Trichlorfon-induced haematological and biochemical changes in Cyprinus carpio: ameliorative effect of propolis.

Trichlorfon is among the most commonly used products to treat fish parasites in aquaculture. We investigated the effectiveness of propolis in alleviating the toxicity of trichlorfon on haematological and oxidant/antioxidant parameters in carp Cyprinus carpio. Fish were exposed to sublethal concentrations (11 and 22 mg l-1) of trichlorfon, and propolis (10 mg kg-1 of fish weight) was simultaneously administered. At the end of 14 d administration, blood and tissue (liver, kidney, gill) samples were collected. Haematological changes (red and white blood cell count, haemoglobin concentration, haematocrit level and erythrocyte indices: mean corpuscular volume, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration) were determined in the blood samples, while antioxidant parameters (malondialdehyde and reduced glutathione levels and superoxide dismutase, catalase and glutathione peroxidase activities) were evaluated in the liver, kidney and gill samples. Trichlorfon led to negative alterations in the haematological and antioxidant parameters investigated. The administration of propolis alleviated this effect and suggests that fish treated with trichlorfon improve their physiological status when fed a propolis-supplemented diet.

Metrifonate treatment of AD: influence of APOE genotype.

OBJECTIVE: To investigate whether an interaction exists between APOE genotype and the response of AD patients to metrifonate treatment and whether APOE genotype independently affects the rate of AD progression. BACKGROUND: Metrifonate is a new acetylcholinesterase inhibitor for the treatment of AD symptoms. METHODS: Data were pooled from four prospective, randomized, double-blind, placebo-controlled clinical trials and analyzed retrospectively. A total of 959 patients who received once-daily placebo (n = 374) or metrifonate (30 to 60 mg based on weight or a 50-mg fixed dose, n = 585) for up to 26 weeks agreed to APOE genotyping. RESULTS: Metrifonate clearly improved the cognitive performance of the AD patients when compared with placebo (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog], p = 0.0001). The interaction of APOE genotype and the metrifonate effect on cognitive performance were not significant (p = 0.25). Metrifonate also clearly improved the global function of the AD patients when compared with placebo (Clinician's Interview-Based Impression of Change with Caregiver Input [CIBIC-Plus], p = 0.0001). The interaction of APOE genotype with the metrifonate effect on global function also was not significant (p = 0.70). No significant three-way interactions were observed among APOE genotype, gender, and response to metrifonate treatment (ADAS-Cog, p = 0.68; CIBIC-Plus, p = 0.26). APOE genotype did not influence disease progression as evaluated by either cognitive performance (ADAS-Cog, p = 0.93) or global function (CIBIC-Plus, p = 0.64). CONCLUSIONS: The findings from these studies of up to 26 weeks' duration do not clearly support an interaction between APOE genotype and metrifonate treatment effects. They suggest that APOE genotypes do not necessarily predict an AD patient's response to metrifonate treatment and that APOE genotype may not influence the rate of disease progression for patients with mild to moderate AD.

Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease.

OBJECTIVE: To evaluate the efficacy and safety of metrifonate, an acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease (AD) of mild to moderate severity. METHODS: A prospective, 36-week, multicenter, double-blind, randomized, parallel group study of metrifonate in probable AD patients, including a 2-week screening period, a 26-week double-blind treatment period, and a follow-up visit at 8 weeks post-treatment. A total of 24 ambulatory clinics in the United States in a variety of settings, including contract research organizations, public health facilities, and universities. Patients met diagnostic criteria for probable AD as defined by the work group of the National Institute for Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association. Patients had Mini-Mental State Examination (MMSE) scores of 10 to 26 and Ischemic Scores (Rosen Modification) of <4. A total of 408 patients were enrolled. Percentages of patients completing double-blind treatment were 88% and 79% in the placebo and metrifonate groups, respectively. Rates of discontinuation due to adverse events were 4% in the placebo group and 12% in the metrifonate group. Placebo or metrifonate was administered once daily. Metrifonate-treated patients received a loading dose of 100 to 180 mg based on weight (2.0 mg/kg) for 2 weeks, followed by a maintenance dose of 30 to 60 mg based on weight (0.65 mg/kg) for 24 weeks. Primary efficacy variables were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-plus). Secondary efficacy variables included the Neuropsychiatric Inventory (NPI), the Disability Assessment in Dementia, the Global Deterioration Scale (GDS), the ADAS-Noncognitive subscale (ADAS-Noncog), the MMSE, and the Clinician's Interview-Based Impression of Severity with Caregiver Input (CIBIS-plus). Outcome measures reflected changes from baseline at week 26 for all variables. Safety was assessed with incidences of premature termination, treatment-emergent events and mortality, and routine safety evaluations. RESULTS: After 26 weeks of metrifonate therapy, a 2.86-point treatment difference (p = 0.0001) was observed in the ADAS-Cog scores of the intent-to-treat AD patients. The treatment difference in the mean CIBIC-plus score at this time was 0.28 points (p = 0.0071). At week 26, treatment differences also were observed in the mean NPI total score (p = 0.0161). Analysis of the remaining secondary efficacy variables showed treatment differences that favored metrifonate but did not reach statistical significance. Metrifonate adverse events were predominantly mild in intensity. No hepatotoxicity was observed. CONCLUSIONS: Metrifonate was safe and well-tolerated. It enhanced not only the cognitive and global function, but also the behavioral function of patients diagnosed with mild to moderate AD. Therefore, metrifonate appears to be useful in the symptomatic treatment of AD.

