Showing papers by "Mahidol University published in 1996"

The Treatment of Malaria

Abstract: Malaria is the world's most important parasitic infection. Although it has been eradicated from temperate zones, increasing numbers of travelers from temperate areas each year visit tropical countries, where the disease remains a major cause of morbidity and death. The treatment of malaria has changed over the past two decades in response to declining drug sensitivity in Plasmodium falciparum and a resurgence of the disease in tropical areas. This review will concentrate on the practical aspects of treatment. Diagnosis Patients with malaria usually present with nonspecific and irregular fever, chills, headache, and malaise. Vomiting occurs in approximately 20 percent of . . .

Clinical Studies of Atovaquone, Alone or in Combination with other Antimalarial Drugs, for Treatment of Acute Uncomplicated Malaria in Thailand

Abstract: The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphthoquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 317 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr, respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquone in the recrudescent parasites. To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of potentiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethamine did not show laboratory evidence of potentiation with atovaquone, it was chosen as an alternative inhibitor of dihydrofolic acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycycline; pyrimethamine showed only minimal improvement. Proguanil was subsequently selected as the preferred drug partner because of its long record of safety and the ability to use the drug in pregnant women and children. Of the 104 patients with falciparum malaria treated with atovaquone plus proguanil for 3–7 days, 101 were cured and had virtually no adverse side effects. The combination of atovaquone and proguanil also was effective in eliminating erythrocytic forms of P. vivax, but parasitemia recurred in most patients.

HIV-1 Langerhans' Cell Tropism Associated with Heterosexual Transmission of HIV

Abstract: Heterosexual transmission by vaginal intercourse accounts for most transmission of human immunodeficiency virus-type 1 (HIV-1) in Africa and Asia but is less important in the HIV-1 epidemics of the United States and Western Europe. Epithelial Langerhans' cells (LCs) represent a possible source of initial cell contact for vaginal infection. Fifteen primary isolates of HIV-1 from U.S. homosexuals and 18 HIV-1 isolates from Thailand heterosexuals were evaluated for growth in LCs of U.S. origin. All the viruses from the Thai heterosexuals, which were subtype E, grew more efficiently in the LCs than any of the viruses from the U.S. homosexuals, which are subtype B. These results suggest that LC tropism is associated with the efficiency of heterosexual transmission of HIV.

Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications.

Abstract: Malaria is associated with a reduction in the systemic clearance and apparent volume of distribution of the cinchona alkaloids; this reduction is proportional to the disease severity. There is increased plasma protein binding, predominantly to alpha 1-acid glycoprotein, and elimination half-lives (in healthy adults quinine t1/2z = 11 hours, quinidine t1/2z = 8 hours) are prolonged by 50%. Systemic clearance is predominantly by hepatic biotransformation to more polar metabolites (quinine 80%, quinidine 65%) and the remaining drug is eliminated unchanged by the kidney. Quinine is well absorbed by mouth or following intramuscular injection even in severe cases of malaria (estimated bioavailability more than 85%). Quinine and chloroquine may cause potentially lethal hypotension if given by intravenous injection. Chloroquine is extensively distributed with an enormous total apparent volume of distribution (Vd) more than 100 L/kg, and a terminal elimination half-life of 1 to 2 months. As a consequence, distribution rather than elimination processes determine the blood concentration profile of chloroquine in patients with acute malaria. Parenteral chloroquine should be given either by continuous intravenous infusion, or by frequent intramuscular or subcutaneous injections of relatively small doses. Oral bioavailability exceeds 75%. Amodiaquine is a pro-drug for the active antimalarial metabolite desethylamodiaquine. Its pharmacokinetic properties are similar to these of chloroquine although the Vd is smaller (17 to 34 L/kg) and the terminal elimination half-life is 1 to 3 weeks.

