Specific and Cross-reactive Plasmablast Response in Humans after Primary and Secondary Immunization with Vi Capsular Polysaccharide Typhoid Vaccine.

Secondary immunization with polysaccharide vaccines may imply a risk of hyporesponsiveness. Despite the wide use of typhoid Vi capsular polysaccharide vaccine, its potential tendency to hyporesponsiveness has been inadequately addressed. While previous studies have explored serum antibody responses, we applied a more sensitive approach, a single-cell assay for circulating plasmablasts, to compare primary and secondary responses. Twelve subjects received primary and booster doses of the Vi vaccine (Typherix® ) at 30- to 37-month intervals. Plasmablasts specific to the Vi or typhoidal O antigens or cross-reactive with paratyphoid and non-typhoidal Salmonella strains were identified as antibody-secreting cells (ASC) with ELISPOT. Before vaccinations, none had plasmablasts specific to the antigens tested. Twelve of 12 subjects showed a Vi-specific response after primary, but only eight of 12 after booster vaccination. All responded to typhoidal O-9,12 antigen after both immunizations. The geometric mean of plasmablasts specific to the Vi antigen was 59 (95% CI 24-119) and 1 (0-54) IgA + IgG + IgM-ASC/106 peripheral blood mononuclear cell (PBMC) after primary and booster immunizations, respectively, and 20 (9-49) and 56 (29-103) to the O-9,12 antigen. We detected 1 (0-28) and 17 (6-36) ASC/106 PBMC cross-reactive with Salmonella Paratyphi A; 3 (0-30) and 22 (8-48) with S. Paratyphi B; 3 (0-29) and 18 (7-47) with S. Paratyphi C; 19 (10-34) and 51 (26-94) with Salmonella Enteritidis; and 1 (0-35) and 23 (9-52) with Salmonella Typhimurium, respectively. One-third of the vaccinees, although responding to the O-9,12 antigen, failed to respond to the Vi antigen after booster immunization, suggesting hyporesponsiveness in part of the vaccinees. The findings warrant further investigation.

A single booster dose of diphtheria vaccine is effective for travelers regardless of time interval since previous doses.

Our study showed the immune response before and after a booster against diphtheria given within the 20-year interval recommended in Sweden or after a prolonged interval. Of 40 travellers, 10/13 in recommended interval group were immune before booster and 19/27 with a delayed interval. After booster, 13/13 versus 26/27 were protected. One booster was sufficient to achieve immunity regardless of the interval.

On the question of dose-dependent chloroquine elimination of a single oral dose.

Subjects (n = 45) were randomly given single oral doses of 2 (n = 11), 3 (n = 9), 5 (n = 8), 10 (n = 10), or 15 mg/kg (n = 7) chloroquine base. Chloroquine was analyzed by HPLC in serum samples taken at 3 to 168 hr after dosing. AUCs, calculated for the time period of 0 to 168 hr were proportional to the doses. Mean AUC value increased 6.7 times when the dose was increased 7.5 times (from 2 to 15 mg/kg). These data do not support the existence of significant capacity-limited chloroquine elimination within the dose range studied.

Standard and reduced doses of mefloquine for treatment of Plasmodium falciparum in Tanzania: whole blood concentrations in relation to adverse reactions, in vivo response, and in vitro susceptibility.

Fifty-three asymptomatic Tanzanian school children with 400-31,000 asexual Plasmodium falciparum parasites/microliter of blood were given standard, one-half, one-quarter, or one-eighth of the recommended mefloquine treatment dose of 25 mg base/kg body weight. Mefloquine and main metabolite concentrations were determined in 100 microliters of capillary blood using a high performance liquid chromatographic method. In the standard, one-half, and one-quarter dose groups, all children cleared the parasites within three days after treatment. Reappearance was noted in one of the children in the one-quarter dose group during 49-56 days of followup. Among the children given one-eighth of a dose, two had an RII response and four had an RI response with early recrudescence. All 24-hour in vitro micro-tests (n = 30) showed full susceptibility for mefloquine. Adverse gastrointestinal reactions were reported by eight children on the first day after treatment, four of whom had been given a standard dose. These children had higher mefloquine concentrations one day after treatment than the other children in this group (P less than 0.05). In the standard dose group (n = 13), the area under the curve of capillary whole blood concentrations of mefloquine versus time was 52.4-112.1 mumol/liter x days. The highest concentration on day 1 was 2.75-7.20 mumol/liter and the median terminal half-life was 17.4 days. The highest concentrations of the main metabolite were observed 1-2 weeks after treatment and the median half-life was 18.9 days. The concentrations in the other groups were approximately proportional to those in the standard dose group both for mefloquine and the metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of different fractions of heparin on Plasmodium falciparum merozoite invasion of red blood cells in vitro.