Physostigmine, tacrine and metrifonate: the effect of multiple doses on acetylcholine metabolism in rat brain.

The effects of two consecutive intramuscular doses of three cholinesterase inhibitors (physostigmine, tetrahydroaminoacridine and metrifonate) were compared in rats. The results revealed major differences in biochemical effects on the brain of the rat including the extent and duration of inhibition of cholinesterase, inhibition of release of acetylcholine and increase in levels of acetylcholine. Side effects were also markedly different in the time of appearance, duration and severity. These results suggest that there are significant differences in the mechanisms of action of various cholinesterase inhibitors. Since all three cholinesterase inhibitors are currently used in the experimental treatment of Alzheimer's disease, these findings have potential implications for the symptomatic therapy of these patients.

Formation of promutagenic methylation damage in tissue-DNA of mice treated with antischistosomal agents.

The existence of the promutagenic methylation damage O6-MedG has been measured at various time intervals in different tissue DNAs of mice received a single therapeutic dose of various antischistosomal agents (hycanthone, oxaminiquine and metrifonate). Liver-DNA exhibited the highest levels of O6-MedG in all treated animals while, spleen DNA contained the lowest. The three antischistosomal agents tested seemed to exert the peak concentrations of their alkylating metabolites over a period of several hours following the administration. In mice which had received hycanthone, liver-DNA contained readily detectable amounts of O6-MedG by 6 h post-treatment (0.089 mol O6-MedG/mol dG) and by the end of 48 h, this was decreased by about 3-fold to reach a level of 0.026 mumol/mol dG. In intestinal-DNA, however, O6-MedG was formed more slowly and contained about half the level of that found in the liver-DNA. In the tissue-DNA of animals which had received oxaminiquine, the highest level of O6-MedG was observed at 6 h after administration and at a 24-h time point, the adduct dramatically decreased in the liver and intestine-DNA to undetectable values. In neither tissues was there any evidence for O6-MedG accumulation in the DNA at the end of a 48-h post-treatment. A pattern of O6-MedG, almost similar to that of oxaminiquine, was also observed in tissue-DNA of mice pretreated with metrifonate. These results demonstrate that treatment with antischistosomal agents leads to the formation of highly promutagenic alkylated lesions in the tissue-DNA. The implication of such existence for antischistosomal-induced toxicity and carcinogenicity are discussed.

