Double-blind placebo-controlled study of concurrent administration of albendazole and praziquantel in schoolchildren with schistosomiasis and geohelminths.

A double-blind placebo-controlled study of the concurrent administration of albendazole and praziquantel was conducted in>1500 children with high prevalences of geohelminths and schistosomiasis. The study sites were in China and the Philippines, including 2 strains of Schistosoma japonicum, and 2 different regions of Kenya, 1 each with endemic Schistosoma mansoni or Schistosoma haematobium. Neither medication affected the cure rate of the other. There was no difference between the side effect rate from albendazole or the double placebo. Praziquantel-treated children had more nausea, abdominal pain, and headache but these side effects were statistically more common in children with schistosomiasis, suggesting a strong influence of dying parasites. The subjects were followed for 6 months for changes in infection status, growth parameters, hemoglobin, and schistosomiasis morbidity. In all 4 sites, a significant 6-month increase in serum hemoglobin was observed in children who received praziquantel, strongly supporting population-based mass treatment.

Efficacy of albendazole against Giardia and hookworm in a remote Aboriginal community in the north of Western Australia.

The parasitological, clinical efficacy and tolerability of albendazole in the treatment for both giardiasis and hookworm infection in a remote Aboriginal population was investigated. Albendazole at a dose rate of 400 mg daily for 5 days was highly effective in reducing hookworm egg numbers and both Giardia antigen and cysts. The 36.6% prevalence of Giardia prior to treatment fell to 12% between days 6 and 9, 15% for days 10-17 and rose to 28% between days 18 and 30. Tolerability and clinical efficacy were excellent. The effect of albendazole on hookworm was longer lasting than that on Giardia, reducing percent infection from over 76-2% on days 6-9 and zero by day 18-30 despite conditions highly conducive to rapid re-infection. We conclude that albendazole is highly efficacious against both parasites when used as described but that long term community benefit may require additional education programmes to avoid re-infection with Giardia although treatment strategies would seem appropriate for hookworm.

Albendazole in treatment of human cystic echinococcosis: 12 years of experience.

This review paper examines the evidence from published and previously unpublished sources for the efficacy and safety of albendazole (ABZ) obtained in the last 12 years. Benzimidazole treatment alone is not ideal, requiring prolonged administration over many weeks, with an unpredictable outcome in terms of response rates in individuals. However, studies have shown that treatment with albendazole in E. granulosus infection can result in an apparent cure in up to 30% of cases, with a further 40-50% showing objective evidence of response when followed in the short term. Some studies have demonstrated that even patients who do not show obvious initial evidence of response may be found to be cured when followed up over several years. Duration of therapy and dose are also important, and with ABZ, efficacy seems to increase with exposure up to 3 months in the commoner cyst sites. Formal dose ranging and minimal effective dose studies have not been performed, but the current dose of 800 mg daily appears to be adequate. The issue of cyclical versus continuous treatment still has to be resolved. Data on ABZ safety has been accumulated over the past 12 years of marketing. The profile shows that liver function abnormalities are common although rarely treatment limiting, while occasional hematological changes affecting the white cells may be more serious. The safety data supplies the rationale for monitoring of patients during treatment. On balance ABZ has been shown to be a useful advance in the management of cystic echinococcosis both when used as sole treatment or as an adjunct to surgery or other treatments.

Albendazole as a future antigiardial agent.

Albendazole, one of the more recently developed of the benzimidazole carbamate anthelmintics, has the broadest spectrum of activity of the benzimidazoles released to date. In this article, Jim Reynoldson, Andrew Thompson and John Horton discuss the role of this drug in the fight against giardiasis.

The treatment of falciparum malaria in children with halofantrine suspension.

Malaria treatment of children is particularly difficult because of the absence of palatable suspensions for young children. Halofantrine hydrochloride is available as a suspension which is both palatable and simple to administer, and has been studied in a number of trials in the past 5 years. Children (331) ranging from 4 months to 17 years of age (mean 4.7 years) were treated with the 5% suspension using various dose regimens and 364 children ranging from 4 months to 14 years of age (mean 5.7 years) were treated with the 2% suspension 6 hourly for 3 doses. Using the 3-dose regimen there were only 2/462 (0.4%) who failed to clear the initial parasitaemia. Recrudescence occurred in 28/367 (7.6%) children with evaluable follow up data. The mean parasite clearance time in this group was 57.1 h (n = 417) and the mean fever clearance time was 50.9 h (n = 325). Symptoms related to malaria cleared rapidly following treatment generally by 24-48 h post treatment. Side effects possibly related to treatment were uncommon but were similar to those reported in adults. The frequency of diarrhoea and abdominal pain was lower than that seen in adults and was also less frequent following multiple doses and the use of the more dilute suspension. Since there was evidence that the majority of recrudescences were seen in younger children or those living in areas with low or seasonal transmission it is recommended that a further course of treatment 7 days later is given to these patients to prevent recrudescence.(ABSTRACT TRUNCATED AT 250 WORDS)

