Efficacy of oxamniquine in treatment of S. mansoni in a closed community in Egypt and the concomitant administration of both metrifonate and oxamniquine in mixed infections.
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Schistosoma mansoni: effects of bromolysergic acid diethylamide, verapamil, and Ca2+-free solution on the motor activity of the isolated male worm induced by electrical stimulation and oxamniquine.
Electrical stimulation and oxamniquine effect the motor activity of isolated Schistosoma mansoni. Electrical stimulation produced contractions that increased with stimulus intensity. Oxamniquine (10(-4) M) produced an increase in basal tonus and in the frequency and amplitude of the worm's spontaneous contractions. Incubation in the absence of calcium produced a decrease in the basal tonus, abolished the spontaneous contractions of S. mansoni, and abolished the mechanical response induced by electrical stimulation and oxamniquine. The effects of electrical stimulation and oxamniquine were, respectively, significantly reduced and abolished by 10(-6) M verapamil (a calcium channel blocking agent). Bromolysergic acid diethylamide (3 X 10(-5) M), a serotonin blocking agent, reduced the motor response induced by high intensity electrical stimulation and blocked the response induced by oxamniquine. The effects of low intensity electrical stimulation were not modified in the presence of bromolysergic acid. We think that external Ca2+ is important for basal tonus, for spontaneous motor activity, and for motor responses of S. mansoni induced by electrical stimulation and oxamniquine. Serotonin may be important for mechanical responses induced by high intensity electrical stimulation and for responses induced by oxamniquine.
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Binding of oxamniquine to the DNA of schistosomes.
Hycanthone-sensitive and hycanthone-resistant schistosomes (which are also sensitive and resistant to oxamniquine) were exposed in vitro to tritium-labelled oxamniquine. The initial uptake of the drug into the schistosomes was essentially the same for the 2 strains. The homogenate of worms incubated with tritiated oxamniquine was fractionated and a purified DNA fraction was obtained by ethanol precipitation, RNAase and protease digestion, repeated phenolchloroform extractions, CsC1 gradient centrifugation and extensive dialysis. The DNA fraction from sensitive worms contained radioactive oxamniquine at a level corresponding to about 1 drug molecule per 50,000 base pairs, while the DNA from resistant worms contained essentially no drug. The results support the hypothesis that oxamniquine, like hycanthone, exerts its activity by alkylating macromolecules of sensitive schistosomes. The possibility is discussed that oxamniquine may lack the mutagenic properties of hycanthone because it is not an intercalating agent.
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Design, synthesis, and in vivo evaluation of oxamniquine methacrylate and acrylamide prodrugs.
Oxamniquine is an antiparasitic agent commonly used in therapeutics against Schistosoma mansoni. Although it is well tolerated, some adverse effects justify the search for new compounds with prolonged biological action, so that monomeric and polymeric oxamniquine prodrugs were designed. Synthetic results assisted by molecular modeling study showed the possibility to obtain the corresponding monomeric forms of the oxamniquine methacrylate (1) and oxamniquine acrylamide (2). Successful copolymerization procedure only occurred on the methacrylic compound, generating the oxamniquine methacrylate copolymer (3). Submitted to a preliminary in vivo biological evaluation, a similar oxamniquine profile was observed to the monomeric forms although an inadequate drug release may be responsible for the methacrylic copolymer failure.
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Effects of oxamniquine on chick isolated esophagus.
The effects of oxamniquine, a potent schistosomicide, on chick isolated esophagus have been examined. Oxamniquine (2.5 X 10(-8)-5 X 10(-5) M) caused rhythmic and tonic contractions of the chick isolated esophagus. The concentration of oxamniquine required to produce 50% of the maximal contractile response (EC50) was 4.2 X 10(-5) M. Pre-incubation of the muscle preparation with procaine (40-120, microM), scopolamine (0.40 microM) or indomethacin (10 microM) attenuated oxamniquine-induced myogenic contractions of the muscle preparation. It is suggested that inhibition of oxamniquine-induced contractions by indomethacin, scopolamine or procaine probably indicates that oxamniquine-induced contractions of the muscle preparation is due to the release of a prostaglandin-like substance and/or a yet unknown contractile compound from the muscle.
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Enzymatic basis for the lack of oxamniquine activity in Schistosoma haematobium infections.
The notion that oxamniquine is active against Schistosoma mansoni but inactive against S. haematobium was confirmed using in vitro cultures of adult worms. Since oxamniquine and hycanthone have been shown to become effective upon activation by a schistosome enzyme, enzymatic tests were carried out to detect possible differences between the enzyme of S. mansoni and that of S. haematobium. It was found that the S. mansoni enzyme could activate hycanthone and, to a lesser extent, oxamniquine. The S. haematobium enzyme, on the other hand, was capable of activating hycanthone but virtually incapable of activating oxamniquine. It is concluded that the different activity of oxamniquine in the two species is due to differences in the drug-activating enzyme.