The effects of metrifonate on the cognitive, behavioral, and functional performance of Alzheimer's disease patients. Metrifonate Study Group.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of metrifonate, a long-acting acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease of mild-to-moderate severity. METHOD: This was a prospective, multicenter, 26-week, double-blind, parallel group study. The 264 randomized patients met diagnostic criteria of the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association for probable Alzheimer's disease. Patients had Mini-Mental State Examination (MMSE) scores of 10-26 and ischemic scores (Rosen modification) of <4. Metrifonate-treated patients received a single 50-mg dose once daily. The efficacy of metrifonate was investigated with respect to 3 symptom domains. Cognitive performance was analyzed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the MMSE. Psychiatric and behavioral disturbances were analyzed using the Neuropsychiatric Inventory (NPI) and the ADAS-Noncognitive subscale (ADAS-Noncog). The ability to perform instrumental and basic activities of daily living was evaluated using the Disability Assessment for Dementia (DAD) scale. Additionally, global state was assessed using the Clinician Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus) scale. RESULTS: After 26 weeks of metrifonate therapy, a statistically significant benefit of metrifonate was observed in the cognitive performance of Alzheimer's disease patients (ADAS-Cog, t = 2.55, df = 237, p = .012; MMSE, t = 4.60, df = 237, p = .0001). Metrifonate also significantly attenuated the deterioration in activities of daily living of the patients (DAD total score, t = -2.11, df = 233, p = .036) and relieved patients' psychiatric and behavioral disturbances (NPI total score, t = 2.51, df = 233, p = .013). In addition, metrifonate significantly improved the scores for the global state of the patients (CIBIC-Plus, t = 2.07, df = 232, p = .039). Metrifonate was well tolerated; adverse events were predominantly mild in intensity, and no hepatotoxicity was observed. CONCLUSION: In this study, metrifonate was safe and well tolerated. It benefited the cognitive decline, psychiatric and behavioral disturbances, impaired ability to perform instrumental and basic activities of daily living, and global state of patients diagnosed with mild-to-moderate Alzheimer's disease.

Efficacy and safety of a loading-dose regimen versus a no-loading-dose regimen of metrifonate in the symptomatic treatment of Alzheimer's disease: a randomized, double-masked, placebo-controlled trial. Metrifonate Study Group.

This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to-moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 of 2 regimens. The loading-dose group (n = 133) received a daily loading dose of metrifonate 100 mg or 150 mg (by weight) for 2 weeks, followed by a daily maintenance dose of metrifonate 50 mg for 4 weeks; the no-loading-dose group (n = 128) received the daily maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS-Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading-dose regimen versus the loading-dose regimen observed in this study, the no-loading-dose regimen appears to be the better strategy for initiating metrifonate treatment in patients with probable AD of mild-to-moderate severity.

Metrifonate: overview of safety and efficacy.

Metrifonate is a cholinesterase inhibitor with a long-lasting inhibition that raises brain acetylcholine levels. It is well-absorbed and has limited binding to serum proteins. In preliminary studies of its utility in the treatment of Alzheimer disease's (AD), it led to improvements of cognition or reduced the rate of decline of cognition compared with placebo. It also benefited the global function of these patients. Side effects include nausea, cramping, and diarrhea. Metrifonate has promise as a well-tolerated treatment of the symptoms of AD.

Seizures in patients receiving concomitant antimuscarinics and acetylcholinesterase inhibitor.

Seizures occurred in two patients with probable Alzheimer's disease who were receiving long-term treatment with metrifonate, an irreversible acetylcholinesterase inhibitor. In both patients seizures were associated with discontinuation of short-term agents with high antimuscarinic properties. Hence, abrupt discontinuation of antimuscarinics or anticholinergics with high antimuscarinic properties in patients receiving long-term acetylcholinesterase inhibition therapy may be associated with a reduction of seizure threshold. With increasing administration of acetylcholinesterase inhibitors for patients with Alzheimer's disease, practitioners should be aware of the potential for drug-drug interactions and other complications. In general, it is good medical practice to avoid concomitant administration with centrally acting anticholinergic agents.

Preclinical pharmacology of metrifonate.

Alzheimer's disease is a chronic neurodegenerative disorder that is characterized by memory impairment, cognitive dysfunction, behavioral disturbances, and deficits in activities of daily living. A consistent observation in these patients is that cholinergic neurons are affected and deteriorate over time, leading to decreased levels of acetylcholine (ACh). Acetylcholinesterase (AChE) inhibitors, which attempt to prevent the breakdown of ACh, may be classified as short acting, intermediate acting, and long acting based on AChE regeneration time. Metrifonate is converted by a nonenzymatic process to the long-acting cholinesterase inhibitor 2,2-dichlorovinyl dimethyl phosphate (DDVP). Acetylcholinesterase inhibition produced by metrifonate occurs rapidly, is dose dependent, can be detected by inhibition measured in red blood cells, and can be reversed by oxime administration. Metrifonate and DDVP improved performance in young rats; cognitive improvement in aged rats also was observed. Both agents were well tolerated and did not have significant effects on various preclinical pharmacologic safety tests.