Bridge populations in the spread of HIV/AIDS in Thailand

Abstract: Objective : To determine the extent to which men provide a bridge population between commercial sex workers (CSW) and the general female population in Thailand. Design : Sexual network and serological data were collected from a systematic quota sample of low income men and truckers during 1992 in three Thailand provinces. Completed sample size was 1075 men aged 17-45 years and 330 truckers. Methods : Sexual network information was used to identify those men who have sex with both female CSW and non-CSW partners (the 'bridge population'). A new method was used for calculating the partner acquisition rate and to establish the potential number of women exposed to HIV via inconsistent condom use among the bridge population. Results : Approximately 17% of men and 25% of truckers can be included in the bridge population. These men are more likely to be HIV-positive and to have had at least one other sexually transmitted infection in the past year (odds ratio, 2.2 and 3.4, respectively). Consistent condom use with CSW is less than 30%, and is less than 1 % with non-CSW partners. As a result, 30 women in the general population were potentially exposed to HIV per 100 sexually active men in the last year : nine women each additional year. Younger men and truckers expose almost twice as many women to HIV ; more female peers than wives are exposed. Conclusion : Bridge populations may be as important as 'core groups' for the spread of HIV into the general Thai population. Young men and women are strategic intervention targets because they have more partners, are more likely to be in bridging networks, and are more receptive to condom use.

The epidemiology of malaria in a Karen population on the western border of Thailand

Abstract: From November 1991 to November 1992 a prospective, descriptive study of malaria epidemiology was conducted in a Karen population on the western border of Thailand. Two study groups were selected at random and more than 80% of the subjects were followed for one year. In Group 1, comprising 249 schoolchildren (aged 4–15 years), daily surveillance for illness was combined with fortnightly malaria surveys. These children experienced 1·5 parasitaemic infections per child-year (95% confidence interval [CI] 1·3–1·7), of which 68% (193285) were symptomatic ( Plasmodium falciparum 84%, P. vivax 57%). The estimated pyrogenic densities were 1460/μL for P. falciparum and 181/μL for P. vivax . In Group 2, comprising subjects of all age from 428 households, malaria was diagnosed during two-monthly surveys, at weekly home visits, and otherwise by passive case detection. Malaria and splenomegaly prevalence rates were low in all age groups (spleen index 2–9%; P. falciparum prevalence rate 1–4%; P. vivax 1–6%). Group 2 subjects had 1·0 infections per person-year (95% CI 0·9–1·1), most of which were symptomatic (312357; 87%). Malaria infections clustered in households. Overall, P. vivax caused 53% and P. falciparum 37% of the infections (10% were mixed), but whereas P. vivax was most common in young children, with a decline in incidence with increasing age, P. falciparum incidence rates rose with age to a peak incidence between 20 and 29 years, although the risk of developing a severe malaria decreased with increasing age. There was no death from malaria during the study. P. falciparum infections were more common in males, subjects with a history of malaria before the study, and in those who had travelled outside their village. These findings suggest a higher transmission rate for P. vivax than P. falciparum , although adults still suffered symptomatic malaria due to both species. The 2 malaria parasites found in this area contribute approximately 50% of infections each, but their clinical epidemiology is very different.

Developmental Changes of Inhibitory Synaptic Currents in Cerebellar Granule Neurons: Role of GABAA Receptor α6 Subunit

Abstract: Eye opening and increased motor activity after the second postnatal week in rats imply an extensive development of motor control and coordination. We show a parallel developmental change in spontaneous IPSC (sIPSC) kinetics in cerebellar granule neurons. sIPSCs were studied by whole-cell recordings in cerebellar slices, prepared from 7–30 postnatal day old rats. Early in development, sIPSCs had slow decay kinetics whereas in older rats faster decaying sIPSCs were found in larger proportion. Currents elicited by 1 mmGABA pulses (GABACs) in nucleated patches excised from cerebellar granule neurons revealed that GABACs kinetics better approximate sIPSC decay in young but not in more developed rats. The expression of α6 subunit of GABAA receptors, unique in cerebellar granule neurons, has been shown to increase during development. Therefore, we took advantage of the recently reported selective inhibition of GABAA receptors by furosemide to characterize the relative contribution of α6 subunits to native receptors in inhibitory synapses of cerebellar granule neurons. Although furosemide inhibition of sIPSCs amplitude was highly variable among distinct granule cells, it increased during development. At the same time, furosemide failed to inhibit sIPSCs recorded from Purkinje neurons. From the comparison of furosemide inhibition and kinetics of sIPSCs with GABACs recorded from mammalian HEK293 cells transfected with combinations of α1 and α6 GABAA receptor subunits together with β2γ2 subunits, we propose that an increased α6 subunit contribution in the molecular assembly of postsynaptic receptors in cerebellar glomeruli is responsible for the developmental changes observed.

