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Described in this paper is the use of nootropics for stimulation of prenatal development of laboratory animals. Investigations, in that context, led to the discovery of so far unknown and unexpected properties of this group of medicaments. Foetal weight gain, reduction of teratogenicity, and decrease in implantation loss proved to be some of them.
A group of 26 patients with the diagnosis of Senile Dementia of Alzheimer type (SDAT) was included by random assignment in a double-blind, cross-over trial of pyritinol versus placebo. The patients had a mild to moderate degree of dementia. Psychiatric and neurological examination, psychometric testing, and measurement of the regional cerebral blood flow (rCBF) at rest and during mental activation were used to assess treatment effects. The results of the study showed that pyritinol was associated with a significant improvement in cognitive performance. RCBF data showed that treatment with pyritinol normalized the pattern of blood flow increase during activation and improved the score on the test used for activation.
Rats after mild chronic postnatal hypoxia always show late sequelae of behaviour and long-term alterations of neurotransmitter release from striatal slices. It was to test preventive or therapeutic actions of drugs using the model of mild chronic postnatal hypoxia of the rat. Pyritinol prevented the learning deficit due to hypoxia and decreases the potassium stimulated DA release from striatal slices. The experiments underline the high plasticity of the CNS during the neonatal period and stress the necessity of early therapy of perinatal brain damage.
In 100 and 200 mumol/l concentration, pyritinol inhibited GABA binding to the GABA receptors of brain synaptosomal membranes. GABA receptors from the cerebral cortex, diencephalon and striatum were inhibited to approximately the same degree; those from the cerebellum and spinal cord were inhibited more. Both high and low affinity receptors were inhibited. Pyritinol did not greatly affect the number of binding sites (Bmax), but reduced the affinity (raised the dissociation constant KD) of both receptors. The benzodiazepine receptor, which is connected with the postsynaptic GABAA receptor, was also inhibited by pyritinol. The character of inhibition was the same as for GABA receptors, i.e. there was no change in the number of binding sites, but there was a decrease in their affinity. It is assumed that the similarity of the effect on GABA and benzodiazepine receptors is associated with their occurrence on one, or on two relatively firmly interconnected, protein molecules. Depression of the affinities of GABA and the associated benzodiazepine receptor, together with inhibition of GABA synthesis, in the presence of pyritinol indicate that diminished activity of the GABA system in the brain might be related to the activating effect of pyritinol.
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Pyritinol, a vitamin B6 derivative considered to have an activating effect on brain inhibited glutamate decarboxylase in concentrations of 0.05-1.0 mmol/l. This effect was not dependent on the pyridoxal-5'-phosphate concentration. An increase in the glutamate level reduced the inhibitory effect of pyritinol, but inhibition was not competitive. It is supposed that this modification of inhibition of glutamate decarboxylase by the substrate concentration might be associated with the presence of two glutamate decarboxylases with different affinities for the substrate. The inhibitory effect of pyritinol was dependent on integrity of the disulphide bond in the pyritinol molecule. Inhibition of glutamate decarboxylase increased in correlation to time--possibly in association with progressive oxidation of the SH-groups of the enzyme. Pyritinol did not influence GABA transaminase activity, but lessened the oxidation of GABA to carbon dioxide. It is assumed that succinic semialdehyde dehydrogenase activity was inhibited.
The high affinity Ca++-ATPase participates essentially in the regulation of intrasynaptosomal calcium homeostasis. Related to posthypoxically restricted transmitter release, we examined the influence of newly-generated free radicals (ascorbic acid-ferric salt mixture) or sodium dodecyl sulfate in vitro and of a mild hypobaric hypoxia in vivo on the activity of synaptosomal high affinity Ca++-ATPase. Moreover we tested the effectiveness of piracetam, meclofenoxate hydrochloride, pyritinol and verapamil on the changed enzyme activity subsequent to a hypoxic exposure. The activity of synaptosomal high affinity Ca++-ATPase (1.04 +/- 0.03 mumol Pi/mg.h) is reduced by not more than 40% depending on the concentration of the ascorbic acid-ferric salt mixture used but is nearly totally inhibited by sodium dodecyl sulfate (0.2 mg/ml). Hypobaric hypoxia (18 h, 8.7 kPa) decreases the enzyme activity to 0.79 +/- 0.03 mumol Pi/mg.h. Piracetam, meclofenoxate hydrochloride and pyritinol are protectively effective on the decrease of enzyme activity induced by hypoxia. The results emphasize the importance of intact protein-phospholipid interactions for the enzyme activity and support relations between synaptosomal high affinity Ca++-ATPase and transmitter release.
