Quinine-tetracycline for multidrug resistant falciparum malaria.

Plasmodium falciparum in Southeast Asia is highly resistant to chloroquine and sulfadoxine/ pyrimethamine. Quinine-tetracycline has been used as a second line treatment for uncomplicated falciparum malaria, but duration of treatment varies from place to place. The 7-days course of this combination has been shown to be very effective. However, due to the cinchonism adverse effects, the patient compliance has not been satisfactory. We have evaluated the efficacy of a 7-days course of tetracycline in combination with either 5 or 7-days course of quinine. Ninety male Thai patients who were admitted to the Bangkok Hospital for Tropical Diseases were randomized to receive tetracycline 250 mg qid for 7 days in combination with either quinine 600 mg tid for 5 days (Q5T7; group A) or quinine 600 mg tid for 7 days (Q7T7; group B). The patients were hospitalized for 28 days. Patients in both groups had a comparable initial response to treatment, with the clearance of fever and parasites within 4 days. There were 46 and 40 patients in group A and B, respectively, who completed the 28 day of follow-up. The cure rates were 87 and 100%, respectively for group A and B. No serious adverse effects were found in either group; transient nausea, vomiting and tinnitus were common findings. The incidence of adverse effects was not different between the two groups. The results from the present study suggest that a short course treatment of quinine (Q5T7) had significantly decreased the cure rate. In areas with quinine resistant falciparum malaria, a full course of 7-days quinine, in combination with 7-days course of tetracycline is recommended for hospital treatment. However, an alternative shorter course of antimalarials is suggested for home treatment.

A simplified and economical intradermal regimen of purified chick embryo cell rabies vaccine for postexposure prophylaxis.

Healthy volunteers were randomized to receive either intradermal purified chick embryo cell rabies vaccine (PCEC) alone (0.1 ml at each of two sites on days 0, 3 and 7, and at one site on days 28 and 90) (n = 81), or intradermal PCEC with one dose of human rabies immunoglobulin (HRIG) intramuscularly at 20 IU kg-1 on day 0 (n = 52). Neutralizing antibody (NAB) was detectable in every volunteer, in both groups, from day 14 up to day 365. The peak NAB occurred on day 28 in both groups. No significant suppressive effects of HRIG on NAB response were observed. Side-effects were mild and self-limiting. These preliminary results suggest that this simplified low-dose intradermal regimen could be an alternative schedule in rabies postexposure prophylaxis, resulting in lower overall costs.

High dose of primaquine in primaquine resistant vivax malaria.

The efficacy of low dose chloroquine, characteristic pattern of relapse and the relapse rate in vivax malaria after high dose primaquine were investigated in 167 Thai patients. 87 patients were allocated at random to receive 300 mg, and 80 received 450 mg of chloroquine on the first day of admission. All patients in both groups showed a rapid response with comparable fever clearance times (27.3 vs. 26.1 h) and parasite clearance times (67.1 vs. 58.1 h). After recovery and clearance of parasitaemia, the patients were allocated at random (double blind) to receive 2 dosage regimens of primaquine, a daily dose of 15 mg or 22.5 mg for 14 d. Relapses in both groups occurred within 6 months; no patient relapsed beyond that period. The relapse rate in the primaquine 15 mg group was significantly higher than that in the 22.5 mg group (17.5% vs. 2.4%).

Clinical trials with halofantrine in acute uncomplicated falciparum malaria in Thailand.