Safety and tolerability of metrifonate in patients with Alzheimer's disease: results of a maximum tolerated dose study.

Metrifonate, a pro-drug that is transformed non-enzymatically into a potent inhibitor of acetylcholinesterase (AChE), has been used in the tropics for over 30 years for the treatment of schistosomiasis. A pilot study, and Phase I and Phase II studies of metrifonate in Alzheimer's disease (AD) patients conducted prior to the current study showed benign, dose-dependent adverse event profiles consisting primarily of gastrointestinal events, optimal daily dosing with a loading phase (in the absence of a loading dose phase, 6-8 weeks were required to attain steady-state AChE inhibition levels), and an improvement in Alzheimer's Disease Assessment Scale (ADAS) scores. The current open-label study was designed to evaluate the safety and tolerability of relatively high loading doses, followed by lower maintenance doses of metrifonate in the same patient population, and to determine the maximum tolerated dose (MTD) of metrifonate. Accordingly, the first cohort of 8 probable AD patients (per National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criteria) were administered once-daily loading doses of 2.5 mg/kg (125-225 mg) for 14 days, followed by 4.0 mg/kg (200-360 mg) for an additional 3 days. These patients were maintained on once-daily doses of 2.0 mg/kg (100-180 mg) for 14 days. AChE inhibition for this cohort ranged from 88% to 94%. On Day 28 of 31, this cohort was discontinued due to moderate to severe side effects in 6 patients; consequently, the second cohort of 8 probable AD patients received a once-daily loading dose of 2.5 mg/kg (125-225 mg) for 14 days followed by a once-daily maintenance dose of 1.5 mg/kg (75-135 mg) for 35 days. This maintenance dose yielded an AChE inhibition level ranging from 89% to 91%. In spite of an AChE inhibition level comparable to that achieved with the higher dose, the reduced dose was associated with a more favorable adverse event profile which was mainly gastrointestinal and musculoskeletal in nature. The maximum tolerated dose was established at 1.5 mg/kg/day (75-135 mg/day) for maintenance dosing in AD patients.

Metrifonate enhances the ability of Alzheimer's disease patients to initiate, organize, and execute instrumental and basic activities of daily living.

The objective of this analysis was to evaluate comprehensively the efficacy of metrifonate, a long-acting acetylcholinesterase inhibitor, in improving the ability of mild-to-moderate Alzheimer's disease (AD) patients to perform activities of daily living (ADLs). Alzheimer's disease patients with Mini-Mental State Examination scores of 10 to 26 were enrolled in three 26-week trials to receive once-daily placebo (n = 430) or metrifonate 30 to 60 mg (by weight, n = 650) or 60/80 mg (by weight, n = 197). Metrifonate efficacy was assessed using the Disability Assessment for Dementia scale. Data from the three studies were pooled and analyzed retrospectively. The intent-to-treat analysis (last observation carried forward) at 26 weeks demonstrated that metrifonate significantly improved the ability of AD patients to perform ADLs when compared with placebo (30-60 mg dose, delta = 3.03; P = .002; 60/80 mg dose, delta = 5.25; P = .0002). Metrifonate significantly improved the ability of the AD patients to perform instrumental ADLs, those abilities typically lost first during the disease process (30-60 mg dose, delta = 3.88, P = .002; 60/80 mg dose, delta = 5.79, P = .003). Metrifonate also tended to improve, relative to placebo, the ability of AD patients to use three levels of executive skills when performing ADLs: initiation (30-60 mg dose, delta = 3.45, P = .001; 60/80 mg dose, delta = 5.44, P = .003), planning/organization (30-60 mg dose, delta = 4.50, P = .004; 60/80 mg dose, delta = 4.89, P = .014), and effective execution (30-60 mg dose, delta = 1.80, P = .076; 60/80 mg dose, delta = 4.06, P = .030). These results indicate that metrifonate has a beneficial effect on the ADLs in mild-to-moderate AD patients.

The effect of food and time of administration on the pharmacokinetic and pharmacodynamic profile of metrifonate.

