Protein binding and ivermectin estimations in patients with onchocerciasis.

We measured ivermectin in plasma, urine, and saliva of nine patients with onchocerciasis. The aim was to establish pharmacokinetic parameters and to assess the most facile medium for use in monitoring compliance. Binding of ivermectin to plasma proteins in vitro was also investigated. The mean (+/- SEM) plasma values for the nine subjects were as follows: weight, 66.3 +/- 2.8 kg; dose, 11.11 +/- 0.4 mg; half-life, 56.50 +/- 7.01 hours; clearance, 142.5 +/- 22.6 L/kg; volume of distribution, 9.91 +/- 2.67 L/kg; area under the plasma concentration-time curve, 1545.3 +/- 190.5 ng/ml.hr; time to reach maximum concentration, 4.7 +/- 0.5 hours; and maximum concentration, 38.2 +/- 5.8 ng/ml. Ivermectin was not detected in the urine of any of the nine subjects. Low levels were found in saliva. Blood specimens remain the only reliable biologic fluid for assessment of compliance after ivermectin oral administration. Ivermectin binds specifically to human serum albumin.

Community-based ivermectin therapy for onchocerciasis: comparison of three methods of dose assessment.

A new method of assessment based on mid-upper arm circumference (MUAC) is described for dosage adjustment for community-based ivermectin distribution. We studied 878 subjects eligible for ivermectin dosing in Awhum, Nigeria. In a previous preliminary study of 40 persons, MUAC (in cm) correlated with weight (kg) in the first 20 male (r = 0.97, r2 = 0.95, P < 0.0001) and the first 20 female subjects (r = 0.94, r2 = 0.88, P < 0.0001). We therefore studied the use of height, physical appearance, and MUAC for calculating the dose of ivermectin. The MUAC-based schedule underdosed only 4.1% of the population. The methods based on height underdosed 3.3% and 21.1%, and assignment based on physical appearance underdosed 10.2% of the population studied. This MUAC-based method (13-15 cm, 0.5 tablet; 16-20 cm, 1.0 tablet; 21-27 cm, 1.5 tablets; > or = 28 cm, 2.0 tablets) is more convenient and corresponds closely to dosing by weight. An adaptation of this method with reference to other prevalent tropical diseases and their respective drugs is therefore advocated.

Adverse events following mass ivermectin therapy for onchocerciasis.

The Achi community of south-east Nigeria was given mass ivermectin therapy to control endemic onchocerciasis. 7556 subjects (75.6% of those eligible) were dosed. 992 patients (13.1%) complained of adverse effects, mostly within one week of dosing. Adverse events were mainly of the Mazzotti type. Exacerbation of pruritus (71.2%), oedema (47.4%), headache (46.4%), and worsening of rash (24.4%) were the most common. In 962 subjects (97%), adverse events were mild and did not prevent work. Two patients suffered severe sustained postural hypotension. The incidence of adverse events was greater in villages with a high load of microfilarial infection.

Compliance to correct dose of chloroquine in uncomplicated malaria correlates with improvement in the condition of rural Nigerian children.

Non-compliance to correct dosing is thought to be one of the main causes of treatment failure of chloroquine in the home management of childhood malaria. There are few studies of compliance to drugs used for tropical diseases. In order to study compliance in the rural setting, chloroquine syrup was packaged with a novel pictorial insert for compliance to correct dosing. Compliance was assessed in a field trial in September 1996-December 1997, involving 632 children with uncomplicated malaria in Udi local government area in Nigeria. Written informed consent was obtained from mothers/guardians before children were enrolled in the study. There were 3 arms to the trial: control villages (group I) received chloroquine syrup without further intervention, group II received a pictorial insert with chloroquine syrup, and group III received chloroquine syrup, the pictorial insert and verbal instructions. Each group was made up of 3 health centres. Compliance was assessed by volumetric measurement of the chloroquine syrup left in 30-mL bottles and by questionnaires administered to mothers/helpers of the children. Control villages recorded full compliance for 36.5 +/- 4.4% of the children, group II for 51.9 +/- 7.9% and group III for 73.3 +/- 4.2%. There was a significant correlation (P < 0.0001) between full compliance, improvement and time for improvement of the condition. This study is deemed important because it focuses on children, who bear the greatest burden of malaria. It is unique for introducing a pictorial insert that illiterate villagers, who may not understand the use of age or weight in drug dispensing, may utilize as a substitute.

