Response to measles revaccination among toddlers in Saudi Arabia by the use of two different trivalent measles-mumps-rubella vaccines.

This trial confirmed the immunogenicity of a standard dose of measles vaccine Edmonston-Zagreb strain administered at the age of 6 months as evaluated serologically at 12 months of age in 94 healthy children in Saudi Arabia. The residual seropositivity rate for measles was 53.4 and 80.6% as measured by enzyme immunoassay (EIA) and plaque neutralization, respectively, and could be increased to virtually 100% seroprotection after immunization with 1 of 2 measles-mumps-rubella (MMR) vaccines (Triviraten Berna or MMR II MSD) at 12 months of age. In both groups, more than 90% of infants showed an immune response to the mumps and rubella vaccine strains at 14 months of age. There was a difference in the geometric mean titres of mumps antibodies in favour of MMR II (P < 0.001). The seroconversion rates for mumps antibodies differed between the 2 vaccines because of the different test systems and/or the different cut-off levels used. The study reconfirmed that for the assessment of Rubini mumps vaccine-induced antibodies the indirect immunofluorescence test is superior to the EIA. The systemic tolerability of both vaccines was excellent. Triviraten Berna is exclusively propagated on human diploid cell cultures and hence free of avian proteins.

Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria.

To examine the effect of iron chelation on mortality in cerebral malaria, we enrolled 352 children in a trial of deferoxamine in addition to standard quinine therapy at 2 centres in Zambia, one rural and one urban. Entrance criteria included age < 6 years, Plasmodium falciparum parasitaemia, normal cerebral spinal fluid, and unrousable coma. Deferoxamine (100 mg/kg/d infused for a total of 72 h) or placebo was added to a 7 d regimen of quinine that included a loading dose. Mortality overall was 18.3% (32/175) in the deferoxamine group and 10.7% (19/177) in the placebo group (adjusted odds ratio 1.8; 95% confidence interval 0.9-3.6; P = 0.074). At the rural study site, mortality was 15.4% (18/117) with deferoxamine compared to 12.7% (15/118) with placebo (P = 0.78, adjusted for covariates). At the urban site, mortality was 24.1% (14/58) with deferoxamine and 6.8% (4/59) with placebo (P = 0.061, adjusted for covariates). Among survivors, there was a non-significant trend to faster recovery from coma in the deferoxamine group (adjusted odds ratio 1.2; 95% confidence interval 0.97-1.6; P = 0.089). Hepatomegaly was significantly associated with higher mortality, while splenomegaly was associated with lower mortality. This study did not provide evidence for a beneficial effect on mortality in children with cerebral malaria when deferoxamine was added to quinine, given in a regimen that included a loading dose.

Effect of food on the bioavailability of triclabendazole in patients with fascioliasis.

AIMS: Preliminary results indicate higher absorption of triclabendazole (TCBZ) administered postprandially. Therefore, the influence of food on the pharmacokinetics of TCBZ and its active sulphoxide (TCBZ-SO) and sulphone (TCBZ-SO2) metabolites was investigated. METHODS: Two single doses (10 mg kg(-1)) of TCBZ were administered to 20 patients with fascioliasis. Ten patients were first given the drug after a high energy breakfast and then, 48 h later, after an overnight fast. The other 10 patients first received the drug in fasting state and then, 48 h later, after breakfast. A low energy breakfast was served 2 h after drug administration for fasting state. RESULTS: Compared with the fasting state, an increased AUC and Cmax after food intake (significant, P < 0.0001) was shown from the values of TCBZ, TCBZ-SO and TCBZ-SO2. The mean AUC for TCBZ (fasting: 1.55, fed: 5.72 micromol l(-1) h), TCBZ-SO (fasting: 177, fed: 386 micromol l(-1) h) and TCBZ-SO2 (fasting: 13.9, fed: 30.5 micromol l(-1) h) indicated a large availability increase with food and the strong systemic predominance of the active sulphoxide metabolite over the unchanged drug. (All patients were cured at the end of the trial except one who required a second course of two postprandial doses of triclabendazole (10 mg kg(-1) each). Tolerability to the treatment among the patients was good. CONCLUSIONS: The administration of triclabendazole with food is recommended for improved systemic availability in patients with fascioliasis or paragonimiasis.

Transferrin saturation and recovery from coma in cerebral malaria.