The treatment of falciparum malaria in children with halofantrine suspension

Malaria treatment of children is particulary difficult because of the absence of palatable suspensions for young children. Halofantrine hydrochloride is available as a suspension which is both palatable and simple to administer, and has been studied in a number of trials in the past 5 years. Children (331) ranging from 4 months to 17 years of age (mean 4.7 years) were treated with the 5% suspension using various dose regimens and 364 children ranging from 4 months to 14 years of age (mean 5.7 years) were treated with the 2% suspension 6 hourly for 3 doses. Using the 3-dose regimen there were only 2/462 (0.4%) who failed to clear the initial parasitaemia. Recrudescence occurred in 28/367 (7.6%) children with evaluable follow up data. The mean parasite clearance time in this group was 57.1h (n = 417) and the mean fever clearance time was 50.9 h (n = 325). Symptoms related to malaria cleared rapidly following treatment generally by 24-48 h post treatment. Side effects possibly related to treatment were uncommon but were similar to those reported in adults. The frequency of diarrhoea and abdominal pain was lower than that seen in adults and was also less frequent following multiple doses and the use of the more dilute suspension. Since was evidence that the majority of recrudescences were seen in younger children or those living in areas with low or seasonal transmission it is recommended that a further course of treatment 7 days later is given to these patients to prevent recrudescence. Halofantrine suspension appears to be effective and well tolerated in children and is a useful addition to the drugs available for the treatment of paediatric malaria

Detection of Plasmodium falciparum infection with the fluorescent dye, benzothiocarboxypurine.

The fluorescent dye benzothiocarboxypurine (BCP) intensely stains nucleic acids. The dye does not penetrate viable white blood cells but does stain these cells following fixation. It has also been found that the dye stains the nucleic acid of viable Plasmodium falciparum. We have subsequently evaluated the staining of P. falciparum by benzothiocarboxypurine within red blood cells and have found that the red blood cell membrane is freely permeable to this dye and consequently P. falciparum is stained within the red blood cell. This finding prompted an in-depth analysis of the dye in the laboratory and in a field study as an alternative to Giemsa-stained blood smears and as a means of enhancing the microscopic diagnosis of malarial infection. In a field study the BCP dye allowed detection of malaria in fresh blood at a level equivalent to the Giemsa method (parasitemia ranged from 0.01% to 30%). The BCP staining procedure could also be used with fixed specimens although the differential staining characteristics were lost following specimen preparation. Of 111 blinded samples obtained in the field 22 were negative by Giemsa-stained thin smear, 16 were negative on thick smear and the same 16 were negative by BCP analysis. We have found that the BCP dye offers many advantages compared with the microscopic diagnosis of P. falciparum infection with standard Giemsa stains. These advantages are especially evident in conditions of low parasitemia, in the speed of staining and evaluation, and the relatively low level of training required to provide consistent results.

Morphine decreases LH secretion in ovariectomized ewes only after steroid priming and not by direct pituitary action.

To determine whether opiates directly modulate pituitary LH secretion in vivo, morphine was administered to hypothalamo-pituitary-disconnected (HPD) ewes which were receiving exogenous pulses of GnRH. To define the steroidal background which is permissive to a morphine-induced decrease in LH secretion, ovariectomized (OVX) ewes were treated as follows in groups of four: group 1, no implant; group 2, small 17 beta-estradiol (E2) (1 cm long x 0.33 diameter) and progesterone (P) implants; group 3, medium E2 (1 cm long x 0.46 diameter) and P implants, and group 4, medium E2 implants. Jugular blood samples were taken at 10-min intervals for 9 h, during which there was a 3-hour pretreatment period, a 3-hour treatment period when the sheep were given six intravenous injections of 10 mg morphine every 30 min, and a 3-hour run-off period. Morphine inhibited the mean plasma concentrations of LH and LH pulse frequency in group 3 only, and in 2/4 ewes in this group LH secretion was abolished and did not return to a pulsatile mode during the 3-hour run-off sampling period. In a second experiment designed to test the pituitary action of morphine, OVX-HPD ewes were primed with medium E2 and P implants and were given hourly pulses of 250 ng GnRH intravenously. Jugular blood samples were taken around each GnRH pulse over an 8-hour period. The first three pulses served as a control sampling period, after which the sheep were treated with morphine (six intravenous injections of 10 mg morphine every 30 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Investigation of the mechanism by which insulin-induced hypoglycemia decreases luteinizing hormone secretion in ovariectomized ewes.

