Drug repurposing: small molecules against Cu(II)-amyloid-ß and free radicals.

Alzheimer's disease (AD) presents a complex pathology entangling numerous pathological factors, including amyloid-ß (Aß), metal ions, and reactive oxygen species (ROS). Increasing evidence reveals pathological connections among these distinct components in AD. For instance, the association between the amyloid cascade and metal ion hypotheses has introduced a novel pathogenic target: metal-bound Aß. Investigation of such interconnections requires substantial research and can be expedited by chemical reagents that are able to modify multiple pathogenic factors in AD. Drug repurposing is an efficient approach for rediscovering previously utilized molecules with desirable biological and pharmaceutical properties as chemical reagents. Herein, we report the evaluation of three pre-approved drug molecules, selected based on their chemical structure and properties, as chemical reagents that can be used for elucidating the complicated pathology of AD.

Serendipity and psychopharmacology.

This article describes several examples where the development of drugs and devices for use in psychiatry followed from initial serendipitous observations. The potential psychotropic properties of chlorpromazine (Thorazine(®)) were first noted in surgical patients when the drug was being investigated as a potentiator of anesthesia. Similar findings were noted with iproniazid (Marsilid(®)), developed for the treatment of tuberculosis, and the drug was later released for clinical use as an antidepressant agent. The development of meprobamate (Miltown(®)), an approved treatment for anxiety, evolved from initial efforts to find a chemical that would inhibit the enzymatic destruction of the antibiotic drug penicillin. The psychiatric uses of lamotrigine (Lamictal(®)) and vagus nerve stimulation were prompted by initial observations that epilepsy patients receiving these treatments had positive mood effects. Nurses should be familiar with the concept of serendipity, as they often are in the best position to observe, record, and report on unexpected clinical effects in patients taking any kind of prescription or nonprescription medication.

A comparative trial of a MAOI, iproniazide, and a polycyclic agent, mianserine, for the search of the most rapidly and frequently active treatment of depressive syndromes in an oncology service.

Many cancer patients of the "Service des Maladies Sanguines et Tumorales" of Hôpital Paul-Brousse, Villejuif, are psychologically studied by: the objective and quantified Szondi test, and in the case a depressive syndrome clinical diagnosis is confirmed, this state is quantified by a quintile questionnaire requiring 25 "yes or no" answers (determined by five grades and five stages), in case an inhibition or/and hysteric component is found, the subjects are submitted to the care of a psychoanalyst. A comparative trial of the MAOI, iproniazide, and the tetracyclic analog, mianserine, has been conducted for the search of the most frequently and rapidly active antidepressant agent among them both. The hypothesis that mianserine is less frequently and rapidly active than iproniazide was drawn from our previous experience of 20 years: thus patients presenting a score less than or equal to 12/25 were given mianserine (20 up to 30 mg/day to be possibly increased according to medical decision), while those presenting a score greater than or equal to 13/25 received iproniazide (50 up to 75 mg/day). The patients who failed with mianserine received iproniazide, while those who failed with iproniazide were supposed to receive mianserine. The registered results are the following: a) out of the 25 patients with major depressive syndromes (score greater than or equal to 13) submitted to iproniazide, 16 (61%) were in complete remission (score at 0/25) and five in partial regression (score decreased by more than half); this makes 21 responses in all, i.e. 80%, obtained between the 10th and the 30th days, which is superior to all placebo responses which have varied in the reliable literature from 13 to 70%; b) out of 18 depressive patients submitted to mianserine, only one had benefited of a complete remission and four of a partial regression at the 30th day, which makes 28% responses. Among the side effects of iproniazide, they were two colon meteorism syndromes, easily corrected by prostigmine, five hyposomnia cases corrected by dipotassium chlorazepate, four anejaculation or delay at ejaculation cases which needed eserine when the patients require their disappearance or attenuation. We did not register either hepatic or hyperthermic or hypertensive complications: this is in good agreement with the true incidences, especially that of hypertensive crisis which could be found in serious and scientifically documented articles, to be 0.3 to 0.5% for their appearance, and 1 per 100,000 for their fatal evolution. Among the side effects of mianserine, we have not registered any of the hepatic, renal and cardiac complications mentioned in the literature.(ABSTRACT TRUNCATED AT 400 WORDS)

Monoamine oxidase inhibitors and alprazolam in the treatment of panic disorder and agoraphobia.