To determine if the elevated transferrin saturations found in some patients with severe malaria are associated with an adverse outcome in cerebral malaria, we retrospectively measured baseline saturations in stored serum samples from 81 Zambian children with strictly defined cerebral malaria. The children had been treated with quinine, sulfadox-ine-pyrimethamine, and intravenous infusions of either placebo (n = 39) or the iron chelator, desferrioxamine B (n = 42), in a previously reported trial (Gordeuk et al, N Engl J Med 327:1473, 1992). More than one-third of children in both the placebo- and iron chelator-treated groups had transferrin saturations exceeding 43%, which is 3 standard deviations above the expected mean for age. Among children receiving quinine and placebo, those with elevated transferrin saturations had a delayed estimated median time to recover full consciousness (68.2 hours) compared with those with saturations < or = 43% (25.4 hours; P = .006). The addition of iron chelation to quinine therapy in children with high saturations appeared to hasten recovery (P = .046). We conclude that increased transferrin saturations may be associated with delayed recovery from coma during standard therapy for cerebral malaria and that serum iron and total iron binding capacity should be measured in future studies.

Iron chelation as a chemotherapeutic strategy for falciparum malaria.

To examine the effect of iron chelation against human malaria, 37 Zambians with asymptomatic Plasmodium falciparum infections were randomly assigned to 72-hr infusions of desferrioxamine B or placebo. Mean concentrations of ring forms decreased significantly with desferrioxamine B (P < 0.001) but not with a placebo. Over seven days of observation, mean parasite concentrations remained at the initial levels in six individuals originally given placebo, but decreased promptly with administration of desferrioxamine B (P = 0.001). Mean parasitemia was significantly lower for up to four weeks in 16 subjects treated with desferrioxamine B when compared with the eight who had received placebo only (P = 0.027). We conclude that iron chelation has antiplasmodial activity and may offer a new therapeutic strategy for falciparum malaria.

Amocarzine investigated as oral onchocercacidal drug in 272 adult male patients from Guatemala / Amocarzina investigada con droga oral antioncercosa 272 adultos pacientes hombres de Guatemala

The clinical investigations with three types of a three days regimen of amocarzine permitted to adjust the fixed dosing to the body weight related dosing and subsequently the adminstration of amocarzine from fasting state to drug intake after food. The main objective to reach a dose woth predictable and sustained absorption was achieved, and this in turn proved to be onchocercacidal and safe. A combined clinicopharmacokinetic study showed enhancement and consistency of amocarzine absorption after food. Quantitative assessment of the urinary excretion confirmed presence of the N-oxide metabolite, which qualitatively was visible by a urine colorimetry. This assay proved useful for drug monitoring. Ultrasonography of onchocercal skin nodules detected changes within the nodules following amocarzine therapy. Histology agter nodul-ectomy at four months post-therapy showed thal 57% of the female worms were dead, 24% necrobiotic, and 19% alive; male worms were more necrobiotic. Skin microfilariae were reduced within one week to about 10% of the initial level and after one year they remained at about 20%. Skin punch biopsies on day 5 showed that most microfilariae were dead or moribund. Ocular reduction of microfilariae was also observed, althought it was slower than in the skin. The visual acuity improved within the one year's observation time. Ocular and clinical tolerability was good, with one exception of neurological disturbance, which was fully reversible. Se quential testing of the liver function showed average values within the normal range. In conclusion, a repeat low dose regimen of amocarzine (3 mg/Kg twice daily postprandially for three consecutive days) was well absorbed with predictable plasma levels, macro-and microfilaricidal with good local and systemic tolerability in patients with moderate to heavy onchocerciasis. Amorcarzine is recommended for further clinical investigations, particularly inf emales and juveniles. Urine colorimetry and nodular ultrasonography are recommended for optional monitoring of amocarzine

Plasmodicidal effect of desferrioxamine B in human vivax or falciparum malaria from Thailand.

Desferrioxamine B (DFO, Desferal), an iron chelator, was earlier shown to be active against Plasmodium falciparum in vitro and in vivo. The present open pilot study served to assess its clinical tolerability and efficacy in human malaria under hospital conditions. Continuous intravenous DFO was administered to 28 Thai males at a dose of 100 mg/kg over 24 h for 3 consecutive days. No other antimalarial therapy was administered unless recrudescence had occurred. The first 14 patients had symptomatic Plasmodium vivax (P.v.) malaria, while the other 14 patients were suffering from uncomplicated Plasmodium falciparum malaria (P.f.). Both groups were treated in Bangkok, where malaria transmission does not take place, and followed up, on the ward, for 3 weeks (P.v. group) or 4 weeks (P.f. group) after the start of therapy. In both groups DFO reduced the parasitaemia to zero within 106 and 57 h respectively. The fever clearance time was 55 and 60 h, respectively. The overall tolerability of DFO was good but 4 P.v. and 5 P.f. patients had transient visual blurring. Recrudescences were observed on average 15, respectively 10 days after the start of therapy. Only 2 P.v. patients and none of the P.f. patients remained free of recrudescences during the observation period. There was no apparent gametocytocidal effect of DFO on P.f.

