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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.To investigate the pharmacokinetics and pharmacodynamics of IN and IM epinephrine absorption in a larger group of healthy adults (n = 12).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.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.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.

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 Mahidol 487A 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.

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.

To evaluate the bioequivalence of50 mg cilostazol tablets manufactured locally (Citazol®) and originally (Pletaal®) in healthy Thai volunteers.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).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 (p0.05). No serious adverse events related to the studied drugs were found.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.

There are few data on the practice of evidence based medicine in the developing world, nor on the actual sources of evidence that clinicians use in practice. To test the hypothesis that there was variation between and within developing countries in the proposed management of a patient with hospital acquired pneumonia, and that part of the variation can be explained by the sources of evidence used. Questionnaire responses to hypothetical case history. Investigators from 6 centres within the International Clinical Epidemiology Network (INCLEN) in China, Thailand, India, Egypt, and Kenya. Doctors chosen to represent primary and secondary hospital practice in the regions of the study centres. Investigations and initial treatments which would be ordered for a hypothetical 60-year-old woman who develops pneumonia 5 days after hospital admission, whether local data on antibiotic sensitivities are available and where information would be obtained to guide management. Chest x-ray and sputum gram stain/culture were consistently the most commonly ordered investigations, there being much greater variation in the initial treatment choices with either penicillin, a third-generation cephalosporin or aminoglycoside being the most popular choice. Textbooks were the commonest form of information source, and access to a library, textbooks and journals were statistically significantly associated with appropriate choice of investigations, but not treatment. Access to local antibiotic sensitivities was associated with appropriate initial treatment choice. Improving access to information in the literature and to local data may increase the practice of evidence-based medicine in the developing world.

Femoral nerve block is commonly established for postoperative analgesia in total knee arthroplasty but no evidence of plasma bupivacaine level has been reported.Determine the plasma concentrations of bupivacaine in patients who had single-injection of femoral nerve block.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.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.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.

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.

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).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.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.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.

Background: The generic product of trimetazidine, an anti-anginal agent, is currently available in Thailand. Bioequivalence study is used to compare rate and extent of absorption between generic and innovator’s products. Objective: To determine the bioavailability of two modified release tablets of 35mg trimetazidine dihydrochloride (Matenol ® MR; generic product and Vastarel ® MR; innovator’s product) Materials and methods: The study was conducted according to a single-dose, two-treatment, two-period, two- sequence randomized crossover design under fasting and fed conditions with a minimum of 7 days washout period. Twenty-four healthy Thai male and female volunteers were enrolled; however, only twenty-two subjects in the fasting group and twenty-three subjects in the fed group were completed the studies. For both conditions, each volunteer received a 35mg trimetazidine modified release tablet of both formulations. Every volunteers were obtained blood samples 16 times over a period of 24 hours after each oral administration.The trimetazidine plasma concentrations were quantified using a validated method employing liquid chromatography with tandem mass spectrometry with the lower limit of quantification of 0.25 ng/mL. All of the pharmacokinetic parameters were investigated using non- compartmental analysis model. Results: The 90% confidence interval of the geometric mean ratio of C max , AUC 0-t and AUC 0-∞ were within the equivalence criteria (80.00-125.00%) which were 105.53% (95.71%-116.36%), 104.28% (96.24%-112.98%, and 105.26% (96.61%-114.67%) under fasting condition and 110.21% (102.72%-118.25%), 101.95% (94.33%- 119.19%), and 99.7% (91.18%-109.02%) under fed condition, respectively. No statistical differences of median T max ( p >0.05) between two formulations in both conditions were observed. Furthermore, both preparations were well tolerated and had a few non-serious adverse events including nausea, dizziness, drowsiness and headache. Conclusion: These two trimetazidine products have comparable bioavailability.

Objective: The purpose of this study was to compare the bioequivalence of 10 mg tablets of olanzapine between a generic drug (Olapin ® -10; Unison Laboratories Co., Ltd., Thailand) and a reference drug (Zyprexa ® ,Eli Lilly, England) in healthy volunteers. Subjects and methods: A single dose, randomized, 2-period, 2-sequence, crossover study was conducted in 24 healthy Thai male and female volunteers. Each volunteer received a 10 mg tablet of the reference or test drug under fasting condition with a washout period of at least 21 days. Blood samples were obtained at pre-dose and at various time points up to 120 hours after dosing. Olanzapine plasma concentrations were quantified by a validated method employing liquid chromatography with tandem mass spectrometry (LC-MS/MS). Results: 24 volunteers completed both treatment periods. The geometric mean ratios (GMR) (test/reference) between the two formulations of olanzapine were 95.76% (90%CI, 88.55-103.55%) for C max ; 103.77% (97.49- 110.46%) for AUC 0-120 ; and 104.39% (98.20-110.98%) for AUC 0-∞(obs) . There was no statistical difference of the Tmax between the two formulations ( p >0.05). One hundred and eight adverse events were reported from both formulations. Most of the adverse events were judged to be mild in intensity and did not require additional medical treatment. Conclusion: No significant difference in the analysed pharmacokinetic parameters was found between the two formulations of 10 mg olanzapine in the healthy Thai volunteers. The 90%CI of GMR of the pharmacokinetic parameters was entirely within the equivalence criteria (80-125%). Therefore, it can be concluded that this two olanzapine tablet formulations were considered bioequivalent.