Ovariectomized ewes were treated with 100 IU insulin, iv, which caused reductions in blood sugar and plasma LH concentrations. The effect was prevented by the infusion (iv) of glucose, suggesting that neuroglycopenia and not a direct action of insulin was the cause of reduced LH secretion. An iv infusion of naloxone (40 mg/h for 2 h), which commenced 25 min before the insulin injection, blocked the inhibitory effect of insulin on LH secretion, but it did not prevent the decrease in plasma glucose concentrations. In this treatment group and in a group treated only with naloxone, the opioid antagonist significantly stimulated LH secretion. To determine whether CRF might be involved in the insulin-induced decrease in LH secretion, 50 micrograms CRF were injected into ovariectomized sheep. Despite producing very high circulating concentrations of CRF within 2 min of injection and the stimulation of cortisol secretion during most of the 4-h posttreatment period, plasma LH levels were not affected. In addition, the intracerebroventricular administration of 10 micrograms CRF or 10 micrograms CRF plus 10 micrograms arginine vasopressin (AVP) did not affect LH secretion. These observations suggest that insulin-induced hypoglycemia decreased LH secretion by neuroglycopenia. This may involve an opioidergic mechanism, but does not involve activation of the hypothalamo-pituitary-adrenocortical axis.

Clinical experience with halofantrine in the treatment of malaria.

Halofantrine hydrochloride (HF) belongs to a new class of antimalarials, the phenanthrene methanols. Preliminary clinical studies suggested that an adult dose of 500 mg 6-hourly for three doses, with a weight-based regimen of 8 mg/kg 6-hourly for three doses in children, would be effective. In an ongoing clinical programme, 1973 patients with acute malaria were analysed, of whom 1474 (1315 with P. falciparum and 122 with P. vivax malaria) received the above regimen. In the studies 931 adults and older children were treated (61 with capsules and 870 with tablets) while 520 infants and young children used 5% or 2% suspension. The majority of studies were performed in areas of high chloroquine or multidrug resistance. Only eight (0.6%) of 1282 evaluable patients with falciparum malaria failed to clear their parasitaemias within 7 days. Recrudescence of parasitaemia occurred in 77 patients (6.0%). Reinfection cannot be excluded in several of the cases, where protection from malaria transmission was not maintained. The majority of recrudescent patients were either non-immune (normally residing in malaria-free areas) or were infants below 2 years of age. In vivax malaria cases, there were six recrudescences (5.4%). The mean parasite clearance time was 57.9 h and the fever clearance time 50.2 h in falciparum malaria cases, while the clearance times for vivax cases were 57.3 h and 49.6 h respectively. Clinical events were uncommon and consisted of mild transient diarrhoea or abdominal pain in less than 5% of cases. Laboratory findings were generally abnormalities related to the acute disease rather than drug treatment. Experience to date would indicate that HF is a safe and useful drug for the treatment of acute malaria, particularly in areas where there is extensive resistance to current antimalarials.

Seasonal and steroid-dependent effects on the modulation of LH secretion in the ewe by intracerebroventricularly administered beta-endorphin or naloxone.