Biochemical characteristics of clinical and environmental isolates of Burkholderia pseudomallei

Abstract: The biochemical characteristics of 213 isolates of Burkholderia pseudomallei from patients with melioidosis and 140 isolates from the soil in central and northeastern Thailand were compared. Whereas the biochemical profiles of all the clinical isolates were similar, all soil isolates from the central area and 25% of isolates from northeastern Thailand comprised a different phenotype. This was characterised by the ability to assimilate L-arabinose (100%), adonitol (100%), 5-keto-gluconate (90%) and D-xylose (84%), but failure to assimilate dulcitol (0%), erythritol (0%) and trehalose (10%). Compared with clinical isolates, these organisms had similar antibiotic susceptibility profiles and were also recognised by a specific polyclonal antibody against B. pseudomallei. As melioidosis is rare in central Thailand, but common in the northeast, this raises the possibility that this biochemical phenotype may be less virulent, or may even represent a different species.

Spinal accessory neurotization for restoration of elbow flexion in avulsion injuries of the brachial plexus

Abstract: Traumatic root avulsion brachial plexus injuries in 216 patients were treated with spinal accessory-musculocutaneous neurotization to restore elbow flexion. The average postoperative follow-up period was 6 years, with a minimum of 2 years for all patients. The percentage of satisfactory biceps recovery (MRC III or better) was 72.5%. The average interval between the operation and MRC III motor recovery was 17 months. The percentage of poor results increased from 25.5% to 62.5% in patients who underwent operation later than 9 months after injury. This method of neurotization produces a result comparable with, if not better than, the results of other types of neurotization in restoration of elbow flexion.

Community and contraceptive choice in rural Thailand: A case study of Nang Rong

Abstract: This paper blends quantitative with qualitative data in an investigation of community and contraceptive choice in Nang Rong, Thailand. Specifically, it develops an explanation of 1) method dominance within villages, coupled with 2) marked differences between villages in the popularity of particular methods. The quantitative analysis demonstrates the importance of village location and placement of family planning services for patterns of contraceptive choice. The qualitative data provide a complementary perspective, emphasizing the importance of social as well as physical space and giving particular attention to the structure of conversational networks.

Lactobacillus GG and Acute Diarrhoea in Young Children in the Tropics

Abstract: A prospective, placebo controlled, triple blind clinical trial was undertaken in Thailand to determine the effect of Lactobacillus GG on recovery from acute diarrhoea in children. Thirty-nine children (mean age = 8 months) were enrolled and following rehydration received either oral Lactobacillus GG (n = 20) as a freeze-dried preparation or placebo (n = 19) twice daily for 2 days. The clinical characteristics of the study groups were similar. There was no significant difference overall in clinical response detected between the study groups. When only those with acute non-bloody diarrhoea (n = 26) were considered, the mean duration of diarrhoea was significantly shorter in the lactobacillus group (1.9 days) than in the placebo group (3.3 days) (P < 0.055). Stool frequency was less on the second day in the lactobacillus group (P < 0.05). The results suggest that Lactobacillus GG accelerates recovery from acute watery diarrhoea in young children in a tropical setting.

Experimental infection of the laboratory rat with the hepatitis E virus.

Abstract: To confirm an earlier report that laboratory rats are susceptible to infection with the hepatitis E virus (HEV), we inoculated 27 Wistar rats intravenously with a suspension of a human stool known to contain infectious HEV. Stool, sera, and various tissues were collected from three rats each on days 0 (preinoculation) and 4, 7, 11, 14, 18, 21, 25, 28, and 35 postinoculation. Stool and sera specimens were examined by reverse transcription-polymerase chain reaction for the presence of HEV genomic sequences. Tissues were examined by light microscopy for detection of histopathological changes and by direct immunofluorescence for detection of HEV antigens. We detected HEV RNA in stools on day 7 in all three animals and in serum intermittently between days 4 and 35. We found HEV antigens in liver, peripheral blood mononuclear cells, spleen, mesenteric lymph nodes, and small intestine. We detected histopathology attributable to the inoculum in liver, spleen, and lymph nodes. The results confirm that HEV can replicate in laboratory rats and suggest new tissue sites for HEV replication.

