determine pharmacokinetic and assess the in-vivo bioequivalence of two different hard capsule formulations of glucosamine sulfate when administered as equal dose of 500 mg. The two formulations contained different salt form where reference product is NaCl and test product is KCl. MATERIAL AND METHOD: A randomized, single dose, two-treatment, two-period, two-sequence crossover study was conducted. Twenty-four healthy volunteers were recruited at Siriraj Clinical Research Unit. Each subject received a dose of 500 mg glucosamine sulfate of both formulations with at least one-week washout period. Blood samples were collected over 24 h after the oral administration. The plasma fractions were analyzed for glucosamine using a liquid chromatography-mass spectrometry (LC-MS/MS). RESULTS: Twenty-four volunteers were enrolled in the present study Pharmacokinetic parameters were determined using the non-compartment model. The 90% confidence intervals of the mean ratios (test/reference) of C(max) (93.69%; ranged from 86.68%-113.32%) and AUC(0-t), (97.73; ranged from 87.38%-112.62%) fell within the acceptable range (80-125%) for bioequivalent eligibility. Both preparations were well tolerated and had a few non-serious adverse events. CONCLUSION: The glucosamine sulfate containing KCl (test product) is bioequivalent to glucosamine sulfate containing NaCl (reference product) in terms of rate and extent of absorption.

Evaluation of the safety and relative bioavailability of a new dihydroartemisinin tablet formulation in healthy Thai volunteers.

A new dihydroartemisinin (DHA) tablet formulation has been developed by the Thai Government Pharmaceutical Organization (GPO). In this report, its in vitro dissolution and in vivo pharmacokinetics as well as its safety in healthy volunteers were evaluated, using the DHA tablet made by Dafra Pharma NV as a reference. A two-period crossover clinical study design was utilised. Twenty-four volunteers were randomly allocated to two sequences (12 volunteers in each) to receive a 200mg single oral dose of either the GPO or Dafra formulation with a wash-out period of 5-7 days. In vitro, the GPO formulation dissolved more readily. In vivo, the GPO formulation had a higher maximum plasma concentration and approximately 149% (90% CI 125-179%) greater bioavailability. Both formulations were well tolerated. Interestingly, significant decreases in haemoglobin and haematocrit values (P<0.001) were noted following administration of one dose of DHA (decrease of 0.73 g/dl haemoglobin and 2.0% haematocrit compared with baseline) or two doses of DHA (decrease of 0.95 g/dl haemoglobin and 3.3% haematocrit compared with baseline). The second dose was associated with additional toxicity compared with one dose with regard to haematocrit (P<0.001) but not haemoglobin. This finding warrants further investigation, since the drug will be used for the treatment of malaria in which anaemia is a consequence.

Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers.

Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40-60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose-response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (-2.65 to -2.95 g/dL [N = 3]) and primaquine (-1.25 to -3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61-80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.

Attitudes of developing world physicians to where medical research is performed and reported.

BACKGROUND: Little is known about the influence of the site of research or publication on the impact of the research findings on clinical practice, particularly in developing countries. The International Clinical Epidemiology Network (INCLEN) is dedicated to improving the quality of health research in the Developing World through institutional capacity building for evidence based medicine, and provided the opportunity to examine the likely impact of research location and journal location on physicians' practice in a number of the participating countries. METHODS: Physicians from secondary and tertiary hospitals in six cities located in China, Thailand, India, Egypt and Kenya were enrolled in a cross-sectional questionnaire survey. The primary outcome measures were scores on a Likert scale reflecting stated likelihood of changing clinical practice depending on the source of the research or its publication. RESULTS: Overall, local research and publications were most likely to effect change in clinical practice, followed by North American, European and regional research/publications respectively, although there were significant variations between countries. The impact of local and regional research would be greater if the perceived research quality improved in those settings. CONCLUSION: Conducting high quality local research is likely to be an effective way of getting research findings into practice in developing countries.

Risk of breast cancer in post-menopausal women using hormone replacement therapy.

OBJECTIVE: To study the relationship of hormone replacement therapy (HRT) in post-menopausal women and risk of breast cancer. PATIENTS AND METHOD: The authors conducted a case-control study comparing the proportion of HRT used between breast cancer and non-breast-cancer women. Cases were breast cancer patients who had natural menopause (excluded hysterectomy) and aged > or = 50-years-old from the Siriraj Breast Cancer database (1983-1996). Controls were post-menopausal volunteers aged 50 year or older who visited Siriraj Hospital for other purposes such as elderly clinics, health check, etc. After informed consent, well-trained surgeons examined the women in the control group to exclude any potential breast cancer. Patient characteristics and risk factors were collected. RESULTS: Of 1,913 patients in the database, 623 were included as the cases. Data from 679 volunteers were collected for controls from May to December 1999. Among 1,302 of the study population 58 women had ever used HRT (4.5%), which distributed to 3.2 per cent (20/623) in cases and 5.6 per cent (38/679) in controls. From univariate analysis, age, age at menopause, number of children, habitat, education, contraceptive pills, familial history of breast cancer and HRT usage were associated with breast cancer (p-value<0.05). After multivariate forward stepwise logistic regression analysis, there was no association between HRT use and breast cancer (adjusted odds ratio (OR) = 0.61, 95% CI = 0.31-1.20). In subgroups analysis, women who had older age, higher education level, history of taking contraceptive pills, or positive familial history of breast cancer in second degree relatives had a decreased risk of breast cancer, while those living outside Bangkok had an increased risk. CONCLUSION: Hormonal replacement therapy in post-menopausal women was not associated with increased risk of breast cancer.

Association of Nevirapine Levels with Rash or Hepatotoxicity Among HIV-Infected Thai Women.

BACKGROUND: We performed a nested case-control study of Thai women prescribed nevirapine-based antiretroviral therapy (ART) to determine if development of rash or hepatotoxicity during the first 24 weeks of treatment is associated with plasma nevirapine concentrations. METHOD: From May 2005-January 2007, we enrolled 217 women initiating nevirapine-based ART in Thailand. Cases (n = 54) were women who during the first 24 weeks of treatment with nevirapine developed rash (any grade, n = 42) or hepatotoxicity (≥grade 2, n = 22, [10 had both]). Controls were the next enrolled woman who was confirmed not to meet the case definition during the first 24 weeks. Nevirapine concentrations after the two week lead-in dose of 200 mg once daily were compared between cases and controls by Wilcoxon rank-sum tests. RESULTS: We found no difference in Week 2 pre-dose nevirapine concentrations: cases median = 3,528 ng/mL (n = 24), controls median = 3,150ng/mL (n = 30), p = 0.5. Cases had higher post-dose nevirapine concentrations (median = 6,150 ng/mL, n = 21) than controls (median = 4,746 ng/mL, n = 20, p = 0.02). When limited to cases who developed a rash at Week 2, we found no differences in the pre-dose (median = 3,270 ng/mL, n = 12, p = 0.9) or post-dose nevirapine concentration (median = 5,443 ng/mL, n = 9, p = 0.4) compared with controls. CONCLUSIONS: We cannot conclude definitively that nevirapine concentrations at two weeks of therapy are associated with rash or hepatotoxicity. It is unlikely that therapeutic drug monitoring at that time will improve identification of patients at risk for rash or hepatotoxicity.