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A double blind trial with oxamniquine in chronic schistosomiasis mansoni.
Ninety-one children with chronic schistosomiasis mansoni were selected for this double blind trial. 48 (Group 1) were treated with a single oral dose of oxamniquine (20mg/kg body-weight) and 43 (Group 2) received the placebo. Clinical, laboratory and radiological examinations were performed before and after treatment. Dark urine and vomiting were observed only in the oxamniquine group. Pulmonary condensations with or without air bronchogram were observed in the chest X-ray of 15% of Group 1 patients, between days 3 and 5 after treatment. In the urinalysis made on the first day after treatment, a false positive reaction was reported for urobilinogen and bilirubin in up to 50% of the patients treated with oxamniquine. In Group 1, 69.6% of the patients were cured. No patient was cured in Group 2. There was a 4.4% incidence of infection in the control group. There was a 77.9% egg excretion reduction in the 14 Group 1 patients not cured by oxamniquine. The authors conclude that oral oxamniquine in the prescribed dosage, has low toxicity and good therapeutic efficacy in children with chronic schistosomiasis mansoni.
Adolescent↗
Use of praziquantel in patients with schistosomiasis mansoni previously treated with oxamniquine and/or hycanthone: resistance of Schistosoma mansoni to schistosomicidal agents.
Fourteen patients with active schistosomiasis mansoni in spite of previous treatment with oxamniquine and/or hycanthone were treated with praziquantel, single oral dose of 45 to 50 mg/kg body-weight. All underwent clinical, laboratory and electrocardiographic examination before and after treatment. Untoward effects (dizziness, drowziness, nausea and abdominal pain) were observed in ten. Laboratory findings disclosed no significant alteration and the electrocardiograms showed no abnormalities. Monthly follow-up examinations of 13 patients for six consecutive months showed parasitological cure in all. Before praziquantel treatment strains of Schistosoma mansoni were isolated from two patients, one treated three times with oxamniquine and the other with hycanthone once and oxamniquine twice. Progenies of these strains were maintained in Biomphalaria glabrata and mice. Groups of these infected mice were then treated with oxamniquine, hycanthone, niridazole and praziquantel and results compared with the BH strain maintained in our laboratory for many years. Schistosomicidal activity was assessed by the localization of worms in the portal vein system and oogram changes. Progenies from the strains isolated in this study were resistant to oxamniquine and hycanthone but sensitive to niridazole and praziquantel. The BH strain was sensitive to all four drugs. The serial runs of S. mansoni strains through intermediate and definitive hosts have not influenced their reactions to these schistosomicides.
Adolescent↗
On the increase of portal pressure during the acute and chronic phases of murine schistosomiasis mansoni and its reversibility after treatment with oxamniquine.
The purpose of the present study was to evaluate the effect of treatment with oxamniquine on the portal pressure of mice infected with Schistosoma mansoni. The animals were infected with 30 cercariae and portal pressure was measured with a polygraph at 70 (acute phase) and 160 (chronic phase) days after infection. On days 70 and 160 two other groups of infected mice were treated with 400 mg/kg of oxamniquine and portal pressure was measured 90 days later (160 and 250 days after infection). A group of uninfected mice was used as control. The measured portal pressures, in mmHg, were: matched uninfected control mice 8.7+/-2.1 and acute phase group, measured at day 70, 13.4+/-3.5. Matched uninfected control 7.5+/-0.6 and chronic phase group, measured at day 160 post-infection, 11.6+/-1.5. Matched uninfected mice 6.9+/-0.9 and chronic phase group, measured at day 250, 10.4+/-1.8. Oxamniquine-treated at day 70 and measured at day 160 7.9+/-0.4; oxamniquine-treated at day 160 and measured at day 250, 7.6+/-1.7. The infection of mice with 30 cercariae of S. mansoni induced portal hypertension, both during the acute and chronic phases and treatment with oxamniquine caused portal pressure to return to normal levels.
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Comparison between the efficacy of oxamniquine and praziquantel in the treatment of Schistosoma mansoni infections on a sugar estate in Ethiopia.