OBJECTIVE: Metrifonate--via its pharmacologically active metabolite DDVP--is an inhibitor of cholinesterase effective in the treatment of Alzheimer's disease. Two separate studies were performed to investigate the influence of food and time of administration, respectively, on the concentration vs. time profiles of metrifonate and DDVP and cholinesterase inhibition. METHODS: In study I, a single dose of metrifonate 50 mg tablet was administered either in the fasting condition or within 5 min after completion of an American breakfast. In study II, a single dose of metrifonate 80 mg tablet was given either at 8:00 a.m. after overnight fasting, 7:00 p.m. (7 h after lunch) or 10:00 p.m. (4 h after dinner). Both studies were performed in a non-blind, randomized, single-centre, cross-over design in healthy Caucasian volunteers. AUC and Cmax of metrifonate and DDVP as primary parameters were compared between treatments by ANOVA and acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition vs. time profiles were assessed. RESULTS: In study I a high-fat/high-calorie breakfast had no effect on the AUC of DDVP, while its Cmax was decreased to 56% and tmax was prolonged, compared to the fasting condition. The effects on metrifonate were similar. In study II bioequivalence was shown for AUC and Cmax of DDVP when comparing administration of metrifonate at 8:00 a.m. and 7:00 p.m. Administration at 10:00 p.m. also had no effect on AUC of DDVP while a reduction in rate of absorption was observed. In both studies the equivalence in AUC of DDVP was paralleled by equivalent effects on BChE inhibition. Following single metrifonate administration little inhibition of AChE was observed. Metrifonate was well tolerated. CONCLUSIONS: Delayed gastric emptying is likely to cause the reduced rate of absorption of metrifonate with food. In view of unchanged bioavailability of its active metabolite, this food effect is considered to be without clinical relevance and metrifonate can be administered with or without food. The decrease in rate of absorption following administration of the drug at 10:00 p.m. is either a protracted food effect or an effect of time. As the bioavailability of DDVP as well as pharmacodynamic profiles were independent of the time of administration it is concluded that metrifonate can be taken in the morning or evening without compromising its safety or efficacy.

Metrifonate: a new agent for the treatment of Alzheimer's disease.

The pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of metrifonate, a long-acting cholinesterase inhibitor, are discussed. Attempts to correct the central cholinergic deficits associated with Alzheimer's disease have included administration of cholinergic precursors, cholinergic agonists, and cholinesterase inhibitors. To date, two reversible cholinesterase inhibitors-tacrine and donepezil-have been marketed. Metrifonate, an organophosphate, is converted nonenzymatically to 2,2-dichlorovinyl dimethyl phosphate (DDVP), the active enzyme inhibitor. DDVP produces irreversible inhibition of brain cholinesterase that lasts for several days; enzyme recovery is dependent on synthesis of new enzyme. Several preclinical studies have demonstrated cognition-enhancing effects of metrifonate in animals. Trials in humans have shown improvement on the Alzheimer's Disease Assessment Scale, in Mini-Mental State Examination scores, and in the Clinician's Interview-Based Impression of Change with caregiver input. Clinical improvement noted with metrifonate appears similar to that seen with other cholinesterase inhibitors. Adverse effects noted in clinical trials have been associated primarily with the gastrointestinal tract and have been mild. Metrifonate appears to be a promising agent for the treatment of the symptoms of Alzheimer's disease.

Redescription of Argulus melanostictus (Branchiura: Argulidae), a parasite of California grunion (Leuresthes tenuis: Atherinidae), with notes regarding chemical control of A. melanostictus in a captive host population.

Adult male and female Argulus melanostictus Wilson, 1935 are redescribed based on detailed examinations of a syntype and recently obtained specimens of both sexes collected from California grunion, Leuresthes tenuis, captured in nearshore Pacific waters at Monterey, California. A 14-16-hr seawater bath containing 0.5 microliter/L trichlorfon administered once weekly for 3 wk killed A. melanostictus while not noticeably harming grunion.

Critical test and safety evaluations of an oral paste preparation of mebendazole and trichlorfon in horses.

Critical tests were done on 24 naturally parasitized horses to compare the antiparasitic activity of an oral paste preparation of mebendazole and trichlorfon with that of the marketed powder formulation. Each formulation was administered at the recommended dosages of 8.8 mg of mebendazole and 40 mg of trichlorfon/kg of body weight. Efficacy of the paste formulation ranged from 97.7% to 100% against 2nd- and 3rd-stage Gasterophilus spp, adult Strongylus vulgaris, S edentatus, Parascaris equorum, small strongyles; and larval and adult forms of Oxyuris equi. Adverse effects were generally limited to slight softening of the feces. Mild and transient restlessness or sweating were also observed in 2 of 12 horses treated with the paste formulation. The toxic effects of the paste, administered at 2.2 times the therapeutic dose, were examined in 6 horses and compared with the effects of a nonmedicated paste, administered in similar volumes to 6 other horses. Drug-related changes were not detected in clinical chemical analyses, hematologic values, or liver function tests. Transient clinical signs of organophosphate toxicosis (primarily the passage of loose feces) and prolonged inhibition of erythrocyte cholinesterase activity were evident within 1 hour after drug treatment. These effects were similar to those reported for the 2.2 X dose of marketed powder formulation.