Heparin and various heparin fractions were separated according to differences in molecular weight or affinity for antithrombin III and used for the inhibition of Plasmodium falciparum merozoite invasion of red blood cells in vitro. No variation in sensitivity to heparin was found among the four strains of P. falciparum tested; all required approximately 5 micrograms/ml (0.5 U/ml) of heparin for 50% inhibition of invasion. The most efficient fraction of heparin was the one with low affinity for antithrombin III. Its 50% inhibition concentration was 1 microgram/ml, indicating that it was more efficient than unfractionated heparin and other heparin fractions. The effect of heparin was reversible, since washing of heparin-treated cultures containing mainly schizonts showed no inhibition of merozoite invasion. The results suggest that a heparin fraction with no anticoagulant effect might be useful in the treatment of patients with falciparum malaria.

Serum concentrations of chloroquine in a patient with a late recrudescence of Kenyan Plasmodium falciparum malaria.

A Swedish tourist who had visited Kenya fell ill with Plasmodium falciparum malaria 11 days after returning home, in spite of taking pyrimethamine (50 mg weekly) as malaria prophylaxis. Chloroquine treatment (25 mg base/kg body-weight) giving serum concentrations of 0.30 mumol/l cleared the patent parasitaemia and the patient recovered. Recrudescence occurred, however, within 42 days. A second chloroquine course (30 mg base/kg) gave serum levels up to 1.28 mumol/l. The patient improved rapidly and remained healthy during 28 days without renewed parasitaemia. Further follow-up for 10 months was uneventful. We consider it urgent to assess chloroquine concentrations in serum in patients being treated for falciparum malaria in order to obtain data on fully effective levels. Ineffective serum levels should be ruled out in cases not responding to chloroquine, especially when chloroquine-resistance is suspected.

Whole blood concentrations of chloroquine and desethylchloroquine during and after treatment of adult patients infected with Plasmodium vivax, P. ovale or P. malariae.

Whole blood concentrations of chloroquine and desethychloroquine were determined during and after chloroquine treatment of 15 adult patients infected with P. vivax, P. ovale or P. malariae. The median of chloroquine concentrations remained practically unchanged in samples drawn three hours after initiation of treatment and in samples drawn immediately before the next dose of chloroquine. Concentrations of chloroquine remained above 1.0 mumol/litre for at least four days. The calculated sum of chloroquine and desethylchloroquine concentrations was above 1.0 mumol/litre for at least seven days. These concentrations are regarded as sufficient for treatment of P. vivax, P. ovale and P. malariae infections.

Susceptibility of Plasmodium falciparum to quinine in vitro: effects of drug concentrations and time of exposure.

We have studied the relationship between quinine concentrations ranging from 0.16 to 332 mumol/L in a blood-medium mixture and the time of exposure (12-168 h) needed for inhibition of Plasmodium falciparum (F32 strain) in continuous culture. When we exposed the parasites for 12 h, only brief inhibition was observed. After 24 h of exposure, parasites were inhibited for 2-3 d at quinine concentrations > or = 10.4 mumol/L. With 48 and 72 h of exposure, the inhibition lasted for 6-8 d at concentrations > or = 1.3 mumol/L and for 8-11 d at concentrations between 2.6 and 166 mumol/L. After 96 h of exposure, parasites were inhibited for 11-17 d at concentrations > or = 0.65 mumol/L. With 168 h of exposure, parasites were inhibited at all quinine concentrations > or = 0.65 mumol/L during 28 d of post-exposure cultivation. After reappearance, parasites multiplied on average 7.6 fold during each parasite schizogony cycle. The calculated parasite elimination rate in the presence of effective concentrations of quinine was 99.7-99.9% per cycle. We conclude that the elimination rate of the parasites is concentration-dependent at low concentrations of quinine in vitro. As soon as a threshold concentration of 0.65-2.6 mumol/L is attained, only the exposure time determines parasite elimination. These experiments suggest that it might be preferable to reduce each dose rather than the duration of treatment in areas where P. falciparum is susceptible to quinine.

Long-term exposure of Trypanosoma brucei gambiense to pentamidine in vitro.