Ayurved Siriraj Chantaleela recipe is a traditional Thai remedy consisting of eight medicinal plants, which is employed for the treatment of fever.To investigate the effects of Ayurved Siriraj Herbal recipe Chantaleela on platelet aggregation.Clinical research; ex vivo with before and after study design.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.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.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.

To determine the bioavailability of 50 mg sertraline tablets between the test product (Zotaline, MH Manufacturing Co., Ltd, Thailand) and the reference product (Zoloft, Pfizer Australia Pty Ltd, Australia).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.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 (p0.05). No serious adverse events related to the study drugs were found.The two formulations of sertraline tablets were bio-equivalent in Thai healthy volunteers.

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.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).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.The glucosamine sulfate containing KCl (test product) is bioequivalent to glucosamine sulfate containing NaCl (reference product) in terms of rate and extent of absorption.

Objective: As part of new drug development initiatives in Thailand, a new tablet formulation of dihydroartemisinin (DHA, an antimalarial drug) has been developed. Our previous bioequivalence study indicated that the new and reference DHA formulations were well tolerated; however, a significant decrease in hemoglobin was detected after a single 200-mg oral dose. To explore further, a clinical study with an emphasis on hematological parameters was conducted. Methods: A single-center, randomized, single-blind, cross-over clinical study was conducted in 18 healthy volunteers with a dosage of 300 mg daily for 2 days. Artesunate was used as a comparator. Adverse events were monitored and laboratory parameters on study Days 0, 2, 5, and 7 post drug administrations were analyzed. Results: Eighteen volunteers completed both rounds of the study. Both drugs were well tolerated. All adverse events were mild. Significant decrease in hemoglobin compared to baseline was detected for both drugs 7 days after administration (DHA: 0.48 g/dl, p = 0.007; artesunate 0.38 g/dl, p = 0.001). Transient bone marrow suppression was evidenced by reduction of reticulocytes with a lowest number on study Day 5 (artesunate 75% reduction in reticulocyte count; DHA 47%, p

Aim: Oseltamivir, an ester prodrug of its active carboxylate metabolite, is an effective neuraminidase inhibitor used to treat influenza A and B virus infections. The purpose of this study was to compare the bioavailability of two 75 mg oral formulations of oseltamivir: a generic drug, GOP-A-Flu™ (test, Government Pharmaceutical Organization, Thailand) and Tamiflu® (reference, Hoffmann-La Roche Ltd., Nutley, NJ, USA) in healthy volunteers. Subjects and methods: A single-dose, randomized, 2-sequence, crossover study was conducted in 24 healthy Thai volunteers. Each volunteer received a 75 mg capsule of the reference or test drugs under fasting conditions. Blood samples were collected before dosing and at various time points up to 48 hours after dosing and analyzed for plasma oseltamivir and oseltamivir carboxylate concentrations. The pharmacokinetic parameters including C max , AUC 0-t , AUC 0-∞ t max and t 1/2 were analyzed using the non-compartmental method. Drug safety was assessed. Results: 23 volunteers completed both treatment periods. The geometric mean ratios (test/reference) between the two formulations of oseltamivir were 96.83% (90% Cl, 76.85 - 123.15%) for C max 103.66% (86.44-113.56%) for AUC 0.-t , and 103.98% (86.44- 113.56%) for AUC 0-∞ . Those of oseltamivir carboxylate were 102.17% (90% Cl, 90.90 - 109.10%) for C max , 103.95% (90.90 - 109.10%) for AUC 0-t, and 103.95% (90.92 - 109.08%) for AUC 0-∞ . No significant difference of the t max of oseltamivir and oseltamivir carboxylate between the two formulations was detected (p > 0.05). Both formulations were well-tolerated. Conclusion: Although the C max of oseltamivir was the only parameter not entirely within the equivalence criteria, the two capsule formulations were considered bioequivalent in terms of rate and extent of absorption regarding its active carboxylate metabolite.