[Distomatosis of the bile ducts. Value of retrograde cholangiography. Efficacy of triclabendazole]. / Distomatose des voies biliaires. Intérêt de la cholangiographie rétrograde. Efficacité du triclabendazole.

A case of chronic biliary fascioliasis is reported, which was confirmed by endoscopic retrograde cholangiography. After unsuccessful attempts of treatment with classic antiparasitic drugs, cure was obtained with triclabendazole the absorption of which was studied.

Amocarzine investigated as oral onchocercacidal drug in 272 adult male patients from Guatemala. Results from three dose regimens spread over three days.

The clinical investigations with three types of a three days regimen of amocarzine permitted to adjust the fixed dosing to the body weight related dosing and subsequently the administration of amocarzine from fasting state to drug intake after food. The main objective to reach a dose with predictable and sustained absorption was achieved, and this in turn proved to be onchocercacidal and safe. A combined clinicopharmacokinetic study showed enhancement and consistency of amocarzine absorption after food. Quantitative assessment of the urinary excretion confirmed the presence of the N-oxide metabolite, which qualitatively was visible by a urine colorimetry. This assay proved useful for drug monitoring. Ultrasonography of onchocercal skin nodules detected changes within the nodules following amocarzine therapy. Histology after nodul-ectomy at four months post-therapy showed that 57% of the female worms were dead, 24% necrobiotic, and 19% alive; male worms were more necrobiotic. Skin microfilariae were reduced within one week to about 10% of the initial level and after one year they remained at about 20%. Skin punch biopsies on day 5 showed that most microfilariae were dead or moribund. Ocular reduction of microfilariae was also observed, although it was slower than in the skin. The visual acuity improved within the one year's observation time. Ocular and clinical tolerability was good, with one exception of neurological disturbance, which was fully reversible. Sequential testing of the liver function showed average values within the normal range. In conclusion, a repeat low dose regimen of amocarzine (3 mg/kg twice daily post-prandially for three consecutive days) was well absorbed with predictable plasma levels, macro- and microfilaricidal with good local and systemic tolerability in patients with moderate to heavy onchocerciasis. Amorcarzine is recommended for further clinical investigations, particularly in females and juveniles. Urine colorimetry and nodular ultrasonography are recommended for optional monitoring of amocarzine.

Onchocercacidal effect of three drug regimens of amocarzine in 148 patients of two races and both sexes from Esmeraldas, Ecuador.

The objective of this multidisciplinary clinical investigation was to test whether amocarzine was absorbed effectively and safely in patients of two races and either sex infected with Onchocerca volvulus while living in the holoendemic area of Esmeraldas Province, Ecuador. The prerequisite for a systemic onchocercacidal effect is the regular absorption of orally administered amocarzine. Single dosing after overnight fasting proved to produce irregular absorption of amocarzine, although some microfilaricidal effect was achieved. A pilot study with repeated low dose and postprandial administration of amocarzine showed a regular and predictable absorption with acceptable tolerability and a microfilaricidal effect lasting up to one year post-therapy. Since amocarzine and its major N-oxide metabolite are coloured agents, urine colorimetry was used to assess the urinary excretion of the N-oxide qualitatively. For the postprandial drug regimens plasma concentrations of amocarzine and its metabolite were determined at two selected time points in patients of two races and either sex; the results showed no major differences. Excision of onchocercal nodules was performed four months post-therapy. The pooled results of the histologic analysis of 100 patients with the same drug regimen read under blinded condition showed that 65% of the adult female worms were dead, 20% necrobiotic and 15% alive. The male worms were fewer and mainly necrobiotic. Control worm populations in Esmeraldas without chemotherapy showed that on the average 81.5% were alive and 18.5% dead. Amocarzine was also microfilaricidal producing a reduction of skin dwelling microfilariae to about 10% of the initial value within the first week after start of therapy and lasting for half a year at a 20% level. The reduction of ocular microfilarial was slower and reached 35-40% after one year. The general tolerability was acceptable to good. Reversible dermal reactions were usually mild and peaked as a rash in 57% of the patients on day 6. No prohibitive ocular intolerance was observed. Mild and reversible dizziness peaked on day 4 in 74% of patients. A positive reversible Romberg sign was found in 12 patients on day 4. Amocarzine, the first oral micro- and macrofilaricidal agent administered as a low dose repeat regimen (3 mg/kg twice daily and postprandial for three consecutive days) can be recommended for oral onchocercacidal therapy in adult patients. Clinical trials in juveniles should be encouraged.

