Kratom abuse in Ramathibodi Poison Center, Thailand: a five-year experience.

Kratom (Mitragyna speciosa Korth), a native tree in Southeast Asia, is misused as an abuse drug and becomes legally widespread to several countries. Currently, it is available through the online market or by some shops. The clinical manifestations of Kratom's effects are not well-defined and the clinical studies are limited. This study was designed to identify the characteristics of Kratom poisoning and withdrawal cases from Kratom exposure cases in Ramathibodi Poison Center (RPC), Thailand, during a five-year period. We used a retrospective review of Kratom exposure cases from the RPC toxic surveillance system. A total of 52 Kratom exposure cases were identified. The trend of case consultations has been increasing. There were Kratom poisoning cases (76.9%) and withdrawal cases (23.1%). Common presenting symptoms in the poisoning group were palpitation (22.5%), followed by seizure (17.5%). For the withdrawal group, the common presenting symptoms were myalgia (33.3%), insomnia (16.67%), fatigue (16.67%), and chest discomfort (16.67%). There was a baby with withdrawal symptoms who was delivered from a chronic Kratom-abusing mother, suggesting possible exposure via the transplacental route. There were no deaths in either group. Kratom abuse can cause either poisoning or withdrawal. Most cases in both groups had good prognostic outcome.

The effect of introducing inpatient mandatory generic drug substitution at Ramathobodi Hospital.

BACKGROUND: Generic substitution is a mechanism for reducing drug expenditure in many healthcare settings. Ramathibodi, a teaching hospital, has introduced mandatory generic drug substitution (228 items) for health schemes in inpatient service since September 1, 2009. OBJECTIVE: Explore prescribing patterns in overall and by patients' health schemes between Thai fiscal year 2009 and 2010, and estimate possible saving if this policy was extended to the outpatient service. MATERIAL AND METHOD: Prescribing data and registered populations between October 1, 2008 and September 30, 2010 were retrieved from the database and analyzed. RESULT: Original and generic expenditure rose 8.42 and 8.61%from 2009 to 2010 respectively. Among 228 mandatory items, more original was switched to generic drugs, both in terms of value (6.5 to 7.2%) and in terms of volume (32.5 to 33.8%). Some inpatients, mainly civil servants and self-pay patients, requested the original from the outpatient service where the mandatory substitution was not applied. If the policy were extended through all services, the government would save approximately 306.5 million Baht (US$ 10.1 million) per year However the hospital would reduce its profit by 53.1 million Baht (US$ 1.7 million). CONCLUSION: After the policy was launched, more original mandatory drugs were switched to generic. To gain more saving, the policy may be expanded to outpatient service, and/or mandatory drug list should be reviewed periodically.

Outpatient drug oversupply at a teaching hospital in Thailand.

BACKGROUND: A part of rising drug expenditure in Thailand was causedfrom drug oversupply, which was a result from policy of civil servants to get direct reimbursement from Ministry ofFinance. OBJECTIVE: Describe the problem oforal drug oversupply at outpatient service in a teaching hospital and determine the cost that affects hospital between October 1, 2008 and September 30, 2009. MATERIAL AND METHOD: Data of oral drug prescribing for outpatients were retrievedfrom the hospital database in the format of Microsoft Visual Fox Pro 9.0 and analyzed by Microsoft Access 2007. Two assessment methods are applied to estimate drug oversupply more than 30 days, by month and by year. In addition, September 2009 was selected to study for a pattern of monthly drug oversupply. RESULTS: Total oversupply expenditure for fiscal year 2009 was 56.9 million Baht when summedfrom monthly basis and 62.0 million when performed as a whole year. Oversupply expenditure was 2.12 to 2.73%per month in term of money and 2.91 to 3.46% in term of quantity. In September 2009, cardiovascular & hematopoietic system had the most oversupply. By brand of drug, the most frequently oversupply were Calcium carbonate (7.60%), Simvastatin (3.69%) and Omeprazole (3.20%). In term of money, the top three highest costs were for Atorvastatin (7.27%), Clopidogrel (6.83%) and Rosuvastatin (4.24%). By health schemes, patients under CSMBS trend to be the most of prescribed drug oversupply at 8.31% (3.21 million Baht in September 2009) with average number of oversupply per patient at 1.83 items and average day left per drug item at 61.83 days. CONCLUSION: The most oversupply expenditures were for chronic diseases. These data will focus the problem for hospital administrators to plan for suitable strategy to control drug oversupply in their hospital.