This article reviews the evidence on the efficacy of monoamine oxidase inhibitors (MAOIs) and of alprazolam in the treatment of panic disorder and agoraphobia. It also presents guidelines to the clinician on how to implement these treatments in practice.

[Action of adrenergic substances on the healing of experimental neurogenic mucosal damages and on the noradrenaline level in the stomach wall]. / Deistvie nekotorykh adrenergicheskikh veshchestv na zazhivlenie éksperimental'nykh neirogennykh povrezhdenii slizistoi i uroven' noradrenalina v stenke zheludka.

A study was made of the effect of the MAO inhibitor iprazide (50 mg/kg), alpha-methyldopa (150 mg/kg), and the beta-adrenoblocker inderal (15 mg/kg) on the rate of the healing of gastric mucosa erosions and noradrenaline content in the gastric wall of rats exposed to 3 hours of electric stimulation and immobilization. Iprazide accelerated the reparation of the gastric mucosa, alpha-methyldopa retarded it, whereas inderal did not influence that process. The drugs did not affect the rate of the recovery of noradrenaline content.

[Plea for monoamine oxidase inhibitors. Retrospective study of 350 cases]. / Plaidoyer pour les inhibiteurs de la monoamine-oxydase. Etude rétrospective de 350 observations.

The case-records of 350 outpatients treated with monoamine oxidase inhibitors have been reviewed. All patients presented with depression, obsessions or phobias. About two-thirds benefited from the drugs, particularly after other treatments (including psychotropic drugs, seismotherapy, psychotherapy and internment) had failed. With the moderate doses administered (iproniazide: 50 mg/day; nialamide: 100 mg/day) side-effects were uncommon and mild and no incident was noted in 32 general anaesthesias given for surgical operations. These findings should help in lifting the ban on this category of drugs. Monoamine oxidase inhibitors are effective, useful and sometimes indispensable after failure of other antidepressants.

Monoamine oxidase inhibitors as anti-depressant drugs and as adjunct to L-dopa therapy of Parkinson's disease.

Monoamine oxidase inhibitors have been used in psychiatric disorders for many years. However, due to the toxic side effects of the drugs they are often replaced by the tri- and tetracyclic antidepressants. Selective monoamine oxidase inhibitors like deprenyl, however, have been tried with success as adjuvant therapy in Parkinson's disease and depression because of their ability to inhibit dopamine oxidation. Perhaps their greatest advantage is their lack of pressor response.

[Effect of a monoamine oxidase inhibitor on the level of seizure readiness and functional asymmetry of the brain]. / Vliianie ingibitora monoaminoksidazy na uroven' sudorozhnoi gotovnosti i funktsional'nuiu asimmetriiu mozga.

The state of seizures readiness in epileptic rats of Krushinsky--Molodkina line is characterised by interhemispheric synchroneity, revealed with electrophysiological methods parallely with the study of the catecholamine content in the brain tissue. On the contrary in animals insensitive to epileptogenic stimulus, considerable manifestations of the functional interhemispheric asymmetry were recorded. The monoaminoxidase inhibitor iprazide increasing the adrenaline and noradrenaline content in the brain and causing their uneven distribution between the hemispheres, leads to a sharp decline in the level of seizures readiness, which is accompanied by the appearance of bioelectrical and catecholamine asymmetry comparable with that in the animals resistent to the epileptogenic stimulus.

[Serotonin inactivation by tissues of the gastrointestinal tract and liver in the presence of dysenteric poisoning]. / Ob inaktivatsii tkaniami zheludochno-kishechnogo trakta i pecheni serotonina v usloviiakh dizenteriinoi intoksitkatsii.