In order to study the sensitivity in vitro of Trypanosoma brucei gambiense to pentamidine, 5 x 10(4) parasites were exposed to 0, 0.1, 1.0, 2.0, 10, 100, 1000 and 10,000 micrograms/L of pentamidine isethionate for up to 10 d. The viability of parasites was determined each day by microscopy. Multiplication was retarded during continuous exposure to 2 micrograms/L. After 4 d no further multiplication took place, although the trypanosomes remained alive for another 3 d. The parasiticidal effect was more pronounced when higher concentrations were used; when exposed to 10 and 100 micrograms/L, all parasites were dead after 4 and 3 d, respectively. Despite exposure to 1000 micrograms/L, 74% of the parasites were still alive the next day. 10,000 micrograms/L killed all parasites within 24 h of exposure. Our results show that the time period of exposure to pentamidine plays a major role in determining the sensitivity in vitro of T. b. gambiense, and we suggest that prolonged exposure in vivo may be more important than attaining high but brief peak concentrations.

Audiometry as a possible indicator of quinine plasma concentration during treatment of malaria.

The spread of chloroquine-resistant malaria has led to a resurgence of quinine in clinical use. One of the well-known side effects of quinine, reversible hearing loss, is closely related to the plasma concentration. We suggest that this hearing effect could be used as an aid in therapy control when quinine drug assay is not available.

Comparison of 3, 5 and 7 days' treatment with Quinimax for falciparum malaria in Guinea-Bissau.

For treatment of malaria, the World Health Organization recommends 10 mg of quinine per kg body-weight 3 times a day for at least 7 d. In Guinea-Bissau, as in several other African countries, a 3 d treatment regimen (10 mg/kg twice daily) is currently used. We therefore compared the 3 d treatment period with periods of 5 and 7 d. A total of 145 children with clinical malaria due to monoinfection with Plasmodium falciparum, with > or = 20 parasites per 200 leucocytes, were treated with intramuscular Quinimax 10 mg per kg body-weight twice daily for 3, 5 or 7 d. The children were then examined once weekly for 4 weeks. Following the 3 d treatment regimen, 34 of 43 children (79%) had parasitaemia on day 28 or before; following the 5 d treatment regimen, 36 of 40 children (90%) did so; and following the 7 d treatment regimen, 7 of 62 children (11%) were parasitaemic at that time. This study thus suggests that the currently recommended 3 d Quinimax treatment regimen in Guinea-Bissau for moderate and severe malaria is not effective.

Pentamidine concentrations in plasma, whole blood and cerebrospinal fluid during treatment of Trypanosoma gambiense infection in Côte d'Ivoire.

Pentamidine concentrations in plasma, whole blood and cerebrospinal fluid (CSF) were determined in 11 patients with Trypanosoma gambiense infection without involvement of the central nervous system in Côte d'Ivoire. Blood samples were drawn during a 48 h period after the first and last dose of pentamidine dimesylate given as 10 intramuscular injections on alternate days. Maximum plasma concentrations were generally attained within one hour after injection but varied extensively (420-13420 nmol/litre). The median plasma concentration 48 h after the last dose was approximately 5 times higher than that after the first dose. The ratio between whole blood and plasma concentration was approximately 2. Small amounts of the drug were found in the CSF after the last dose. The findings showed inter-individual differences in the pharmacokinetics of pentamidine. The currently recommended daily dose regimen could be questioned, as drug accumulation was pronounced. All patients were cured and the concentrations attained should be considered as parasiticidal. Further studies on the kinetics and distribution after single and multiple doses of pentamidine as well as studies on the possible relationship between adverse effects and plasma concentrations are, however, needed.

Plasma concentrations of sulfadoxine-pyrimethamine and of mefloquine during regular long term malaria prophylaxis.

The plasma concentrations of sulfadoxine, pyrimethamine, mefloquine and its major metabolite were determined in 18 healthy male volunteers who had regularly taken either 500 mg of sulfadoxine and 25 mg of pyrimethamine (Fansidar) weekly or 250 mg mefloquine regularly every 14 d during 6 months for malaria prophylaxis. The mean trough concentrations of sulfadoxine, pyrimethamine and mefloquine were 194, 0.28 and 1.48 mumol/litre and the mean half lives were 7.7, 4.2 and 25 d respectively. The variation in area under the curve for the 3 drugs was only 2-3 fold. The findings do not indicate that drug accumulation or induction of metabolism occurred during long-term usage.