Budget impact analysis of pemetrexed introduction: case study from a teaching hospital perspective, Thailand.

OBJECTIVE: Thailand does not currently require Budget Impact Analysis (BIA) assessment. The present study aimed to estimate the annual drug cost and the incremental impact on the hospital pharmaceutical budget of the introduction of pemetrexed to a Thai teaching hospital. MATERIAL AND METHOD: The budget impact model was conducted in accordance with the Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee (PBAC). The model variables consisted of number of patients, growth rate of lung cancer, uptake rate of pemetrexed over time, unit prices of drugs, and the length and cost of treatment. Sensitivity analysis was performed to determine changes in budgetary impact due to variation of parameters or assumptions in the model. RESULTS: The introduction of pemetrexed was estimated to cause considerable costs for the teaching hospital. In the base-case analysis, the incremental costs were estimated at 8,553,984 Baht in the first year increasing to 12, 118, 144 Baht, 17,820,800 Baht and 17,820,800 Baht in the following years. The 4-year net budgetary impact was 20,154,480 Baht or approximately 127,560 Baht per patient. Sensitivity analyses found that number of treatment cycles andproportion of patients assumed to be treated with pemetrexed were the two most important influencing factors in the model. CONCLUSION: New costly innovative interventions should be evaluated using the BIA model to determine whether they are affordable. The Thai government should consider requiring the BIA study as one of the requirements for drug submission to assist in the determination of listing and subsidizing decision for medicines.

Cadmium bioavailability from vegetable and animal-based foods assessed with in vitro digestion/caco-2 cell model.

BACKGROUND: Chronic dietary cadmium (Cd) exposure results in kidney dysfunction and decrease in bone mineral density. OBJECTIVE: To determine and compare the bioavailability of Cd from vegetable and animal-based foods. MATERIAL AND METHOD: Caco-2 cells were exposed to Cd in boiled pig kidney, ark shell, kale, raw kale, mixed boiled pig kidney with raw kale and CdCl2 after in vitro digestion. Then cellular Cd uptake from the digests and reference CdCl2 solution was measured by atomic absorption spectrometry. RESULTS: Cd bioavailability from animal-based foods was higher than that from vegetable-based foods. In addition, raw kale exhibited an inhibitory effect on Cd bioavailability when mixed with boiled pig kidney. However Cd in kale was increasingly absorbed after boiling. CONCLUSION: Cd binding to different molecular species, other food components in vegetable and animal-based foods, food combination, as well as cooking processes influenced the uptake of dietary Cd. A relative bioavailability factor accounted for the food matrix might be necessary for exposure assessment and consequently for estimation and prevention of the risk of dietary Cd.

Pattern of statins' utilization at Ramathobodi Hospital, 2005 to 2007.

BACKGROUND: The use of statins at Ramathibodi, a teaching hospital, has been rising rapidly OBJECTIVE: Determine how price, volume, and drug mix (use of five brands and one generic) affect expenditure. MATERIAL AND METHOD: Dispensing records of the six statins were retrieved from database and analyzed for factors contributing to increased drug expense. RESULTS: Overall, statins' expenditure rose 35.6% and 6.4% in 2006 and 2007 respectively, mainly from civil servant outpatients who are more likely to be prescribed with brand drugs, even among new patients. In all schemes, volume effect was positive, more people use statins, and each one used a larger quantity of drug in 2007 than in 2005. The price effect was negative. Drug mix effect indicated that there was a shift from higher to lower priced drugs in capitation scheme and from lower to higher priced original drugs in a fee-for-service scheme. CONCLUSION: There is a trend of more statins utilization but with a different pattern of drug prescribed between health schemes and possible drug over-prescribed in some patients. However indication for statin use was not studied, which needs to be considered. With high use of original drugs, effective policy initiative to promote generic drug use should be implemented in order to efficiently use the limited health care resources.