Ivermectin: concentration-dependent effects on adenosine triphosphatases in adult worms of Onchocerca volvulus.

The effect of increasing concentrations of ivermectin on adenosine triphosphatase (ATPase) activity was investigated in adult worms of Onchocerca volvulus. Mean Mg- and Na,K-ATPase activities decreased significantly (F ratio = 29.82, P < 0.01 and F ratio = 28.54, P < 0.01, respectively) with increasing concentrations of ivermectin (0-100 ng/ml) in the female worms. When male and female worms were mixed with equal amounts of proteins from each, only the Na,K-ATPase activity was significantly decreased (F ratio = 56.61, P < 0.01) over a similar range of ivermectin concentrations. Since ivermectin exhibits concentration-dependent effects on both ATPases in female adult worms, this might provide an insight into other effects of the drug. However, the adjustment of the dose of ivermectin to obtain a nodular concentration of at least 40 ng/ml is therefore recommended in the complete chemotherapy of onchocerciasis.

An improved dosing schedule for ivermectin as a microfilaricidal agent against onchocerciasis.

The introduction of ivermectin therapy has proved to be the most important advance in the management and control of onchocerciaisis. By using the standard dosing schedule (150 micrograms/kg) in a mass chemotherapy campaign in Awhum, Nigeria, 128 (14.6%) of 875 eligible subjects used in this study were underdosed while 696 (79.6%) and 51 (5.8%) were overdosed and correctly dosed, respectively. Since underdosing is more serious than overdosing, an improved dosing schedule (300 micrograms/kg) is hereby suggested, bearing in mind that ivermectin is safe at doses well in excess of the standard dose. 824 (94.2%) And 51 (5.8%) of these eligible subjects would be overdosed and correctly dosed respectively, if this improved dosing schedule (< 15 kg, 0 mg (0 tablet); 15-20 kg, 6 mg (1 tablet); 21-40 kg, 12 mg (2 tablets); 41-60 kg, 18 mg (3 tablets); > 60 kg, 24 mg (4 tablets)) were to be employed. This dosing schedule is worth adopting and an investigation of the effects of these high single doses of ivermectin on adult Onchocerca volvolus worms is advocated. Furthermore 'non-responders' may be investigated for doses administered.

Simultaneous determination of chloroquine and metronidazole in human biological fluid by high pressure liquid chromatography.

Chloroquine (CQ) and metronidazole (MZ) were measured in human urine and plasma by HPLC with UV detection. This method was used to analyse plasma levels in 4 African volunteers after an oral dose of 1000 mg CQ and 750 mg MZ, in a European on weekly prophylaxis of 500 mg CQ, and on 50 hospital urine samples. In the Africans peak plasma levels were over 1 microgram/ml and peak time was 1 1/2-2 hr. In the European plasma levels ranged from 0.58 to 0.36 microgram/ml. Over 80% of the urine samples contained CQ, MZ or both. The assay system was found flexible and economical for the therapeutic monitoring of these two important tropical drugs.

Fleroxacin vs Ciprofloxacin in the Management of Typhoid Fever: A Randomised, Open, Comparative Study in Nigerian Patients.