This study compared the efficacy of spiramycin with that of amoxicillin in treating patients with acute community-acquired upper respiratory tract infections (URTIs). The study was an open, randomised, comparative parallel design and patients received either spiramycin 3 MIU (2 tablets, 500mg or 1.5 MIU per tablet) twice daily after meals, i.e. 6 MIU/day for 7 days or amoxicillin (500 mg/capsule) 1 capsule three times daily after meals, i.e. 1500 mg/day for 7 days. Patients attending the ENT outpatient clinic at Siriraj Hospital in Bangkok for treatment of acute URTIs were included in the study after giving their informed consent. Eligible patients comprised those aged 18 years and over, of either gender, who had at least two of the following symptoms: fever (/=38 degrees C oral), nasal discharge/obstruction, sore throat, cough and/or hoarseness of voice that did not require parenteral drug therapy or hospitalisation. A total of 99 patients were included in this study, 49 patients received spiramycin and 50 received amoxicillin. Of the 45 assessed patients treated with spiramycin, 40 were judged by the investigators as a 'success' (89%), and five were judged a 'non-success' (11%), compared with 48 assessed patients in the amoxicillin group where 40 patients were classified as a 'success' (83.3%) and 8 were judged a 'non-success' (16.7%). No statistically significant differences between treatments were demonstrated regarding the overall efficacy of treatment. This study demonstrated that the prescribed regimens of spiramycin and amoxicillin were similarly effective in the treatment of adult acute URTIs. The tolerability of both drugs was also similar. Furthermore, it was noted that the convenient twice-daily dosage regimen of spiramycin may allow better patient compliance.

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

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.

To study the relationship of hormone replacement therapy (HRT) in post-menopausal women and risk of breast cancer.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 agedor = 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.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-value0.05). 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.Hormonal replacement therapy in post-menopausal women was not associated with increased risk of breast cancer.

The objective of this study was to determine whether the dorsal hand vein could be used as a model to study tolerance to oral nitrates, and whether oral N-acetylcysteine (NAC) could reverse tolerance if present. Dose-response curves to nitroglycerin were constructed for 11 normotensive volunteers before and during treatment with a sustained-release formulation of isosorbide dinitrate, 80 mg, three times daily for 7 days and followed by concurrent treatment with NAC at a mean dose of 150 mg/kg/day, in divided doses, for 2 days. In separate studies, dose-response curves were constructed for seven normotensive volunteers before and after treatment with oral NAC at the same dose for 2 days. Nitroglycerin's Emax was significantly attenuated from 115 +/- 36 to 77 +/- 22% after treatment with isosorbide dinitrate alone (p < 0.009). Concurrent treatment with NAC reversed this decrease, as nitroglycerin's Emax of 108 +/- 26% during coadministration of isosorbide dinitrate and NAC was not different from its Emax in the control period. There was also no difference in the dose of phenylephrine required to cause 80% of maximal venoconstriction throughout the study. These studies demonstrate that smooth muscle tolerance to nitrates can be demonstrated in medium-sized veins in humans. In addition, high-dose oral NAC can reverse existing tolerance to oral nitrates in human veins. These results indicate that the dorsal hand vein compliance technique is a good model for the clinical investigation of tolerance to nitrates in humans.

In some blood vessels, the alpha 2-adrenergic agonist clonidine simultaneously activates vasoconstrictive alpha-adrenoceptors on smooth muscle cells and endothelial alpha 2-adrenoceptors mediating release of endothelium-derived relaxing factor (EDRF), with the net vascular response representing a balance between these two counteracting pathways. To investigate whether clonidine's modest constrictor effect in human veins is due to simultaneous release of EDRF, the dorsal hand vein compliance technique was used to measure vascular responses in healthy volunteers. Clonidine-induced venoconstriction was not potentiated by methylene blue, an inhibitor of EDRF-mediated relaxation. After preconstriction with angiotensin II, clonidine did not cause venodilation but rather promoted further constriction, which could be reversed by the alpha 1-antagonist labetalol. However, in veins preconstricted with the full alpha 1-agonist phenylephrine, clonidine induced venodilation, suggesting that clonidine is a partial agonist at venous alpha 1-adrenoceptors. In conclusion, we found no evidence for endothelial alpha 2-adrenoceptor-mediated release of EDRF in human hand veins. The results further suggest that postjunctional alpha 1-adrenoceptors participate in clonidine-induced venoconstriction in humans.