Low-dose quinine for treatment of Plasmodium falciparum malaria in Guinea-Bissau.

The recommended dose of 10 mg quinine/kg bodyweight 3 times a day for 7 days for treatment of malaria is so high that many patients experience cinchonism. We have earlier obtained good results with 7 days' treatment with 20 mg Quinimax/kg bodyweight divided into 2 daily doses. In order to identify the lowest effective dose, children with symptomatic malaria were treated with quinine twice a day for 7 days. They were assigned to 1 of 3 groups treated daily with 10 mg/kg, 15 mg/kg, or 20 mg/kg bodyweight, respectively; 42, 46, and 34 children, respectively, received treatment and completed 5 weeks of follow-up. The cumulative percentages of all children with parasitaemia during follow-up on day 28 or before were 33%, 13% and 12%, respectively. Treatment with 10 mg quinine salt/kg daily for 7 days gave a significantly higher rate of recrudescence than did treatment with 15 or 20 mg/kg daily. Thus at least 15 mg of quinine salt/kg bodyweight daily should be recommended for treatment of symptomatic Plasmodium falciparum malaria in Guinea-Bissau.

Standard and reduced doses of sulfadoxine-pyrimethamine for treatment of Plasmodium falciparum in Tanzania, with determination of drug concentrations and susceptibility in vitro.

88 asymptomatic Tanzanian schoolchildren with Plasmodium falciparum parasitaemia were given all, half or quarter of the recommended standard therapeutic dose of sulfadoxine-pyrimethamine (Fansidar). All children cleared the parasites by day 3 and all remained negative during 28-42 days of follow-up. All 32 successful in vitro micro-tests showed full sensitivity. High performance liquid chromatographic methods were applied for drug determinations. Using 100 microliter capillary blood dried on filter paper for sulfadoxine determination the inter-individual variation during follow-up of the standard dose group was 2-4 fold and the median half life was 8.9 d. Sulfadoxine concentrations in the half and quarter dose groups were roughly proportional to those in the standard dose group. The median whole blood to plasma concentration ratio for sulfadoxine was 0.72 and the correlation coefficient 0.95. There was only a weak correlation (r=0.46) between plasma concentrations of sulfadoxine and pyrimethamine. The uniform efficacy of sulfadoxine-pyrimethamine in vivo, even when reduced doses were used, makes this combination a good alternative for treatment of P. falciparum in Tanzania.

[Travellers to high-risk areas actively seek information on health hazards. A questionnaire study among Swedish charter tourists]. / Resenärer till riskområden söker aktivt information om hälsorisker. Enkätundersökning gjord bland svenska charterresenärer.

UNLABELLED: In order to study attitudes to travel-associated risks and adherence to advice, we sent a questionnaire to 2 x 2000 Swedish charter tourists who traveled to the Canary Islands, South East Asia or Gambia. METHODS: Questionnaires were answered either before the journey (n = 1249) or after return (n = 1223). RESULTS AND CONCLUSION: The travelers were usually well informed and followed the advice given. The opinion of the personnel who gave advice had a profound influence on which vaccines were taken. Those who more closely followed advice on what to eat and drink also reported diarrhea more frequently.

[Serious effects of chloroquine overdose. Prescribe the smallest possible dosage-packages and inform about the risks]. / Allvarliga skador vid överdos av klorokin. Skriv ut minsta möjliga förpackning och informera om riskerna.

An increasing number of acute overdoses with chloroquine has been reported in Sweden--some with fatal outcome. This substance is clearly one of the most toxic pharmaceuticals on the Swedish market. Four cases are described. Travelling to the tropics has become very popular, and chloroquine is often given as a prophylactic antimalarial. This inexpensive drug is often prescribed in 100-tablet packages, and any surplus is often stored in the home. Awareness of toxicity is low among users and doctors in this country. Preventive measures are suggested.

Immunogenicity of delayed TBE-vaccine booster.

Information is scarce regarding the antibody response when TBE-vaccine booster doses are delayed, which is a common situation in daily life. We have investigated the immune response after a delayed booster dose compared to a normal booster interval in an every-day setting. Overall, 250/260 (96%) of the study participants had neutralizing antibodies post-booster, with no significant difference between normal and delayed booster intervals. Based on our findings we propose that healthy individuals who have failed adherence to the recommended schedule of TBE-vaccination can be given a delayed dose without concern of immunogenicity.