The antimalarial efficacy of halofantrine was compared with mefloquine in an open-label, randomized comparative trial in adult male patients with acute uncomplicated falciparum malaria. Twenty-eight patients received halofantrine and 27 received mefloquine. Halofantrine was administered in 3 doses of 500 mg at 6 hour intervals and mefloquine was administered in divided doses of 1,250 mg or 1,500 mg depending on whether the patients weighed less than or more than 60 kg. The patients were followed for 42 days and observed for drug tolerance and evidence of recrudescence. Response to treatment was favorable with both drugs, but three patients (two treated with halofantrine and one with mefloquine) did not completely eliminate malaria parasites from peripheral blood films in seven days. The parasite and fever clearance times were 75.6 and 55.7 hours, and 80.1 and 61.3 hours, respectively for halofantrine and mefloquine. However, 12 patients recrudesced during the 42 day follow-up period. Nine of these had been treated with halofantrine and three with mefloquine. The 42-day cure rate for the two drugs was 56% and 84%, respectively. The side-effects of halofantrine and mefloquine were comparable and transient. These are diarrhea, dizziness, orthostatic hypotension and black out. However, vomiting was found to be more common in mefloquine group (41% vs 22%).

Albendazole stimulates outward migration of Gnathostoma spinigerum to the dermis in man.

Human gnathostomiasis is characterized by space-occupying inflammatory lesions and/or hemorrhage as a result of the migration of, very often, a single larva of Gnathostoma spinigerum. Intermittent cutaneous migratory swellings occurring over years is the most common manifestation and the rare cerebral invasion may be fatal. There are currently no effective anthelminthics for this infection. During a double-blind randomized placebo control trial evaluating the efficacy of albendazole in cutaneous gnathostomiasis at a dosage of 400 mg twice daily for two weeks, it was observed that gnathostome larvae tended to migrate outward as a result of the treatment so that they could be recovered by excisional biopsy or by picking with a needle. In the placebo-treated group (N = 40), no such migration was observed during the 8,470 patient-days of follow-up while in the albendazole-treated group (N = 41) there was one worm in an excisional biopsy done on day 16 and two worms were removed from the skin by the patients themselves on days 8 and 0. Assuming that the period of drug exposure of the gnathostomes was the 14 days of albendazole administration plus another washout period of 7 days (equivalent to 20 half-lives of the active detectable metabolite), the total patient-days of albendazole exposure was 830. The rate of outward migration of gnathostomes in the drug treated group (3 per 830 patient-days) was significantly (p < 0.0001) higher than in the placebo group (0 per 8,470 patient-days).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of quinine, quinidine and Cinchonine when given as combination.

Pharmacokinetics of quinine, quinidine and cinchonine when given as a combination were evaluated in Thai patients with falciparum malaria during acute infection and convalescence. The combination of quinine, quinidine and cinchonine was randomly given to thirteen patients at 400 mg or 600 mg (consisting of one-third of each component; 7 patients were enrolled in 400 mg regimen and 6 in 600 mg regimen) intravenously every 8 hours for 7 days. The drug combination was given again at day 35 to define the pharmacokinetics of each drug during convalescence. All patients with the 600 mg regimen had good response with 100% cure rate while patients with the 400 mg regimen had a good initial response but one patient recrudesed on day 46. This particular patient had plasma concentrations of all three drugs lower than the mean values of patients with sensitive responses. The plasma levels of quinine and quinidine obtained from the present study were higher than that expected from one-third of the conventional dose (600 mg) when given alone, suggesting drug combination interaction. The terminal half-lives of each of the three components were prolonged during acute malaria when compared to those obtained during convalescence.

Fansimef for prophylaxis of malaria: a double-blind randomized placebo controlled trial.

At a time when Fansimef, the fixed combination of mefloquine, sulfadoxine and pyrimethamine was considered for prophylaxis of falciparum malaria, a randomized double-blind study comparing the efficacy and tolerability of Fansimef with that of Lariam (mefloquine), Fansidar, chloroquine and placebo in malaria prophylaxis was performed in Thailand from July 1987 to January 1988. The study population of 602 adult males was recruited in Pak Tongchai District, some 360 km North-East of Bangkok, where multiresistant P. falciparum is endemic. All active treatments and placebo were given once weekly for 24 weeks with doses as follows: Fansimef: 125 mg mefloquine + 250 mg sulfadoxine + 12.5 mg pyrimethamine (1 half-strength tablet); Lariam: 125 mg mefloquine (1 half-strength tablet); Fansidar: 500 mg sulfadoxine + 25 mg pyrimethamine; chloroquine; 300 mg. A loading dose of 2 half-strength tablets was given in the Fansimef group in weeks 1 and 2 and in the Lariam group in weeks 1 to 4. The incidence of acute episodes of P. falciparum per 100 person months of prophylaxis was 0.17 each in the Fansimef and the Lariam groups, 1.18 in the Fansidar group, 0.69 in the chloroquine group and 0.64 in the placebo group (differences statistically not significant). Clinically adverse events were reported by 170 subjects (Fansimef 28, Lariam 29, Fansidar 41, choroquine 43, placebo 29; differences statistically not significant). The most frequent adverse events in all groups were headache, sleepiness, dizziness and weakness.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of the coagulation cascade in falciparum malaria.