Intravenous administration of serotonin into healthy rabbits was accompanied by an increase in content of serotonin in blood of vena cava inferior but the level of serotonin in blood of vena portae and vena centralis hepatis was unaltered. Concentration of serotonin was increased in all parts of the venous system studied after administration of serotonin into andogenous histamine was stimulated. Administration of iproniazid, simultaneously with the dysenteric toxin, led to decrease in inactivation not only of serotonin, but also of histamine.

Brain monoamines in seizure mechanism (review).

A majority of experimental studies have strongly suggested that catecholamine and/or 5-HT play an important role for regulating the seizure susceptibility. As mentioned previously, however, the relative significance of individual monoamine has not yet been fully clarified. Since it is well known that the interaction between catecholaminergic and serotonergic neuronal activity is quite complex, a causal relationship between each monoamine and seizure susceptibility cannot be easily established if results are obtained from the whole brain study on pharmacologic manipulation of experimental seizures. The extensive study, including the monoamine turnover rates and concentrations in specific brain regions, may help to delineate such a correlation in the future. Further, when an object of study is concerned in excitability of the central nervous system, it should be necessary to elucidate the mutual relationship of monoamines to the other putative neurotransmitters (e.g., acetylcholine, amino acid). Does there exist an abnormal metabolism of monoamines in the brain of epileptic patients? If so, how is it related to the elaboration or maintenance of epileptic seizures? Unfortunately, we have no sufficeint information on the monoamine metabolism of epileptic patients.

Identification and quantitative GLC determination of iproniazid in human urine.

A GLC method for the specific identification and quantitation of iproiazid, a potent monamine oxidase inhibitor drug, is described. The free drug isolated from urine samples by two-phase extraction reinforced with salting out. Identification and quantitative determination at the microgram level are done on aliquots of the chloroform extract by GLC, using the 2-butyl analog as an internal standard. Iproniazid and potentially interfering compounds present in the extracts are also identified by GLC-mass spectrometry and TLC for supporting evidence of the GLC method's specificity.

A neglected modality in psychiatric treatment--the monoamine oxidase inhibitors.

The monoamine oxidase inhibitors are at present being used relatively infrequently in my opinion because of reports of severe and dangerous side effects such as toxic hepatocellular damage and hypertensive crises and also on account of several studies which have not given a very encouraging picture regarding the efficacy of this group of drugs. The purpose of this article is to demonstrate that this group of antidepressant drugs is very useful when the proper indications for their employment are observed and are relatively safe provided that appropriate precautions such as the avoidance of cheese and other foods high in tyramine content are taken by the patients being treated with these compounds. The history, pharmacology, side effects, and indications for their use are reviewed, and it is indicated that the MAO inhibitors are the therapeutic agents of choice in atypical depressions associated with anxiety, phobic and hysterical symptoms, and depressive illnesses (including endogenous depressions) which have failed to respond satisfactorily to tricyclic antidepressants. It is then demonstrated both from a review of the literature relating to these drugs and also from my own clinical experience that these compounds are very effective when used in the treatment of the psychiatric conditions for which they are indicated and are also relatively safe when the appropriate precautions are conscienciously observed.

Fifteenth Emil A. Gutheil Memorial Conference. The range of therapies in the treatment of severely depressed suicidal patients.

The treatment of patients with suicidal drives and ideas is often less than adequate due to theoretic and technical prejudices. This paper describes the requirements that one who treats suicidal patients should meet. The phases of treatment and aims of each phase are outlined. Finally the combined antidepressant drug-psychotherapy thechnique and electroshock procedures are described in detail.

Is there an increase in monoamine-oxidase activity in depressive illness?

In a group of depressed patients who had either been treated with or considered suitable for monoamine oxidase (M.A.O.) inhibitor therapy, a highly significant decrease in conjugated tyramine output was observed after an oral tyramine load compared with normal controls. However, there was no difference in conjugated isoprenaline output between the two groups after isoprenaline ingestion, even though this amine is almost solely metabolised by what is likely to be the same conjugation mechanism. Whilst some explanation in terms of altered gut motility is conceivable, it seems more likely that the apparent deficit in tyramine conjugation in depression represents an increase in functional M.A.O. activity. Consequently, this enzyme would metabolise a greater proportion of available amine, causing a proportionately large decrease in the smaller conjugate pool.