The natural opioid ligand, beta-endorphin, and the opioid antagonist, naloxone, were administered intracerebroventricularly (i.c.v.) to evaluate effects on LH secretion in ovariectomized ewes and in ovariectomized ewes treated with oestradiol-17 beta plus progesterone either during the breeding season or the anoestrous season. Ovary-intact ewes were also studied during the follicular phase of the oestrous cycle. Jugular blood samples were taken at 10-min intervals for 8 h and either saline (20-50 microliters), 100 micrograms naloxone or 10 micrograms beta-endorphin were injected i.c.v. after 4 h. In addition, luteal phase ewes were injected i.c.v. with 25 micrograms beta-endorphin(1-27), a purported endogenous opioid antagonist. In ovariectomized ewes, irrespective of season, saline and naloxone did not affect LH secretion, but beta-endorphin decreased the plasma LH concentrations, by reducing LH pulse frequency. The effect of beta-endorphin was blocked by administering naloxone 30 min beforehand. Treating ovariectomized ewes with oestradiol-17 beta plus progesterone during the breeding season reduced plasma LH concentrations from 6-8 micrograms/l to less than 1 microgram/l. In these ewes, saline did not alter LH secretion, but naloxone increased LH pulse frequency and the plasma concentrations of LH within 15-20 min. During anoestrus, the combination of oestradiol-17 beta plus progesterone to ovariectomized ewes reduced the plasma LH concentrations from 3-5 micrograms/l to undetectable levels, and neither saline nor naloxone affected LH secretion. During the follicular phase of the oestrous cycle, naloxone enhanced LH pulse frequency, which resulted in increased plasma LH concentrations; saline had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemotherapy of Echinococcus infection in man with albendazole.

Since 1983 data have been collected on the outcome of treatment of apparently active Echinococcus granulosus hydatid cysts with albendazole. Most patients received 800 mg albendazole daily in cycles of 28 d with 14 d between cycles, with a mean duration of 2.5 cycles (range 1-12). From an initial set of over 500 cases, 253 patients were evaluated for efficacy, with 269 hepatic, 86 pulmonary, 50 peritoneal and 51 cysts at other sites being individually assessed. 72 patients (28.5%) were regarded as cured, 129 (51%) as improved, 46 (18.1%) as unchanged and 6 (2.4%) were worse. 47 patients underwent surgery after treatment and viability was demonstrated in only 5 cysts (10.6%). Recurrence was observed in 4 of 29 non-surgical cases (13.8%) from whom a follow-up of at least 24 months was available. 35 cases of E. multilocularis infection were assessed, with cure in 2, improvements in 4, stabilization in 25 and progression in 4 cases. Side effects of treatment were uncommon. Liver function abnormalities occurred in about 20% (4% withdrawn) and there was a tendency for leucopenia to occur in E. multilocularis patients. Albendazole appears to be effective both for chemotherapy in inoperable cases of hydatid disease and for prophylaxis before surgery.

Lack of an effect of morphine or naloxone on the oestrogen-induced LH surge in anoestrous ewes.

To determine whether opioid mechanisms modulate the positive feedback effect of oestrogen on LH secretion, anoestrous ewes were given a single injection of 50 micrograms oestradiol benzoate (OB), followed by infusions of morphine or naloxone. All sheep were injected i.m. with 50 micrograms OB at 00.00 h. In experiment 1, sheep were given i.v. infusions of the following: group 1, 12 ml saline/h from 09.00 to 15.00 h (n = 12); group 2, 40 mg naloxone/h from 09.00 to 12.00 h (n = 5); group 3, 40 mg naloxone/h from 10.00 to 14.00 h (n = 5); group 4, 10 mg morphine/h from 09.00 to 15.00 h (n = 5); and group 5, 20 mg morphine/h from 09.00 to 15.00 h (n = 5). Jugular blood samples were taken at 30-min intervals to monitor LH surges, which commenced 13.0 +/- 0.6 h after injection of OB in control (OB plus saline) ewes. The infusions of naloxone or morphine did not affect the timing or magnitude of the oestrogen-induced LH surge. To examine the possibility that opioidergic regulation of the LH surge occurred earlier than the infusion regimens in experiment 1, sheep were infused from the time of the OB injection (00.00 h) until 15.00 h. In this experiment (experiment 2), sheep were given i.v. infusions of the following: group 1, 4.2 ml saline/h (n = 5); group 2, 20 mg naloxone/h (n = 5); and group 3, 20 mg morphine/h (n = 5). As in experiment 1, treatment with neither the opioid agonist or antagonist was able to alter the positive feedback response of OB.(ABSTRACT TRUNCATED AT 250 WORDS)

Naloxone evokes large-amplitude GnRH pulses in luteal-phase ewes.