OBJECTIVE: The antibacterial efficacy of fleroxacin was compared with that of ciprofloxacin in 72 adult Nigerian patients with typhoid fever. PATIENTS AND METHODS: On inclusion into the study, patients were randomised to treatment with either fleroxacin 400mg once daily for 7 days or ciprofloxacin 500mg twice daily for 14 days. Clinical evaluations were performed on days 0, 1, 2, 3, 5 and 7 or 14, and 2 weeks after treatment. Bacteriology was performed on days 0, 3, 7 or 14, and 21 or 28. Laboratory tolerability parameters were monitored for all patients as well as incidence of adverse events. RESULTS: Bacteriological response on day 3 was 93.5 and 64.0% for fleroxacin and ciprofloxacin, respectively. At term and follow-up there was bacteriological cure in 97.0% of patients with fleroxacin and 100% with ciprofloxacin. The clinical cure was 100% for both groups at term. The incidence of adverse events was 5.4% with fleroxacin and 2.8% with ciprofloxacin. CONCLUSION: The results demonstrated that while the clinical response rate with both drugs was comparable, fleroxacin exhibited a faster bacteriological clearance rate. We therefore concluded that 7 days' therapy with fleroxacin 400mg once daily was as effective as 14 days' therapy with ciprofloxacin 500mg given twice daily in the management of typhoid fever in Nigerian patients. It was also observed that the quinolones possessed greater potential and benefits as first-line therapy for the management of typhoid fever in this environment. The tolerability profile was good for both treatment regimens.

Influence of health education on community participation in rapid assessment of onchocerciasis prior to distribution of ivermectin.

OBJECTIVE: To investigate the impact of health education on community participation in the rapid assessment of onchocerciasis prior to distribution of ivermectin in Nigeria. DESIGN: There was health education with use of pictorial monographs to an adult population and school children in Umulumgbe and Okpatu communities, respectively. The school children in turn transferred the knowledge acquired to their parents through a health club, and a third community (Awhum) had no health education. Randomly selected subjects in each community were then assessed for their ability to recognise clinical manifestations of disease. SETTING: The study took place in three onchocerciasis-endemic, autonomous communities in Udi local government area of Enugu state in eastern Nigeria. SUBJECTS: Fifty, thirty seven, and thirty three male subjects, aged 20 years and above in Umulumgbe, Okpatu and Awhum respectively were involved in the study. RESULTS: 89.3%, 100% and 25.6% of the total number of onchocercal nodules were rightly indicated by the subjects in Umulumgbe, Okpatu and Awhum respectively. 100% of skin depigmentation was also reported in Umulumgbe and Okpatu each, and 50% in Awhum. Although some of the clinical manifestations (onchocercal nodules and skin depigmentation) were wrongly indicated, others (hanging groin and enlarged scrotum) were not reported by the subjects at all. CONCLUSION: This study clearly shows that health education is necessary for control programmes that are meant to be sustainable, especially the WHO-supported community-directed treatment with ivermectin (CDTI).

PIP: This article examines the impact of health education on community participation in the rapid assessment of onchocerciasis before distributing ivermectin in Nigeria. The study was conducted in three onchocerciasis-endemic areas of Nigeria--Awhum, Umulumgbe, and Okpatu--involving 33, 50, and 37 male subjects, respectively, in each community. A health education activity on onchocerciasis was conducted among the adult population and school children of Umulumgbe and Okpatu communities, after which, a rapid assessment of onchocerciasis was carried out. On the other hand, a rapid assessment was also conducted in Awhum in March 1995 before ivermectin distribution without prior health education. The study found that onchocercal nodules were more frequent in the lower part of the subject's body, especially around the pelvic region. Onchocercal nodules were indicated by 89.3% of the subjects in Umulumgbe, by 100% of the subjects in Okpatu, and by 25.6% of the subjects in Awhum. Skin pigmentation was also reported by 100% of the subjects in Umulumgbe and Okpatu and by 50% of the subjects in Awhum. The investigation discovered that some onchocercal nodules were incorrectly identified by the three communities, resulting in failure of reporting other clinical manifestations of the disease. Despite these limitations, researchers still feel that health education greatly influenced their knowledge on the parasitic disease.

