Improved efficacy with amodiaquine instead of chloroquine in sulfadoxine/pyrimethamine combination treatment of falciparum malaria in Uganda: experience with fixed-dose formulation.

Amodiaquine (AQ) is an affordable compound, chemically related to chloroquine (CQ) but often effective against CQ resistant Plasmodium falciparum. In Uganda, a pre-packed fixed-dose combination of CQ plus sulfadoxine/pyrimethamine (CQ+SP) called Homapak is used in the home based management of fever program (HBM). We performed a single blind randomized trial to determine the efficacy of AQ+SP in comparison with the fixed-dose CQ+SP (Homapak) in the treatment of uncomplicated falciparum malaria in Ugandan children aged 6 months to 5 years. The study was done in 2004 at Walkuba Health Center, a sub-urban area in Jinja district, Uganda. Primary outcome was the day 14 per protocol clinical and parasitological response according to the WHO. A total of 183 children were included (mean age 28 months) and 90% completed 28 days of follow up. The day 14 adequate clinical and parasitological response was 70.9% for CQ+SP and 97.4% for AQ+SP (p<0.001). In those given CQ+SP, treatment failure rates for the 6 months to 2 years age group were much higher (48.2%) than in the older children (18.2%, p=0.004). The day 28 PCR adjusted parasitological failure rates were also higher in the CQ+SP (31.3%) than in the AQ+SP group (13.1%) (p=0.003), with a higher gametocyte carriage among the CQ+SP group. We conclude that the efficacy of AQ+SP was significantly superior to the fixed-dose CQ+SP (Homapak), particularly among the youngest children. Thus, AQ could be used instead of CQ in combination with SP to improve the effectiveness against falciparum malaria in Uganda.

Pharmacokinetic interactions between chloroquine, sulfadoxine and pyrimethamine and their bioequivalence in a generic fixed-dose combination in healthy volunteers in Uganda.

BACKGROUND: A pre-packaged fixed-dose formulation of chloroquine (CQ) and sulfadoxine/pyrimethamine (S/P) combination (Homapak) is widely used for the treatment of falciparum malaria in Ugandan children. It is however a product whose pharmacokinetics and interactions have not been studied. OBJECTIVES: To explore possible pharmacokinetic interactions between CQ and S/P during co-administration, and to determine their bioavailability in the locally made Homapak compared to the Good Manufacturing Practice (GMP) made formulations. METHODS: Thirty-two adult healthy volunteers were randomized into four groups and given single oral doses of fixed-dose CQ+S/P combination (Homapak), or GMP formulations of S/P (Fansidar), CQ (Pharco), or their combination. Plasma samples were followed for 21 days, analysed by HPLC-UV methods, with pharmacokinetic modeling using the WinNonlin software. RESULTS: Sulfadoxine in Homapak was more rapidly absorbed (ka = 0.55 h(-1)) than in Fansidar + CQ (ka = 0.27 h(-1), p=0.004), but not more than S in Fansidar alone group (ka = 0.32 h(-1), p=0.03). No significant differences were observed in the other pharmacokinetic parameters of S, P and CQ when given together or separately. The relative bioavailability of CQ and S in Homapak showed bioequivalence to reference formulations. CONCLUSIONS: There were no pharmacokinetic interactions between CQ, S and P when the compounds were given together, however, more investigations would be needed to explore this further. Compared with GMP made drugs, both S and CQ are bioequivalent in Homapak, the Ugandan made fixed-dose formulation. Furthermore, the absorption of S was more rapid which could be advantageous in malaria treatment.

Epidemiology and clinical features of vivax malaria imported to Europe: sentinel surveillance data from TropNetEurop.

BACKGROUND: Plasmodium vivax is the second most common species among malaria patients diagnosed in Europe, but epidemiological and clinical data on imported P. vivax malaria are limited. The TropNetEurop surveillance network has monitored the importation of vivax malaria into Europe since 1999. OBJECTIVES: To present epidemiological and clinical data on imported P. vivax malaria collected at European level. MATERIAL AND METHODS: Data of primary cases of P. vivax malaria reported between January 1999 and September 2003 were analysed, focusing on disease frequency, patient characteristics, place of infection, course of disease, treatment and differences between network-member countries. RESULTS: Within the surveillance period 4,801 cases of imported malaria were reported. 618 (12.9%) were attributed to P. vivax. European travellers and immigrants were the largest patient groups, but their proportion varied among the reporting countries. The main regions of infection in descending order were the Indian subcontinent, Indonesia, South America and Western and Eastern Africa, as a group accounting for more than 60% of the cases. Regular use of malaria chemoprophylaxis was reported by 118 patients. With 86 (inter-quartile range 41-158) versus 31 days (inter-quartile range 4-133) the median symptom onset was significantly delayed in patients with chemoprophylaxis (p < 0.0001). Common complaints were fever, headache, fatigue, and musculo-skeletal symptoms. All patients survived and severe clinical complications were rare. Hospitalization was provided for 60% and primaquine treatment administered to 83.8% of the patients, but frequencies varied strongly among reporting countries. CONCLUSIONS: TropNetEurop data can contribute to the harmonization of European treatment policies.