Paraoxonase (PON1) polymorphism and activity as the determinants of sensitivity to organophosphates in human subjects.

Paraoxonase (PON1) plays an important role in mechanism of organophosphorus compound (OP) toxicity, as seen both in vitro and in vivo studies. Polymorphisms of PON1 gene at coding and promoter regions have also been to affect on the hydrolytic activity and PON1 level. The objectives of this study were to determine PON1 polymorphism and activity in an OP-exposed population and the effects on inhibition of cholinesterase activity. The studied population consisted of control (n=30) and exposed groups (n=90). All enzyme activities (AChE, BuChE, paraoxonase, arylesterase and diazonase) were measured once for control group and two periods of exposure for exposed group. Three polymorphisms of PON1 (Q192R, L55M and T-108C) were identified only in the exposed subjects. The results demonstrated that AChE activity in both high (345.5 microkat/gHb) and low exposure periods (496.9 microkat/gHb) of the exposed group were significantly different from control group (649.7 microkat/gHb, p<0.01). For BuChE activity, the exposed group also showed the statistically lower level in both periods (high exposure period: 62.17 microkat/L and low exposure period: 81.84 microkat/L) than those in the control group (93.35 microkat/L). Serum paraoxonase activity was significantly different among individual genotypes, RR>QR>RR, LL>LM and -108CC>-108CT>-108TT, but this was not found for those of arylesterase and diazonase activities. Q192R and L55M as well as Q192R and T-108C also presented substantial linkage disequilibrium. Further analysis was performed with haplotypes and various enzyme activities. AChE activity was not affected by haplotypes. Individuals with "211" haplotype showed significantly higher paraoxonase activity and BuChE activity than other haplotypes but not in diazonase activity. In conclusion, PON1 gene exhibited a wide variation in enzyme activities both within and between genotypes which implied insights of a potentially difference in sensitivity to OP toxicity.

Human poisoning in Thailand: The Ramathibodi Poison Center's experience (2001-2004).

OBJECTIVE: To identify poisoning and toxic exposure pattern, severity, and clinical outcome in Thailand during 2001 to 2004. METHOD: This is a prospective study. All inquiries were registered, followed up, and verified. Interlocutors, poisons, patients' profiles, severity, and medical outcome after exposure or poisoning were analyzed. RESULTS: A total 14,428 events was suspected as human poisoning or exposure. After follow-up and verification, 98.9% were confirmed as poisoning or poison exposure. These involved 15,016 patients and accounted for 6.0 per 100,000 populations per year. The vast majority of calls (92.4%) were from physicians. Pesticides, household products, and pharmaceutical products were the most common poisons involved in human exposure, which were 41.5%, 19.5%, and 18.9%, respectively. Patients aged 0-6 years, teenagers and adults with 20-29 years of age had the highest rates of exposure, which were 33.0, 24.5, and 10.5 exposures per 100,000 per year, respectively. Unintentional accidental exposure is the major reason of exposure in children, but intentional suicide was the main reason of exposure in teenagers and adults. The death rate of all exposure was 5.5%. Pesticides cause more severe clinical course and the highest death rate (10.0%). CONCLUSION: Features of poisoning in Thailand were different from those in Western countries. Pesticide poisoning was the major problem in Thailand. Intentional suicide was the major circumstance of poison exposure in adults, but accidental exposure was the major reason of exposure in children.

Specific antivenom for Bungarus candidus.