The efficacy of the antischistosomal drugs praziquantel and oxamniquine was tested on four groups of Ethiopian sugar estate workers. The cure rates, determined by the absence of eggs in stools, were 96, 93 and 74% at one, three and six months post-treatment for patients receiving a single dose (40 mg kg-1 body weight) of praziquantel, and 82, 78 and 78% for patients on a single dose (15 mg kg-1 body weight) of oxamniquine. When split doses of these drugs were used, praziquantel achieved cure rates of 96, 95 and 89%, while the corresponding cure rates for oxamniquine were 98, 96 and 88% at one, three and six months post-treatment. In general, there were no statistically significant differences within the single and split doses of each drug, nor between the two drugs except that single doses of praziquantel had significantly higher cure rates than oxamniquine at one and three months post-treatment. Although both drugs produced mild and transient side-effects such as dizziness, abdominal discomfort and diarrhoea, serious side-effects such as seizures were seen only among patients on oxamniquine. As praziquantel is also effective against other forms of schistosomiasis as well as against cestodes, we recommended the use of this drug in mass chemotherapy and in the ambulatory treatment of schistosomiasis in Ethiopia.
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Evaluation of hepatic fibrosis after oxamniquine therapy of murine schistosomiasis.
Chemical and histological indices of liver fibrosis were measured after eight, 18 and 28 weeks in mice infected with Schistosoma mansoni and treated at eight weeks with oxamniquine, in mice infected with S. mansoni and not treated and in mice not infected with S. mansoni. Total worm burdens and liver egg counts were determined in the infected mice to determine severity of infection. Treatment with oxamniquine resulted in near total eradication of S. mansoni worms after 10 weeks and in their complete killing and marked reduction of eggs in the liver at 10 and 20 weeks. Liver fibrosis 10 weeks after oxamniquine treatment was not significantly different than in the untreated, infected group but there was no progression between 10 and 20 weeks after oxamniquine treatment. Fibrosis did however increase between 10 and 20 weeks in the untreated infected group. In the murine model, oxamniquine is an effective treatment for S. mansoni and prevents progression of liver fibrosis.
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Oxamniquine pharmacokinetics in hepatosplenic schistosomiasis in the Sudan.
Oxamniquine pharmacokinetics were determined in five normal Sudanese subjects and nine Sudanese patients with advanced hepatosplenic schistosomiasis, given 1 g as a single oral dose. There were no significant differences in oxamniquine mean area under the plasma concentration time curve (AUC), plasma half life (T1/2), or time to reach peak concentration (Tmax). However, patients had a 19% lower mean AUC, a 36% higher T1/2, and a 23% increase in Tmax. The peak concentration (Cmax) was 36% lower in patients (P = 0.04). There was no correlation between disease severity and oxamniquine pharmacokinetic values. A significant correlation between oxamniquine AUC and T1/2 suggests that its elimination may be non-linear. The higher dosage requirements for oxamniquine in the Sudan are unlikely to be due to lower plasma concentrations amongst the Sudanese.
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Efficacy of oxamniquine and praziquantel in the treatment of Schistosoma mansoni infection: a controlled trial.
OBJECTIVE: To evaluate the therapeutic efficacy of oxamniquine and praziquantel, the two most clinically important schistosomicide drugs, and to compare the accuracy of faecal examination with the accuracy of oogram in testing for Schistosoma mansoni infection. METHODS: In a triple-masked and randomized controlled trial, 106 patients infected with S. mansoni were randomly allocated to one of three statistically homogeneous groups. One group was given 60 mg/kg praziquantel per day for three consecutive days, another was given two daily doses of 10 mg/kg oxamniquine, and the placebo group received starch. Faecal examinations (days 15, 30, 60, 90, 120, 150, and 180 after treatment) and biopsy of rectal mucosa by quantitative oogram (days 30, 60, 120, and 180) were used for the initial diagnosis and for evaluating the degree of cure. The chi2 test and the Kruskal-Wallis test were used to compare variables in the three groups. Survival analysis (Kaplan-Meier) and the log-rank test were used to evaluate the efficacy of the treatments. FINDINGS: The sensitivity of stool examinations ranged from 88.9% to 94.4% when patients presented with >5000 S. mansoni eggs per gram of tissue (oogram); when the number of eggs dropped to <1000 eggs per gram, sensitivity was reduced (range, 22.7-34.0%). When cure was evaluated by stool examination, oxamniquine and praziquantel had cure rates of 90.3% and 100%, respectively. However, when the oogram was used as an indicator of sensitivity, the oxamniquine cure rate dropped dramatically (to 42.4%), whereas the rate for praziquantel remained high, at 96.1%. CONCLUSIONS: Praziquantel was significantly more effective than oxamniquine in treating S. mansoni infection. The oogram was markedly more sensitive than stool examinations in detecting S. mansoni eggs and should be recommended for use in clinical trials with schistosomicides.
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Effects of oxamniquine on neuromuscular transmission.