Initially reported in Japan, autoimmune hypoglycemia is related to the presence of insulin-binding antibodies, even in patients who have never been treated with insulin. The authors report a case of spontaneous autoimmune hypoglycemia in a French woman receiving pyritinol. The difference between insulin and C peptide radioimmunoassay levels prompted a search for insulin antibodies. In vitro studies confirmed their presence and showed that they were immunoglobulins G with two binding sites without species specificity. The outcome of autoimmune hypoglycemia is usually favourable, with a rapid decrease of insulin antibodies but steroid therapy is needed when serious clinical manifestations are present. The differential diagnosis with factitious hypoglycemia may be difficult. The reasons for the appearance of the insulin antibodies and the exact mechanisms of hypoglycemia remain hypothetical. However, drugs with a sulfhydril group, such as pyritinol, could play a causative role in this syndrome.
High affinity choline uptake (HACU) in the hippocampus and striatal concentration of dopamine (DA) and homovanillic acid (HVA) as measures of the in vivo acetylcholine and DA turnover, respectively, were estimated in male rats, Long-Evans, following 6-day administration of various nootropics in clinically relevant doses: piracetam and its derivatives pramiracetam and oxiracetam (100 mg/kg/day), pyritinol (50 mg/kg/day). Piracetam treatment was without effect on HACU, but induced significant increase of HVA in the striatum leaving striatal DA concentration unchanged. On the contrary, pyritinol, pramiracetam and oxiracetam increased HACU, but did not change striatal DA and HVA levels.
The auto-immune hypoglycemic syndrome is characterized by the association of hypoglycemia (clinical and/or biological) and anti-insulin antibodies in patients who have never received exogenous insulin. Initially this syndrome was most often described in Japanese patients some of whom were treated with drugs containing a sulfydril group. We now recall the case of a female caucasian patient treated with Pyritinol for rhumatoid polyarthritis and who presented severe spontaneous hypoglycemia linked with the presence of anti-insulin antibodies in her serum. The level of her antibodies decreased abruptly on suspension of the drug. The recent and more developed characterization techniques of the different forms of circulating insulin and of their antibodies may help to differenciate an auto-immune hypoglycemia from hypoglycemia due to the secret auto-administration of bovine and porcine insuline, and permit us to suggest that an abnormality in the structure of the molecule of insulin might be a cause of this syndrome. However, the exact mechanism of hypoglycemia linked with the presence of anti-insulin auto-antibodies is not yet clear as is the predisposition of a drug with a sulfydril group to induce such an auto-immune phenomenon.
Kindling is a long-lasting, transsynaptic, pathway-specific plastic change in brain function. It has been proposed as a model of neural plasticity, learning and memory, as well as a model of epilepsy. To elucidate the action of substances characterized by their ability to improve learning and memory and to have an activatory, protective and function restoring effect on nerve cells in distress, the effects of nootropic drugs and of antioxidative acting substances on the development of kindling and the seizure behavior in the kindled state were investigated. Nootropic drugs suppress the development of pentetrazol (PTZ)- and amygdala-kindling and possess anticonvulsive potency preferentially in kindled rats. In comparison to amygdala-kindling the substances were found to be more effective against PTZ-kindled seizures. Chemically different antioxidants in doses known to scavenge free radicals suppress markedly the development of kindling and possess anticonvulsant potency in chemically and electrically kindled rats. The results provide arguments in favor of functional alterations of transmission relevant membrane processes with structural and functional reorganization of membrane constituents and lead to the assumption that the changes mainly in part rest on a selective and focal involvement of free radicals. It is proposed that enhanced calcium entry into neurons and consequent biochemical alterations connected with a focal increase in free radicals is part of the mechanisms underlying kindling phenomenon.
With respect to the enhancing effect of nootropics on learning and memory, the influence of some of these drugs on the high affinity choline uptake has been investigated. Meclofenoxate competes with choline uptake in vitro because of its similar side chain; other nootropics are without in vitro effects. A single dose of pramiracetam enhances the choline uptake in cortex and hippocampus. Application of meclofenoxate decreases the uptake of choline. Other nootropics lack acute effects. Possible increases of uptake after repeated dosage disappear within 24 h.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
In a series of 130 patients with asthenic conditions related to borderline forms of neuro-mental disturbances the authors compared clinico-pharmacological action of the actoprotector bemitil with that of nootropic drugs (piracetam and piridotol). The treatment with bemitil was either continuous or intermittent, being conducted according to the scheme elaborated in the course of the study. Bemitil proved to be more effective than piracetam and piriditol in relation to its influence on the manifestations of the asthenic symptom complex in general. Its application was characterized by a faster onset of the therapeutic effect and a peculiar mild psychostimulating action, primarily manifested in the impact on obligate manifestations of the asthenic disorders. The degree of the psychotropic action of the drug was found to be subject to changes depending on the scheme of its use.
A review of the literature on previous cases of drug-induced pemphigus as well as two case reports of pyritinole-induced pemphigus show a few characteristics: D-penicillamine was responsible in 42 cases, pyritinole in 4 cases, the two case reports included. Superficial pemphigus was seen in about 75% of the cases, most times associated with preexistent autoimmunological disorders. Immunological findings were identical with normal, non-drug-induced pemphigus, while the prognosis was better under mostly necessary immunosuppressive therapy at relatively low doses.