Imported schistosomiasis in Europe: sentinel surveillance data from TropNetEurop.

BACKGROUND: Schistosomiasis is a major parasitic disease, increasingly imported into temperate climates by immigrants from and travelers to endemic areas. METHOD: To generate valid data on imported infectious diseases to Europe and to recognize trends over time, the European Network on Imported Infectious Diseases Surveillance (TropNetEurop) was founded in 1999. Three hundred and thirty-three reports of schistosomiasis were analyzed for epidemiologic and clinical features. RESULTS: Male patients accounted for 64% of all cases. The average age of all patients was 29.5 years. The majority of patients were of European origin (53%). Europeans traveled predominantly for tourism (52%). Main reasons for travel for people from endemic areas were immigration and refuge (51%) and visits to relatives and friends (28%). The majority of infections were acquired in Africa; 92 infections were clearly attributable to Schistosoma haematobium, 130 to Schistosoma mansoni, and 4 to Schistosoma intercalatum. Praziquantel was the only treatment used. No deaths were recorded. CONCLUSION: TropNetEurop sentinel provides valuable epidemiologic and clinical data on imported schistosomiasis to Europe.

Epidemiology and clinical features of imported dengue fever in Europe: sentinel surveillance data from TropNetEurop.

Travelers have the potential both to acquire and to spread dengue virus infection. The incidence of dengue fever (DF) among European travelers certainly is underestimated, because few centers use standardized diagnostic procedures for febrile patients. In addition, DF is currently not reported in most European public health systems. Surveillance has commenced within the framework of a European Network on Imported Infectious Disease Surveillance (TropNetEurop) to gain information on the quantity and severity of cases of dengue imported into Europe. Descriptions of 294 patients with DF were analyzed for epidemiological information and clinical features. By far the most infections were imported from Asia, which suggests a high risk of DF for travelers to that region. Dengue hemorrhagic fever occurred in 7 patients (2.4%) all of whom recovered. Data reported by member sites of the TropNetEurop can contribute to understanding the epidemiology and clinical characteristics of imported DF.

[Clostridium difficile-associated diarrhea--a growing problem in geriatric care]. / Clostridium difficile-associerad diarré--ett växande problem inom geriatriken.

From 1994 to 1998 the incidence of Clostridium difficile-associated diarrhoea (CDAD) in the Department of Geriatric Medicine, Huddinge University Hospital increased from 0.5% to 2.2% of all admissions. Corresponding figures for the whole hospital were 0.3% and 0.6%, respectively. The increase in CDAD at the Department of Geriatric Medicine was parallel with a more than doubled consumption of antibiotics. All geriatric patients with CDAD had been treated with antibiotics before onset of diarrhoea. Out of the antibiotic prescriptions 48% were a cephalosporin (mainly cefuroxim). In a matched reference group of geriatric patients 51% had been treated with antibiotics during the hospital stay. The patients with CDAD spent 27 +/- 14 days in hospital as compared to 13 +/- 9 days (P < 0.05) in the reference population.

The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quinine in vivo.

OBJECTIVE: To investigate the roles of CYP3A4 and CYP1A2 in the 3-hydroxylation of quinine in vivo. METHODS: In a randomized, three-way crossover study, nine healthy Swedish volunteers received single oral doses of quinine hydrochloride (500 mg), quinine hydrochloride (500 mg) plus ketoconazole (100 mg twice daily for 3 days), and quinine hydrochloride (500 mg) plus fluvoxamine (25 mg twice daily for 2 days) on three different occasions. Blood and urine samples were collected before quinine intake and up to 96 hours thereafter. Plasma and urine samples were analyzed for both quinine and its main metabolite 3-hydroxyquinine with HPLC methods. RESULTS: Coadministration with ketoconazole (which inhibits CYP3A4) decreased the mean apparent oral clearance of quinine significantly (P < .001) by 31% (from 8.7 to 6.0 L/h), whereas coadministration with fluvoxamine (which inhibits CYP1A2 and to some extent CYP2C19) had no significant effect (P > .05) on the mean apparent oral clearance of quinine. Coadministration with ketoconazole also decreased the mean area under the plasma concentration versus time curve (AUC) of 3-hydroxyquinine (from 28.4 to 19.7 micromol x h x L(-1); P < .001), whereas coadministration with fluvoxamine increased 3-hydroxyquinine AUC significantly (from 28.4 to 30.2 micromol x h x L(-1); P < .05). CONCLUSION: Cytochrome P450 3A4 is important for the 3-hydroxylation of quinine in vivo. On the other hand, CYP1A2 had no significant effect on this metabolic pathway.

Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose.

AIMS: To investigate the kinetics of the (+)RS- and (-)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers. METHODS: Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250 mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method. RESULTS: A two-compartment model adequately described the disposition of (+)RS-MQ. CL/F was 6.5 +/- 1.8 l h(-1), V(ss)/F 815 +/- 165 l, and k 0.0081 +/- 0.0023 h(-1). The kinetics of (-)SR-MQ were time- and/or concentration dependent with a lower oral clearance (0.92 +/- 0.25 vs 2.14 +/- 0.63 l h(-1), 95% CI for the difference 0.86-1.60 l h(-1)) and a longer half-life (345 vs 185 h, 95% CI for the difference 47-291 h) after the last dose compared with the first dose. Clearance of (+)RS-MQ and (-)SR-MQ was significantly correlated within subjects (r = 0.69, P < 0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS-MQ and 12.3% for (-)SR-MQ. The elimination of MMQ was disposition rate-limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound. CONCLUSIONS: The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.

In vitro susceptibility of Plasmodium falciparum to quinine: relation to parasite density and drug distribution in culture fractions.

We have studied the importance of parasite density (2, 0.2, 0.02 and 0.002%) for the in vitro susceptibility of Plasmodium falciparum (F32 strain) to quinine. Shorter exposures (< or = 48 hours) only briefly inhibited parasites in wells with the highest initial density. Parasites reappeared after 3-5.5 days in wells with intermediate (0.2 and 0.02%) and lowest density (0.002%). Longer exposures (> or = 72 hours), however, inhibited them for much longer periods and parasites did not reappear in most of the wells with the lowest density during the 28 days of follow-up. The mean multiplication rate following reappearance was tenfold per parasite schizogony cycle. The mean elimination rate per schizogony cycle was calculated to be 99.91%. The elimination and multiplication rates were not correlated to initial parasite density. The mean ratio between quinine concentrations in erythrocytes and medium was 3.6 regardless of quinine concentrations and presence of parasites. Mean quinine-free fractions of 36 and 67% were found from total concentrations of 0.33 and 10.4 mumol/l. We conclude that initial parasite density determines the time to reappearance of parasites following quinine exposure while the elimination and multiplication rates are independent of the initial parasite density, and that quinine protein binding is concentration-dependent in vitro and lower than during treatment.

Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance.

This longitudinal study of travellers to Africa taking mefloquine (MQ) chemoprophylaxis aimed to quantify and assess non-serious adverse events (AE) occurring during short-term prophylaxis and relate these to concentrations of racemic MQ, its enantiomers and metabolite. A total of 420 volunteers (52% F) participated. AEs with some impact on activities were reported by 11.2% of participants including 7.9% of neurological/psychiatric symptoms. Women were more likely to report AEs (P = 0.02). The standardized questionnaires used showed more pathological indicators in travellers who reported subjective AE with significantly more dizziness, distress, sleep disturbances and a high total mood disturbance (TMD) in the AE group. There was, however, no significant performance deficit in computerized psychomotor tests in those experiencing AE. Furthermore, no significant differences were observed in enantiomer ratios, metabolite concentrations, or racemic MQ levels in participants with or without AEs suggesting that these factors are not the main predictors of mefloquine intolerability.

Homeopathic Resistant Malaria.