Ewes were sampled during the mid-late luteal phase of the oestrous cycle. Hypophysial portal and jugular venous blood samples were collected at 5-10 min intervals for a minimum of 3 h, before i.v. infusions of saline (12 ml/h; N = 6) or naloxone (40 mg/h; N = 6) for 2 h. During the 2-h saline infusion 2/6 sheep exhibited a GnRH/LH pulse; 3/6 saline infused ewes did not show a pulse during the 6-8-h portal blood sampling period. In contrast, large amplitude GnRH/LH pulses were observed during naloxone treatment in 5/6 ewes. The mean (+/- s.e.m.) amplitude of the LH secretory episodes during the naloxone infusion (1.07 +/- 0.11 ng/ml) was significantly (P less than 0.05) greater than that before the infusion in the same sheep (0.54 +/- 0.15 ng/ml). Naloxone significantly (P less than 0.005) increased the mean GnRH pulse amplitude in the 5/6 responding ewes from a pre-infusion value of 0.99 +/- 0.22 pg/min to 4.39 +/- 1.10 pg/min during infusion. This episodic GnRH secretory rate during naloxone treatment was also significantly (P less than 0.05) greater than in the saline-infused sheep (1.53 +/- 0.28 pg/min). Plasma FSH and prolactin concentrations did not change in response to the opiate antagonist. Perturbation of the endogenous opioid peptide system in the ewe by naloxone therefore increases the secretion of hypothalamic GnRH into the hypophysial portal vasculature. The response is characterized by a large-amplitude GnRH pulse which, in turn, causes a large-amplitude pulse of LH to be released by the pituitary gland.

Prolonged secretion of prolactin in response to thyrotrophin-releasing hormone after hypothalamo-pituitary disconnection in the ewe.

Surgical disconnection of the ovine hypothalamus from the pituitary gland (hypothalamo-pituitary disconnection; HPD) has provided a useful experimental model for studying the control of gonadotrophin secretion. The objective of the present study was to define the characteristics of prolactin secretion using stimuli acting through the hypothalamus or directly on the pituitary gland in HPD ewes. Prolactin responses to either a stressful stimulus or the dopaminergic antagonists metoclopramide (20 mg i.v.) or chlorpromazine (50 mg i.v.) seen in intact animals (sham-HPD) were completely abolished by HPD. Injection of TRH (100 micrograms i.v.) caused an immediate release of prolactin in both groups of ewes. In the HPD ewes plasma prolactin concentrations remained raised for at least 3 h after TRH injection, whereas in sham-HPD ewes prolactin concentrations began to decline after 20 min. Administration of bromocriptine (1 mg i.v.) 10 min after TRH inhibited the prolonged response to TRH in HPD ewes. The results support the hypothesis that prolactin exerts a short-loop feedback effect on its own secretion at the hypothalamic level.

Comparative safety and efficacy of auranofin and parenteral gold compounds: a review.

The comparative safety and efficacy of the orally active gold compound, auranofin, and parenteral gold compounds, principally gold sodium thiomalate, are reviewed. No difference in efficacy was detected in eight of the 12 published studies which compared auranofin and gold sodium thiomalate. Two studies favoured auranofin and two gold sodium thiomalate. Other parenteral gold compounds appeared more effective than auranofin. Adverse reactions and withdrawal rate from parenteral gold was found to be 2-3 times greater than from auranofin. Withdrawals due to inefficacy were found to be higher for auranofin than for parenteral gold although the incidence of inefficacy in the parenteral gold treated population was lower than that reported in other series. The nature of side effects from the two treatments was noticeably different; lower bowel symptoms with auranofin, and mucocutaneous lesions with parenteral gold compounds. Significant laboratory index changes were uncommon with both treatments, proteinuria being the most usual reason for withdrawal. Again the incidence of proteinuria and other laboratory abnormalities was less in the parenteral gold group than previously reported. Auranofin is possibly as effective and is definitely safer than parenteral gold compounds, and allows for longer periods of treatment.

The efficacy of histamine antagonists as antipruritics in experimentally induced pruritus.

1. The antipruritic ability of histamine (H1 and H2) antagonists alone and in combination in experimentally induced pruritus has been investigated in 12 normal human volunteers. 2. A combination of cimetidine (H2 anatagonist) and chlorpheniramine (H1 antagonist) proved effective in suppressing itch that was artificially induced by the application of papain and histamine. 3. The combination was more effective than chlorpheniramine or cimetidine alone or placebo. 4. The results suggest that both H1 and H2 receptors are involved in the mediation of pruritus.