Synthesis and pharmacological activity and some derivatives of 1-phenyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one.

4-N-Alkylamino derivatives and corresponding ammonium quaternary salts of tetrahydro-1,4-benzodiazepin-5-one were synthesized and evaluated for psychotropic activity in mice by ip via. This study was also extended to some nitro and amino derivatives of tetrahydro-1,4-benzodiazepin-5-one. Compounds were devoid of tranquilizing activity and in comparison with two classical benzodiazepines, chlordiazepoxide and diazepam, they showed high toxicity and little or no effect on motor coordination, motor activity, and maximal electroshock. On some "in vitro" tests the compounds exhibited pharmacological properties when they were used at high concentrations.     

Die anomalen Fusionsbewegungen: Der senso-motorische Aspekt des anomalen Binokularsehens

Zusammenfassung Es wurde nachgewiesen, daß bei konkomitierender Esotropie außer sensorischen Folgen auch senso-motorische Folgezustände vorkommen. Sie lassen sich vor allem mit Prismen nachweisen und werden als fusionsbedingt aufgefaßt (anomale Fusionsbewegungen).Bei 30 Patienten wurden die Eigenschaften dieser Vorgänge untersucht und erklärt. Schließlich wurde der Zusammenhang zwischen den anomalen Fusionsbewegungen und schon früher von anderen Autoren beschriebenen Krankheitsbildern analysiert, die je nach der ihnen zugrundegelegten Auffassung, unter verschiedenen Namen bekannt waren.

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Anomalous fusional movements: The sensorimotor aspect of anomalous binocular vision

Summary It has been demonstrated that, besides sensory adaptation phenomena, sensorimotor phenoma may also develop in concomitant esotropia. The existence of the latter entity can be shown particularly by means of prisms and is interpreted as fusional in origin. It is therefore defined as anomalous fusional movements.The features of these anomalous fusional movements were studied in a group of 30 patients, mainly in order to investigate their finality.Correlations were evaluated between anomalous fusional movements and entities previously described by different names according to the interpretation given them by various authors.

     

Influence of the H2-receptor blocking agent metiamide on the clonidine-induced changes in the brain catecholamine turnover

Summary Metiamide (800g intracerebroventricularly to rats) enhanced the DOPA accumulation in noradrenaline-predominant brain areas following DOPA decarboxylase inhibition and it accelerated the-methyltyrosine-induced disappearance of noradrenaline in the brain, both normally and after clonidine (0.1 mg/kg i.p.). These findings indicate that metiamide stimulates the release of noradrenaline. They can explain why metiamide antagonizes the clonidine-induced hypotension.     

Recent advances in the treatment of Parkinson's disease: The role of bromocriptine

Summary We have treated 102 Parkinson patients with bromocriptine for up to 6 years; most of these posed problems of management when referred to us. Forty-two continue to take bromocriptine, at a mean dose of 49 mg daily (range 10–160), in combination with some 50% of their previous optimal dose of levodopa (with or without a decarboxylase inhibitor). We consider the main indications for bromocriptine are severe dyskinesia, early morning dystonia, and wearing off reactions. Contraindications include hallucinations, delusions, substantial confusion, acute myocardial infarction, active peptic ulceration, and active pleuropulmonary disease.     

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system

We used a modified version of the popliteal lymph node assay in rats to investigate the immunosuppressive potential of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 10 months we conducted 3 experimental series. Animals were treated with single s.c. injections of TCDD and 7 days later human red blood cells (HRBC) were injected s.c. into the right hind footpad of the rat. Another 7 days later, both popliteal lymph nodes were prepared, weighed, the cell number was counted and the quotients (index) of these variables from the treated and the untreated side were determined. The doses applied in three experimental series were 600, 60, 6, 0.6, and 0.06 ng TCDD/kg body wt. In the first experimental series only the three highest doses were tested, in a second experimental series doses of 60, 6, 0.6, 0.06 ng TCDD/kg body wt were applied. Combining the results of these two experimental series, a statistically significant difference was found in the cell number index between the controls and the two highest doses tested (60 and 600 ng/kg body wt;p <0.01). This result was recently published as an abstract (Korte et al. 1990). However, with slight methodological changes in the third series of experiments (doses applied: 600, 60, 6, 0.6, and 0.06 ng TCDD/kg body wt) and using a greater number of animals we could not confirm these preliminary results. No difference was seen in the immune response to the antigen challenge in controls and in any of the treatment groups. We conclude that TCDD does not clearly influence the immune response as observed in the popliteal lymph node assay under our experimental conditions.     

Chlorpyrifos-induced delayed polyneuropathy

Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60–90 mg/kg p.o., corresponding to 4–6 times the estimated LD₅₀. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (>70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5–6 days. High AChE inhibition (>90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10–20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A-esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.Part of this work was presented at the 25th Annual Meeting of the Society of Toxicology held in New Orleans, LA, USA, March 1986, at the International Symposium on Biochemical and Cellular Indices of Toxicity in Occupational and Environmental Medicine held in Milan, Italy, June 1986, and at the 9th Meeting of the Peripheral Nerve Study Group, Praglia (PD), Italy, August – September, 1989     

Reduced cardiotoxicity of doxorubicin given in the form ofN-(2-hydroxypropyl) methacrylamide conjugates: an experimental study in the rat

Summary A rat model was used to evaluate the general acute toxicity and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of threeN-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg;P<0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was 12% lower than that measured in age-matched control rats (P<0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P<0.05). In addition, no significant histological change was observed in the hearts of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P<0.01). This study demonstrates that covalent binding of DOX to HPMA copolymer conjugates via both stable and biodegradable peptidyl linkages considerably reduces both the general acute toxicity and the late cardiotoxicity of DOX in the rat and could offer the potential for improving the therapeutic index in the clinical application of DOX.