Multiresistant Plasmodium falciparum malaria is a major threat to travelers to subSaharan Africa. However, even if chemoprophylaxis does not prevent clinical malaria in some individuals, it does lead to a reduction in the severity of the disease.1 In Sweden, we have recently seen five patients with malaria (three due to P. ovale and two due to P. falciparum) who have used homeopathic drugs for prophylaxis during visits to West Africa. We are concerned about this incidence and afraid that reduced confidence in modern medical malaria prophylaxis will encourage some individuals to try totally ineffective alternatives. Three women (57, 40, and 39 years old) visited Guinea Conacry in January 1995 as members of a group of 24 persons learning about African dances. The 57-year-old woman took mefloquine irregularly but vomited each time after intake. She also used Spenglersan M, which is a homeopathic drug that is administered (one drop daily in the bend of the arm) as malaria prophylaxis. The two other women used Spenglersan M only. They all fell ill with P. ovale malaria despite ongoing intake. Spenglersan M is said to contain both antigen from P. falciparum and antibodies against the parasite diluted to 1:1,000,000,000 concentration. The fourth case was a 26-year-old man who visited Ghana and Burkina Faso in October and November 1994. He used China D-6 for prophylaxis. This is a homeopathic preparation of the bark from the cinchona tree. Not even trace amounts of quinine were found in the tablets with a very sensitive high-performance liquid chromatographic method.2 Four days after returning from Africa he fell ill with P. falciparum malaria and received sulphadoxine-pyrimethamine treatment. After clinical relapse (RI), mefloquine was given and the patient was eventually cured. The fifth case was a 34-year-old woman admitted to hospital because of P. falciparum malaria after a visit to Guinea Conacry in January 1995. She had taken a homeopathic drug, Charaka comp 118, as prophylaxis. The drug is said to contain different extracts from herbs diluted 30 times. At first she refused to stay in hospital, but 2 days later she was readmitted and treated in the intensive care unit because of severe malaria with hypotonia and anemia. She had hyperparasitemia with 23% infected erythrocytes. Exchange transfusion was done, quinine was given, and the patient recovered without sequelae. The mortality is about 1% in people with P. falciparum infection.3 We therefore urge the readers to stand up against the dangerous use of homeopathic drugs and instead motivate travelers to use protective malaria prophylaxis.

Comparison between concentrations of racemic mefloquine, its separate enantiomers and the carboxylic acid metabolite in whole blood serum and plasma.

OBJECTIVE: To compare concentrations of the separate enantiomers of mefloquine (MQ), total racemic MQ and the carboxylic acid metabolite in different blood fractions at steady state. SETTING: Human volunteer laboratory, Unit of Clinical Pharmacology, Karolinska Institute. VOLUNTEERS: Ten healthy adult Caucasian volunteers. METHODS: Drug concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS: Trough concentrations of the (+)RS enantiomer were higher in venous whole blood than in plasma and serum (mean ratios, 1.41 and 1.38). For the other enantiomer, (-)SR, concentrations were lower in whole blood than in plasma (mean ratio 0.89) and for the metabolite this ratio was 0.5. CONCLUSION: Stereoselective distribution might be important for antimalarial activity and should be considered when pharmacokinetic studies are performed.

Mefloquine Prophylaxis and Hearing, Postural Control, and Vestibular Functions.

Background: Mefloquine (MQ) is an important antimalarial drug. Dizziness and other adverse neuropsychiatric reactions have however restricted its use. Method: Ten healthy adult volunteers were given MQ (Lariam) 250 mg once weekly for 16 weeks. Measurement of postural sway (posturography), nystagmus recording, determinations of hearing thresholds (Bekesy audiometry), and determinations of drug concentrations were done before, after 4, 32, and 109 days of weekly MQ intake and 3 months after the last dose. Results: All volunteers were able to continue their professional work and normal daily activities. Several mild symptoms were reported. In at least one of the volunteers, these symptoms were probably caused by the MQ intake. Hearing thresholds remained normal. No significant changes were noted in the nystagmus tests. The recorded values of sway index were within the normal range (99% confidence interval) in all volunteers in all test situations, and no differences were seen at the time of maximal drug concentrations (day 109) compared to before or after the study. There was no correlation between the plasma concentrations of MQ, the two MQ enantiomers (RS and SR), or the main mefloquine metabolite and the sway index. Conclusion: Although no effect was seen on the vestibular system in the present study, further tests in a flight simulator will be needed before MQ can be recommended for pilots. (J Travel Med 2:66-69, 1995)

Magnitude changes in transient evoked otoacoustic emissions and high-level 2f1-f2 distortion products in man during quinine administration.

Quinine reversibly affects the outer hair cells (OHC). It is therefore an ideal drug for studying OHC-related phenomena, such as transient evoked otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs). Pure-tone thresholds (PTTs), 1,000-4,000 Hz, TEOAEs, and DPOAEs were measured monaurally in 5 normal-hearing volunteers during quinine administration. DPOAE was evoked at 75 dB SPL (f2/f1 = 1.22) and analysed at 2f1-f2 with f2 at 6 frequencies (700-4,000 Hz), while TEOAE was obtained at 79 dB SPLp and analysed at the f2 frequencies (1/3 octave). The PTT-shift was flat, 10 dB, whereas the TEOAE-power and the global mean of the DPOAEs decreased 4.5 dB and 1.4 dB, respectively. No correlation was found between the intra-individual emission shifts. It is concluded that TEOAE is more sensitive than high-level DPOAE for identifying minor cochlear hearing losses. Support is given to the hypothesis that different sources are involved in generating DPOAEs at different evoking levels.

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.