Community financing of local ivermectin distribution in Nigeria: potential payment and cost-recovery outlook.

The preferred payment mechanism in a community financing scheme for local ivermectin distribution was elicited from randomly selected household heads from three communities in Nigeria using interviewer-administered structured questionnaires. The majority of the respondents in the three communities were prepared to pay for local ivermectin distribution. Additionally, the average amounts the respondents were prepared to pay per person treated ($0.28, $0.30 and $0.38 in Nike, Achi and Toro, respectively) were all more than the $0.20 ceiling recommended by the partners of the African Programme on Onchocerciasis Control (APOC). Thus, the cost-recovery outlook is bright in these communities. However, the preferred payment modality varied. Fee-for-service was the predominant payment modality in the Achi and Nike communities, while the Toro community preferred pre-payment. This study demonstrates that many communities have different payment preferences for endemic disease control efforts. This knowledge will help in developing acceptable and sustainable schemes. The imposition of unacceptable payment mechanisms will lead to an unwillingness to pay.

Interference by malaria in the diagnosis of typhoid using Widal test alone.

A total of 270 febrile patients (130 males and 140 females) aged between 15 and 59 were screened using thick and thin blood film stains for malaria, bacteriologic culture and Widal test for enteric fevers. Sixty (22%) were positive for malaria while 38 (14%) were positive for enteric fevers out of which 16 (26.6%) concomitantly had malaria parasite. Cases without malaria parasite (MP) or enteric fever organism were 172 (63.7%) and classified as pyrexia of unknown origin (PUO). Forty-four were strictly malaria cases out of which 36 (82%) were due to Plasmodium falciparum, and all had antibody Widal titres > or = 160 to 0 antigen while 4 (9%) were due to Plasmodium malariae, 3 (6.8%) were due to P. ovale and 1 (2.3%) was due to P. vivax. Twenty (52.6%) of the 38 patients with enteric fever had typhoid, all had Widal titres > or = 160 to 0 antigen. In all, antibody reaction Widal titres to H antigen were < 20. There was no statistical significant difference [chi2 = 327.2, P > 0.05] between Widal titres of malaria and typhoid cases. Hence using Widal test alone, one cannot differentiate typhoid fever from malaria. In another 250 healthy adults, of equal sex distribution, used as controls 12 (4.8%) had malaria parasite and 4 (1.6%) had enteric fever organisms. While only 4 (1.6%) gave Widal titre of 80 to 0 antigen the rest had antibody titres of < 20 to O antigen. Malaria could interfere with serological diagnosis of typhoid and hence lead to over diagnosis of typhoid in Nigeria.

Low-dose lisinopril in normotensive men with idiopathic oligospermia and infertility: a 5-year randomized, controlled, crossover pilot study.

The outcomes of drug treatment for male infertility remain conjectural, with controversial study results. Our pilot study employed a randomized, placebo-controlled, crossover methodology with intention-to-treat analysis. Thirty-three men with idiopathic oligospermia were randomized to start either daily oral lisinopril 2.5 mg (n = 17) or daily oral placebo (n = 16). Lisinopril was found to cause a normalization of seminal parameters in 53.6% of the participants. Although the mean ejaculate volume was unchanged (P ≥ 0.093), the total sperm cell count and the percentage of motile sperm cells increased (P ≤ 0.03 and P < 0.001, respectively), whereas the percentage of sperm cells with abnormal morphology decreased (P ≤ 0.04). The pregnancy rate was 48.5%, and there was no serious adverse drug event. It is concluded, albeit cautiously, that prolonged treatment with 2.5 mg/day of oral lisinopril may be well tolerated in normotensive men with idiopathic oligospermia, may improve sperm quantity and quality, and may enhance fertility in approximately half of those treated.