BACKGROUND: Bungarus candidus (Malayan krait) snake is a neurotoxin snake. Previous treatment after snakebite was mainly respiratory support until the patient had spontaneous breathing. Recently specific antivenom for the Bungarus candidus snake was produced by the Queen Saovabha Memorial Institute and distributed in June 2004. The present article is the first report on the clinical response to the specific antivenom for Bungarus candidus. OBJECTIVE: To analyze the signs and symptoms of patients after snakebite and the response of the patients after receiving specific antivenom for Bungarus candidus snake. STUDY DESIGN: Retrospective chart review. MATERIAL AND METHOD: Four cases of Bungarus candidus snakebite were identified and divided into two groups. Group I (Case 1, 2, and 3) had received specific antivenom for Bungarus candidus while group 2 (case 4) had not. Onset, signs and symptoms after snakebite, antivenom dosage, and response time after receiving antivenom were analyzed. RESULTS: The first three patients received specific antivenom for Bungarus candidus and the fourth patient did not receive any. All four patients developed neurological signs and symptoms from this neurotoxic venom. In case 1, 2, and 4, the first signs and symptoms were dyspnea, difficulty with speech, and opening the eyelids at 50 minutes (30-60 minutes). The onset ofother signs and symptoms included respiratory paralysis with intubation 3 hours (2-4 hours), full ptosis 3.66 hours (3-4 hours), mydriasis and fixedpupils 4.33 hours (4-5 hours), no response to stimuli 5.66 hours (4-10 hours), tachycardia 5.5 hours (47 hours), and hypertension 14 hours (4-24 hours). The first two patients received specific antivenom for Bungarus candidus after being bitten at 10 and 12 hours, respectively. The first clinical response in case 1, were 12 hours after receiving 16 vials, and in case 2, were 20 hours after receiving 16 vials. These were slight movement of feet phalanxes. At 40 hours after receiving specific antivenom 30 vials in case 1 and 32 vials in case 2, they were able to respond to commands, motor power changed from grade 0 to grade 1 and there was 50% elevated eyebrows. The motor power changedfrom grade I to grade 4 with 100% elevation of eyebrows from full ptosis was 65 hours after receiving specific antivenom 60 vials in case 1 and 70 hours after receiving specific antivenom 87 vials in case 2. The patients had spontaneous opening ofeyelids at 90 hours after receiving 80 vials for case I and 88 hours after receiving 87 vials for case 2. Case 2 was extubated on day 4 after the snakebite while case 1 was extubated later on day 10 because of superimposing pneumonia. The third case had delayed onset of signs and symptoms of neurotoxicity compared to the other three patients. Dyspnea, difficulty with speech, and opening eyelids occurred at 5 hours after the snakebite. No response to stimuli and respiratory paralysis occurred at 20 hours after the snakebite. His consciousness improved 10 hours after receiving 3 vials of specific antivenom. This was noted by being able to respond to commands and the motor power changed to grade 2 however, full ptosis was still present up to 24 hours. After receiving 23 vials ofspecific antivenom, he accidentally extubated himself however, he could breathe adequately using a mask with a bag. His motor power changed to grade 4 with 100% elevated eyebrows but full ptosis 34 hours after receiving 38 vials of specific antivenom. He could spontaneously open his eyelids 40 hours after receiving 38 vials specific antivenom. Cases 1, 2, and 3 had persistent mydriasis andfixed pupils until discharge. Case 4 did not receive specific antivenom for Bungarus candidus. He did not respond to stimuli 10 hours after snakebite and he was treated with respirator and symptomatic treatment. On day 2, his blood pressure dropped, he was on dopamine to raise his BP On day 3, he developed ventricular fibrillation. Defibrillation was administered and ECG returned to normal. He was given further supportive care. On day 7, he was discharged at the request of his relatives without any improvement. CONCLUSION: The patients who received specific antivenom had more rapid improvement ofsigns and symptoms comparing to the patient who did not receive the antivenon.