Influence of food related to dose on the pharmacokinetics of amocarzine and of its N-oxide metabolite, CGP 13 231, after oral administration to 20 onchocerciasis male patients from Guatemala.

Twenty male patients from Guatemala infected with Onchocerca volvulus received a 3 mg/kg oral dose of amocarzine twice daily for three days. The patients were randomly assigned to the sequence fasting/non-fasting and non-fasting/fasting for the morning administration on days 1 and 3. All other doses were given after food intake. Blood samples on days 1 and 3 and urine fractions from days 3 to 5 were collected for the determination of the unchanged drug and of its N-oxide metabolite, CGP 13 231. The absorption of amocarzine and CGP 13 231 was slower and sustained for longer time in fed patients than in fasting ones. The mean AUC of amocarzine was significantly higher (about 20%) in fed patients. No significant difference was found for CGP 13 231. The relative improvement of bioavailability of amocarzine due to food was less prominent than previously obtained after a high dose of 1200 mg which demonstrated a bioavailability improvement of a factor of three. Therefore, saturable dose dependent absorption processes are likely to be involved for the administration in fasting conditions. Conversely, the concentrations of amocarzine in fed patients after 150 and 1200 mg were dose proportional, thus indicating linear kinetics. The cumulative urinary excretions of CGP 6140 ranged from 0.1 to 3.8% of the daily dose. Those of CGP 13 231 ranged from 31 to 64%. This total excretion was larger than that previously recorded in fasting patients after a single oral dose. The present results confirm the improvement of the bioavailability of the drug administered after food intake.

Microfilaricidal effect of amocarzine in skin punch biopsies of patients with onchocerciasis from Latin America.

Skin punch biopsies were performed in 54 selected patients with onchocerciasis participating in a clinical trial with amocarzine (CGP 6140) in Ecuador and Guatemala. Skin snipping for counting microfilariae of Onchocerca volvulus was done before treatment (day 0) and day 4 and 8 following start of the therapy which consisted of 3 mg/kg amocarzine postprandially twice daily for three consecutive days. The mean microfilarial skin density has been reduced by 45% on day 4 and 95% on day 8. Skin punch biopsies were taken on day 5, within 1 cm from the snip site on the iliac crest. Histopathologic examination revealed that the vast majority of the microfilariae in the upper as well as in the deeper dermis were degenerated or necrotic, surrounded often (57%) by minute foci of fibrinoid change of the collagen. There was usually slight, less frequently moderate eosinophilic, lympho-plasmocytic and initial histocytic inflammatory reaction in the vicinity. Microfilariae were frequently (69%) found at the dermal-epidermal junction and in the epidermis. Occasionally (7%) intra-epidermal microabscesses were noted. Microfilariae were detected also in the lumen of some dermal lymphatic vessels. Therefore it is concluded that amocarzine showed marked microfilaricidal effects in the skin of patients with onchocerciasis as evidenced histologically by mainly destroyed or moribund microfilariae which induced a mild to moderate inflammatory cell reaction.

Concentrations of amocarzine in plasma of 71 Ecuadorian patients of two different races receiving 3 mg/kg b.i.d. and 5 mg/kg o.d. oral postprandial doses for 3 days.

The possible influence of sex, race and of postprandial administration conditions (either immediately after the end of meal or one hour later) on the plasma concentrations of amocarzine and its N-oxide metabolite, CGP 13 231, was investigated. 71 Ecuadorian patients (48 males and 23 females) of two different races (Indio and Negro) infected with Onchocerca volvulus participated in the study. The concentrations were measured on day 3 at times 3 and 6 h after postprandial administration in the morning of a treatment with either a dose of 5 mg/kg of amocarzine once daily (12 patients) or 3 mg/kg twice daily (59 patients) for 3 days. The concentrations of unchanged drug and of CGP 13 231 measured after the 5 mg/kg treatment were in the low range of those expected from dose proportionality by the comparison with the 3 mg/kg. After the 3 mg/kg dose, no significant difference in concentration of both compounds were detected between the male and female patients between Indio and Negro patients, between the administration immediately after food intake and one hour later. The only detected difference (P = 0.05) was that between Indio and Negro patients for the concentrations of CGP 13 231 at time 3 h. This difference was not confirmed at time 6 h. Therefore, the administration of amocarzine either immediately or one hour after food intake appeared to produce reproducible absorption conditions which were not influenced by sex and race.