The effects of oxamniquine on neuromuscular transmission have been investigated in some experimental animals in an effort to unveil some of the unwanted effects of this commonly prescribed schistosomicide. Results obtained show that relatively low concentrations of the drug (oxamniquine, 10-100 micrograms/ml) potentiated acetylcholine-, carbachol- and nicotine-evoked contractions of the toad (Bufo regularis) isolated rectus abdominis muscle. Moderate to high concentrations of the compound (oxamniquine, 500 micrograms/ml and above) contracted rectus abdominis muscle preparations, and depressed indirect electrically-induced twitches of the rat isolated hemidiaphragm and chick isolated biventer muscle preparations. The depression of electrically-evoked twitches of the chick biventer and rat phrenic nerve-hemidiaphragm muscle preparations in vitro induced by moderate to high concentrations of oxamniquine (500 micrograms/ml and above) were resistant to bath-applied physostigmine (1-15 micrograms/ml), but deepened by d-tubocurarine (3-10 micrograms/ml). These findings suggest that the neuromuscular blocking action of oxamniquine is probably post-junctional in origin.
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High-performance liquid chromatographic resolution of oxamniquine enantiomers: application to in vitro metabolism studies.
A method is described for the HPLC analysis of oxamniquine enantiomers in liver fraction incubates, using a second-generation alpha 1-acid glycoprotein-based column (Chiral-AGP). Oxamniquine is extracted from the incubation media by liquid-liquid extraction, using diethyl ether. The dried residue is redissolved in eluent, filtered, then injected directly onto the analytical column. The extraction method affords recoveries of oxamniquine of approximately 93%, at concentrations up to 525 micrograms/ml, with an average relative standard deviation of 5.9%. The limit of detection of the method (to give an SNR = 2 at 246 nm) is 0.3 ng on-column for the first eluting, laevorotatory enantiomer and 2.3 ng for the dextrorotatory isomer. The method allowed study of the depletion of oxamniquine enantiomers in liver postmicrosomal incubates. In the rat, a turnover of 21.9% was observed, with no apparent enantioselectivity. Similar observations were made for a mouse liver subcellular fraction incubation. The absence of enantioselectivity in this biotransformation may be attributable to the low substrate specificity of the oxidase or dehydrogenase enzymes involved.
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Determination of oxamniquine in serum.
A method for the analysis of oxamniquine in serum (or plasma), sensitive to 10 ng/ml, was developed. Oxamniquine and a close structural analog as the internal standard were extracted from serum with ether. After derivatization with N,O-bis(trimethylsilyl)acetamide, oxamniquine was determined as its trimethylsilyl ether derivative by GLC using an electron-capture detector. The method was developed to study serum concentration profiles of different dosage forms of oxamniquine.
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Inhibition of in vitro RNA synthesis by hycanthone, oxamniquine and praziquantel.
The schistosomicides, hycanthone, oxamniquine and praziquantel, were found to inhibit the in vitro RNA synthesis using isolated hamster liver nuclei. Preincubation of the nuclei with these drugs revealed that the inhibitory effect of oxamniquine was irreversible and progressed with time, whereas that of hycanthone and praziquantel was reversible. On the other hand, hycanthone and praziquantel have a high affinity for DNA but oxamniquine does not. The data indicate that the mechanism of inhibition by oxamniquine is different from that of hycanthone and praziquantel.
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Pharmacokinetics of oxamniquine in rabbit and rat.
The pharmacokinetics of the schistosomicidal agent oxamniquine (6-hydroxmethyl-2-isopropylaminomethyl-7-nitro-1,2,3,4-tetra hydroquinoline) were studied in 8 (4 male, 4 female) New Zealand White rabbits and 5 female Wistar rats, following intravenous administration (15 mg/kg). The pharmacokinetic parameters (mean +/- SD) in the rabbit and rat, respectively, were as follows: plasma clearance, 65.5 +/- 33 and 17.2 +/- 5.7 ml/min/kg; steady-state volume of distribution, 7.9 +/- 4.5 and 2.1 +/- 0.5 l/kg; terminal elimination half-life, 1.8 +/- 0.3 and 1.8 +/- 0.9 h. Oxamniquine appeared to be widely distributed in both species, although significantly higher in the rabbit. Similarly, plasma clearance was significantly higher in the rabbit. Using reported estimates of liver blood flow and fractions excreted unchanged in urine of the rabbit and rat, calculations based on blood clearances indicated that oxamniquine has a low hepatic extraction ratio (0.2) in the rat and an intermediate hepatic extraction ratio (0.6) in the rabbit. From separate experiments, however, hepatic extraction appeared to be low in the rabbit, suggesting that oxamniquine disposition is probably broadly similar in both rabbit and rat.
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