Environmental lead exposure, catalase gene, and markers of antioxidant and oxidative stress relation to hypertension: an analysis based on the EGAT study.

Lead has been linked to the development of hypertension via oxidative stress. Catalase plays an important role in the disposal of hydrogen peroxide in erythrocyte and its activity was determined by CAT gene. The aims of this study were to investigate (1) the association between blood levels of antioxidant markers such as catalase, superoxide dismutase, glutathione, glutathione peroxidase, oxidative stress-marker (malondialdehyde), and blood lead level and (2) the influence of genetic polymorphism of CAT gene (rs769217) on change in blood pressure in general population of EGAT study project. This is a cross-sectional study of 332 normotensive, 432 prehypertensive, and 222 hypertensive male subjects. Hypertensive subjects had significantly higher blood lead level (5.28 µg/dL) compared to normotensive (4.41 µg/dL) and prehypertensive (4.55 µg/dL) subjects (P < 0.05). These significant findings are also found in MDA levels. Moreover, individuals with TT genotype in hypertensive group had significantly higher blood lead and MDA levels (6.06 µg/dL and 9.67 µmol/L) than those with CC genotype (5.32 µg/dL and 8.31 µmol/L, P < 0.05). Our findings suggested that decreased blood catalase activity in this polymorphism together with low level lead exposure induced lipid peroxidation may be responsible for hypertension.

Serum diazepam levels after oral administration in children.

OBJECTIVE: To determine serum levels of diazepam after oral administration in children. PATIENTS AND METHOD: Forty six children admitted with febrile seizures were orally administered with 0.25 mg/kg/dose of diazepam six hourly for four doses. Trough (prior to the next dose) and peak (at 1 hour 20 minutes after the dose) serum levels of diazepam were analyzed. The patients were observed for adverse effects of the medication. RESULTS: The peak levels after 1st, 2nd, 3rd and 4th doses were above 0.15 microg/ml which is considered the therapeutic level in 93.5, 97.8, 97.7, and 100 per cent of the patients, respectively. The trough levels prior to the 2nd, 3nd, and 4th doses were greater than 0.15 microg/ml in 75.0, 84.0, and 91.3 per cent, respectively. Neither recurrent seizure nor serious adverse effects occurred in any of the patients. CONCLUSION: Serum concentrations above the therapeutic level were achieved after orally administered diazepam at 0.25 mg/kg/dose six hourly for four doses. Oral diazepam may be used as another method in the prevention of recurrent febrile seizures.

Association between inflammatory marker, environmental lead exposure, and glutathione S-transferase gene.

A number of studies suggested that lead is related to the induction of oxidative stress, and alteration of immune response. In addition, modifying these toxic effects varied partly by GST polymorphism. The objectives of this study were to assess the association between the lead-induced alteration in serum hs-CRP, with GSTM1, GSTT1, and GSTP1 Val105Ile genetic variations and the health consequence from environmental lead exposure. The 924 blood samples were analyzed for blood lead, CRP, and genotyping of three genes with real-time PCR. Means of blood lead and serum hs-CRP were 5.45 µ g/dL and 2.07 mg/L. Both CRP and systolic blood pressure levels were significantly higher for individuals with blood lead in quartile 4 (6.48-24.63 µ g/dL) compared with those in quartile 1 (1.23-3.47 µ g/dL, P < 0.01). In particular, in men with blood lead >6.47 µ g/dL the adjusted odds ratio (OR) of CRP levels for individuals with GSTP1 variants allele, GSTM1 null, GSTT1 null, double-null GSTM1, and GSTT1 compared with wild-type allele was 1.46 (95% CI; 1.05-2.20), 1.32 (95% CI; 1.03-1.69), 1.65 (95% CI; 1.17-2.35), and 1.98 (95% CI; 1.47-2.55), respectively. Our findings suggested that lead exposure is associated with adverse changes in inflammatory marker and SBP. GST polymorphisms are among the genetic determinants related to lead-induced inflammatory response.