Use of an ophthalmologic ultrasoundscanner in human onchocercal skin nodules for non-invasive sequential assessment during a macrofilaricidal trial with amocarzine in Guatemala. The first experiences.

Ultrasonography of onchocercal skin nodules was performed with an ophthalmologic real time linear scanner with a B probe of 10 MHz. A clinical trial in Guatemala with amocarzine (CGP 6140)--a new oral macrofilaricidal compound--investigated three repeat dose regimens and one placebo control group, each group consisting of six patients. Onchocercal nodules were scanned before treatment and on day 10, 30 and 60 after start of amocarzine. A total of 28 treated and 8 additional untreated nodules were analysed and compared with the histologic findings following nodulectomy at day 60. Of the 28 treated nodules, 21 were of onchocercal origin and seven were lymph nodes. The correlation between ultrasonography and histology was good in 25 patients, but did not match in three. In 20 out of 21 treated nodules a progressive ultrasonographic change over two months was seen. Of the eight additional untreated nodules, five were of onchocercal origin, one was a lymph node, one an epidermoid cyst and in one only fibrous tissue was detected. The ultrasonography correlated well to histology in seven nodules but not in one. In five onchocercal nodules no change was observed over two months. For initial control purposes six nodules were excised around day 10, four were of onchocercal origin and two were lymph nodes. The correlation was good in four. The present results indicate that an ophthalmologic real time linear scanner can be used in the bidimensional mode as a non-invasive method to assess sequentially the events in superficial onchocercal nodules following chemotherapy with amocarzine. This is the first objective non-invasive method permitting sequential assessment of the content of onchocercal nodules and it is far superior than subjective sequential manual palpation.

Longterm follow-up of onchocerciasis patients in Latin America after treatment and retreatment with amocarzine. Preliminary results.

Amocarzine has been reported to have onchocercacidal effects. Four months posttherapy the majority of adult worms were dead or moribund. The effect of skin microfilariae lasted up to one year as reflected by markedly reduced microfilaridermia. Since the duration of the onchocercacidal effect of amocarzine beyond one year was unknown and since such an effect may influence the planning of future control strategies, efforts were made to follow-up the already treated amocarzine patients for a second year. The present study from Latin America showed that various amocarzine drug regimens produced a prolonged reduction of microfilaridermia at the end of the second year following the initial therapy, the best levels were about 7-17% of the initial parasite load in the skin for some three days amocarzine regimens. Such an effect occurring in a transmission area of onchocerciasis in Latin America provides additional, although indirect, evidence of a macrofilaricidal effect of amocarzine. Similar experiences of a prolonged amocarzine effect on skin microfilariae has also been observed in West Africa (Ghana, Mali). Preliminary results of retreatment schedules at the start of the third year post-initial therapy showed that simplified postprandial dose regimen of one or two days were well tolerated. It is premature at the time of this report to judge upon their ultimate efficacy, but they had significantly reduced levels of moderate microfilaridermia.

Fine structure of microfilariae in the skin of onchocerciasis patients after exposure to amocarzine.

Transmission electron microscopy was used to demonstrate the effects of amocarzine (CGP 6140) on the fine structure of Onchocerca volvulus microfilariae (mf) in skin biopsies from patients treated orally in Guatemala or transepidermally exposed in Liberia. After 6-10 hours exposure to the drug most mf did not show any alterations and only a few mf contained increased numbers of vacuoles in the cytoplasm and clefts between cuticle and hypodermis. At 20-48 hours after treatment most of the mf showed distinct signs of damage. Most frequently seen was disintegration of the cytoplasm of the afibrillar portion of the muscle cells. Some mf showed also disintegration of the myofilaments and of the internal structure of the mitochondria in the muscle cells. Other signs were progressive separation of the cuticle from the hypodermis, increase of intracellular vacuoles and clefts and in some mf condensation of the cytoplasm. The type and the site of the morphological alterations were the same after both forms of amocarzine administration. The degree of morphological changes increased with the length of time of exposure to the drug. Microfilariae with morphological alterations were nearly always surrounded by adherent host cells, mostly eosinophils and macrophages.