The incidence and progression of coagulation abnormalities were studied in 52 patients with acute falciparum malaria. The patients were prospectively divided into 3 groups; severe (parasitaemia greater than or equal to 5% or vital organ dysfunction), 12 patients; moderate (parasitaemia 1%- less than 5% without complications), 16 patients; and mild (parasitaemia less than 1%), 24 patients. No case died or developed clinical evidence of disseminated intravascular coagulation. Conventional indices of coagulation (prothrombin time, partial thromboplastin time, fibrinogen, fibrin degradation products) were usually within the normal range but reduced plasma concentrations of antithrombin III (AT-III) levels were noted in all groups, and the incidence was significantly higher in patients with severe and moderate malaria (83% and 81%) compared with the mild group (37%; P less than 0.005). Depletion of AT-III was associated with thrombocytopenia, decreased AT-III activity and elevated plasma concentrations of thrombin-antithrombin III complexes (P less than 0.01), confirming activation of the coagulation cascade and increased clotting factor consumption. AT-III levels returned to normal coincident with clinical improvement. Activation of coagulation is a common and sensitive measure of disease activity in acute falciparum malaria. It is not a specific feature, nor is there evidence to suggest it has a primary pathological role in severe infections.

Purified chick embryo cell rabies vaccine: economical multisite intradermal regimen for post-exposure prophylaxis.

The standard six-dose intramuscular (i.m.) rabies post-exposure vaccine regimen using a new purified chick embryo cell (PCEC) vaccine was compared with two economical multisite intradermal (i.d.) PCEC regimens, a multisite i.m. PCEC schedule and a subcutaneous regimen using a suckling mouse brain (SMB) rabies vaccine manufactured in Thailand. The neutralizing antibody results for the four-site and eight-site i.d. and the standard i.m. PCEC regimens were similar over 3 months. A three-site i.m. PCEC regimen had no advantage. The SMB vaccine gave the lowest antibody levels. Human rabies immune globulin therapy significantly increased the GMT of all groups on day 7, unlike equine antirabies serum (EARS). Both antisera suppressed antibody responses to PCEC on days 14 and 28. Three generalized reactions probably related to EARS were the only serious side effects. An eight-site i.d. PCEC vaccine regimen proved as immunogenic as the routine i.m. schedule and, if implemented as post-exposure prophylaxis, would be the cheapest widely available tissue culture vaccine regimen. The protective efficiency should now be tested in patients bitten by rabid animals.

High rate of Plasmodium vivax relapse following treatment of falciparum malaria in Thailand.

Within two months of treatment for falciparum malaria, Plasmodium vivax infections developed in 58 (33%) of 174 patients who had received a quinine or quinidine regimen and in 46 (32%) of 145 patients who had received mefloquine with inpatient follow-up of more than six weeks. The time to vivax relapse was significantly longer after mefloquine treatment (median 47 days, range 30-65) than after quinine or quinidine treatment (21 days, 15-36; p less than 0.0001). All patients remained outside areas of malaria transmission. These findings suggest a very high rate of double infection in Thailand with acute suppression of vivax by falciparum malaria, and warrant evaluation of radical therapy with primaquine in certain patients with acute falciparum malaria.