Factors Influencing Oral Coxibs Utilization and Expenditure at a Thai Teaching Hospital, Fiscal Year 2007 to 2009.

OBJECTIVE: This study aimed to examine factors that influenced the rising Coxibs expenditure. METHODS: Retrospective utilization data were retrieved from hospital's database. Changes in Coxibs expenditure in 2007 and 2009, calculated by using the Laspeyres index, were attributed to two factors: cost per patient (P) and number of patients (Q) per year. By measuring quantity as defined daily dose, changes in P comprised two subfactors: cost per day (p) and days of therapy per patient (q); p was weighted average cost of Coxibs per day, and q was weighted average days of therapy of new and current patients. Furthermore, the pattern of concomitant drugs, proton pump inhibitors, was analyzed. RESULTS: Expenditure on Coxibs rose from 57.7 to 69.4 million baht from 2007 to 2009. With Laspeyres index, total index of 1.20 was a result of three main factors. The highest impact was from change in cost per day (p index at 1.17), which was a result of a slight increase in drug cost, mainly weighted by product mix, which tended to switch drug from low to high cost. Another positive impact was the number of Coxibs patients (Q index at 1.04). Finally, the negative impact was from days of therapy per patient (q index = 0.98). Although days of therapy per patient for both new and current patients were decreased, patient mix of more current patients slowed the decrease down. In addition, the percentage of proton pump inhibitors coprescription also rose from 30.8% in 2007 to 32.3% in 2009. CONCLUSION: Switching drug from low to high cost is a major factor that impacted the rising of expenditure on Coxibs.

Genetic variations of glutathione s-transferase influence on blood cadmium concentration.

The glutathione S-transferases (GSTs) are involved in biotransformation and detoxification of cadmium (Cd). Genetic polymorphisms in these genes may lead to interindividual variation in Cd susceptibility. The objective of this study was to assess the association of GSTs (GSTT1, GSTM1, and GSTP1 Val105Ile) polymorphisms with blood Cd concentrations in a nonoccupationally exposed population. The 370 blood samples were analyzed for Cd concentration and polymorphisms in GSTs genes. Geometric mean of blood Cd among this population was 0.46 ± 0.02 µg/L (with 95% CI; 0.43-0.49 µg/L). Blood Cd concentrations in subjects carrying GSTP1 Val/Val genotype were significantly higher than those with Ile/Ile and Ile/Val genotypes. No significant differences in blood Cd concentrations among individual with gene deletions of GSTT1 and GSTM1 were observed. GSTP1/GSTT1 and GSTP1/GSTM1 combinations showed significantly associated with increase in blood Cd levels. This study indicated that polymorphisms of GSTP1 combined with GSTT1 and/or GSTM1 deletion are likely to influence on individual susceptibility to cadmium toxicity.

The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentration in Thai bus drivers.

Polycyclic aromatic hydrocarbons (PAHs) are associated with an increased cancer risk. CYP1A1 and GSTs enzymes are important in metabolism of PAHs. Genetic polymorphisms of these enzymes are responsible for enzyme activity and concentration variation. The objectives of this study were to evaluate association of 1-OHP concentration with genetic polymorphisms of CYP1A1 and GSTs in Thai bus drivers. The results showed that 1-OHP levels in bus drivers were significantly higher than that in the control group. Significant difference in 1-OHP was found between smokers and non-smokers, in only bus drivers. Significantly increasing of 1-OHP levels were observed in bus drivers with CYP1A1 MspI and exon 7 variants. Whereas, bus drivers with GSTP1 Val and GSTM1 null genotypes showed decreasing in excretion of 1-OHP. No association between 1-OHP and polymorphisms of GSTT1 was found. This study indicated that 1-OHP concentrations were associated with exposure to air pollution, cigarette smoking and polymorphisms of CYP1A1, GSTM1 and GSTP1 genes.