Comparative bioavailability of oral, rectal, and intramuscular artemether in healthy subjects : use of simultaneous measurement by high performance liquid chromatography and bioassay

Abstract: 1 The pharmacokinetic and effect kinetic properties of oral (p.o.), intramuscular (i.m.), and intrarectal (i.r.) artemether (5 mg kg-1) were compared in a crossover study in eight healthy adult volunteers. Plasma concentrations of artemether (AM) and its active metabolite dihydroartemisinin (DHA) were measured by high performance liquid chromatography with reductive mode electrochemical detection (h.p.l.c.-ECD), and plasma antimalarial activity in vitro (effect) was assessed on the same samples by a sensitive bioassay (BA). 2 Artemether was absorbed rapidly after oral administration with a mean (95% CI) Cmax for the parent compound of 406 (249 to 561) nmol l-1 and for DHA of 1009 (639 to 1379) nmol l-1 with tmax values of 1.7 (1.2 to 2.2) and 1.8 (1.4 to 2.2) h respectively. The mean (95% CI) elimination half-life of AM was 2.6 (1.8 to 3.4) h and for DHA was 1.9 (1.4 to 2.4) h. Plasma concentration and effect profiles with h.p.l.c.-ECD and BA were similar suggesting that other unidentified bioactive metabolites contributed little to antimalarial activity in vivo. 3 Absorption was slower, more variable, and DHA concentrations were lower following the i.m. and i.r. routes of administration. The mean (95% CI) relative bioavailability compared with oral artemether in the 6 h following administration AUC(0,6h) was 25 (9 to 41)% following i.m. and 35 (10 to 60)% following i.r. artemether. 4 These data demonstrate that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA. Plasma antimalarial activity following oral administration is significantly greater than following i.m. administration. The i.r. route of administration provided similar bioavailability to i.m. injection but there was considerable variability in absorption following both routes. Further studies are needed to determine whether i.r. artemether would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible.

Antimalarial Drugs Reduce Cytoadherence and Rosetting of Plasmodium falciparum

Abstract: The in vivo and in vitro effects of antimalarials on cytoadherence and rosette formation were studied in 17 patients with severe and 46 with uncomplicated falciparum malaria. Cytoadherence was increased in severe malaria (P 50% inhibition of both cytoadherence and rosetting in vivo and in vitro within 2 hr of drug exposure. Exposure to quinine for > or = to 4 h in vivo reduced rosetting by >50%, but not cytoadherence. Quinine did not reduce cytoadherence or rosetting significantly in vitro with exposure times of < or = to 8 h. These results suggest that artemisinin derivatives are more effective than quinine in preventing pathologic processes in parasitized erythrocytes that contribute to microvascular obstruction in severe malaria.

Cytoadherence characteristics of Plasmodium falciparum isolates from Thailand: evidence for chondroitin sulfate a as a cytoadherence receptor.

Abstract: The association between cytoadherence of Plasmodium falciparum-infected erythrocytes and the severity of malaria has been evaluated. In this study, we investigate adherence to C32 melanoma cells, CD36, intracellular adhesion molecule-1 (ICAM-1), thrombospondin (TSP), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and chondroitin sulfate A (CSA) of 36 P. falciparum isolates from patients suffering from acute falciparum malaria. Adherence to purified adhesion molecules varied greatly among different parasite isolates. All isolates but one adhered to CD36, but none bound to E-selectin and VCAM-1 beyond control levels. Some P. falciparum isolates adhered to ICAM-1 and to CSA, a newly identified receptor for adherence. There was no correlation between in vitro binding to any one receptor and the patients' conditions. In addition, we investigated the characteristics of adherence to CSA and to C32 melanoma cells. Infected erythrocytes continued to adhere after trypsin digestion and soluble CSA inhibited adherence to C32 melanoma cells in a dose-dependent manner. The results imply a role for CSA in the natural infection of P. falciparum.

Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand.

Abstract: One hundred one adult patients with acute uncomplicated falciparum malaria were treated with pyronaridine. All patients were admitted to the Bangkok Hospital for Tropical Diseases for 28 days to exclude reinfection. Sixty-nine patients (Group I) received pyronaridine 1,200 mg over a three-day period and 32 patients (Group II) received 1,800 mg pyronaridine over a five-day period. Cure rates for the two groups were 63% (38 of 60) for Group I and 88% (23 of 26) for Group II (P<0.05). No RII or RIII type response was seen. Mean fever and parasite clearance times were not significantly different in the two groups. The drug was well-tolerated. In vitro drug sensitivity tests of the paired parasite isolates obtained prior to treatment and after recrudescence indicated that the Plasmodium falciparum isolates of the successfully treated patients had a lower mean concentration for 50% inhibition of growth (IC50) and a much narrower range of the individual IC50 values (15.69 +or- 3.82 ng per ml (mean +or- SD)) as compared with those from the recrudescence cases (22.98 +or- 12.05 ng per ml). Nevertheless, there was no evidence of an increase of the IC50 and IC95 values after recrudescence. The results of the study show that pyronaridine alone at a total dose of 1,800 mg given over five days is well-tolerated in patients suffering from acute uncomplicated malaria and has evident activity against multidrug-resistant falciparum malaria. However, it cannot be recommended for use in Thailand as long as the recrudescence rate is as high as 12%. Further studies of its combinations with other antimalarial drugs are needed.

Rapid detection and identification of dengue viruses by polymerase chain reaction (PCR).

Abstract: A polymerase chain reaction (PCR) method using sets of newly designed primers for rapid detection and simultaneous identification of dengue virus serotypes was developed and tested. The test is based on two sets of primers specific within the envelope (E) and non-structural (NS1) regions of the dengue-virus genome. Two sets of universal primers that bind to two target sequences which are shared by all the four serotypes of the virus within the E and NS1 regions are used. The resulting products are further amplified by another pair of inner or nested universal primers, which also bind to another set of shared sequences within the E and NS1 regions, respectively. The nested PCR of both the E and NS1 regions can detect dengue virus of all the four serotypes at a sensitivity of 1 plaque forming unit (pfu) or less. For the identification of serotypes, a mixture of four pairs of serotype-specific primers, specific to the E region, was used. The primers have been designed to bind to serotype specific sequences within the regions flanked by the outer universal primers, and giving the amplified products of different sizes, each corresponds to one particular serotype (405 bp for Den1, 346 bp for Den2, 196 bp for Den3, and 143 bp for Den4). A protocol has been developed and successfully applied to detect dengue virus in cell-culture supernatants and patients sera. The technique is simple and rapid, capable of not only detecting the dengue virus but also identifying the serotypes of the virus in clinical specimens.

Early nutritional support in severe traumatic patients

Abstract: Multiple trauma is associated with altered metabolism, wasting of the lean body mass and compromised wound healing. Nutritional support is one way to improve the condition of these critically ill patients. We performed a prospective randomized study on the effect of early nutritional support in severely injured patients admitted to the Division of Traumatic Surgery, Siriraj Hospital between June 1992 and January 1994. Thirty-eight severe traumatic patients with ISS between 20-40 were randomly divided into control and study group. The 17 patients in the control group were treated in the conventional method with administration of hypo caloric intravenous regimen and supplement with oral diet as soon as the bowel function was returned. The 21 patients of the study group were fed either by enteral or parenteral feeding or both with an appropriate caloric and protein requirement as soon as hemodynamic status was stabilized. We found the study group had a lower mortality rate, a lower complication rate, a shorter period of ICU stay, and an earlier weaning from the ventilator than the control group. The study group also lost less weight than the control group. Nitrogen balance in the study group was significantly lower than the control group.

Mefloquine in infants and young children.

Abstract: SummaryIn an area where multi-drug resistance in Plasmodium falciparum is a particular problem, more than 500 children under 5 years of age weighing > 5 kg were treated with mefloquine, either alon...