Using the Hungarian Birth Defects Registry for surveillance, research and intervention.

The Hungarian Congenital Abnormality Registry (HCAR) was established in 1962 due to the growing public health importance of congenital abnormalities (CAs). The HCAR is a population-based registry; it collects and keeps permanent records of medical and personal information about malformed newborns and infants (notification of CAs Is mandatory for physicians) in order to develop baseline data for different types of CAs, to search for increases in the incidence of specific CAs, to provide rates, and identify geographic areas of concern for cluster investigation. In the last 25 years numerous studies have been carried out. In the 1970s two significant increases were noticed: i) in the rate of terminal transverse type of limb reduction defects and ii) in the rate of hypospadias. As a result of our epidemiological investigations and case-control studies we were able to identify the possible factors which caused these increases. In the first case, for example, the Ministry of Health changed the policy of using high oestrogens dosage (which increased the risk of this defect 6.1 times) for artificial abortions in 1978 and after this time the increase was stopped. In 1989-1990 a geographical cluster was found. An extremely high rate of cases with Down's syndrome (27%) was identified in a small village and the case-control study and environmental investigations pointed suspicion on the excessive use of a chemical, trichlorfon at local fish farms. All mothers of babies with Down's syndrome had consumed contaminated fish during critical period. The use of this chemical was prohibited and no CAs were recorded after this time at this place. A special case-control surveillance system has been operating since 1980 in Hungary based on the HCAR. The objective of this system is to obtain information on pregnancy exposures and other risk factors for the study and identification of causes of CAs. The teratogenicity of several drugs taken during pregnancy has been examined so far, most of them ended up with negative results. Our system is suitable for surveillance, research and intervention.

[Twenty-years health surveillance of workers in dipterex packaging].

Data of health surveillance from 1970 to 1989 for the workers employed in dipterex packaging were collected and statistically analyzed with a microcomputer by scoring their whole blood choline esterase activities and symptoms and signs. Results showed working environment improved and air pollution and absorption of pollutants via skin decreased with technology innovation and longterm hygienic supervision, monitoring and health surveillance in the factory. Incidence of dipterex poisoning in workers employed in the department of pesticide packaging lowered significantly, from 25.26% in the early 1970's to 5.17% in late 1970's and to 1.85% during 1980's, with periodical physical examinations for them, and timely management of the patients with poisoning and the cases at high risk.

Aggravation of experimental allergic conjunctivitis by environmental chemical and physical factors.

The effects of trichlorfon (DEP, Dipterex, anticholinesterase pesticide) and paraquat dichloride (Gramoxon, inhibitor of superoxide dismutase) on passive anaphylactic reaction in guinea pig conjunctiva using Japanese cedar pollen were quantitatively studied. For estimation of allergic conjunctivitis, Evans blue after i.v. injection was extracted from conjunctiva and measured spectrophotometrically. Allergic conjunctivitis was apparently aggravated by extremely low dosages of organophosphorus pesticide (10(-5) mg/kg) and organochlorine herbicide (10(-4) mg/kg). The aggravation of allergic conjunctivitis was also observed after exposure to cathode ray tubes used in commercial television, possibly due to electromagnetic waves. IgE-mediated allergic reaction could be non-specifically potentiated by such environmental factors.

[Treatment of drug resistant scabies]. / Tratamineto del enfermo escabiósico resistente a los medicamentos

Thirty patients suffering from scabies who had previonsly received other kinds of treatment were administered "Metrifonate" at daily doses of 10 mg./kg. b.w. during two consecutive days repeated every week and associated with atropine sulfate. The number of weeks lapse until the treatment finished was as follows. (see article.) Four patients developed intolerance, but it was transitory (nausea and vomiting). Cures (skin lesions and prutitus) were obtaind in 29 our of 30 cases.