[Possibilities of «therapeutic retargeting¼ of 3-hydroxypyridine and succinic acid derivatives due to their dopaminergic action]. / Vozmozhnosti «terapevticheskogo perenatselivaniya¼ proizvodnykh 3-oksipiridina i yantarnoi kisloty, obuslovlennye ikh dofaminergicheskim deistviem.

The review is devoted to a comparative analysis of the clinical efficacy of the original domestic derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) in comparison with the results of an experimental study of their dopaminergic action. The position that the dopaminomimetic activity of emoxipin, reamberin and mexidol largely determines their anti-ischemic, antihypoxic, insulin-potentiating neuroprotective, nootropic and antidepressant potential has been substantiated. A comparative analysis of the safety profile of emoxipine, reamberin and mexidol was carried out, taking into account potential and real side-effects caused by iatrogenic deviations from the eudopaminergic state. It has been shown that mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate), which is simultaneously a derivative of 3-hydroxypyridine and succinic acid, has the best balance of efficacy and safety. A generalized assessment of the available data on the successful use of off-label derivatives of 3-hydroxypyridine and succinic acid indicates the advisability of a significant expansion of indications for their clinical use. The authors resume that the «therapeutic retargeting¼ of emoxipin, reamberin and mexidol (i.e. their use for qualitatively new indications) will contribute to progress in the treatment of socially significant and most common diseases.

[Dopaminergic potential of domestic 3-hydroxypyridine and succinic acid derivatives and prospects for their therapeutic «retargeting¼]. / Dofaminergicheskii potentsial otechestvennykh proizvodnykh 3-oksipiridina i yantarnoi kisloty i perspektivy ikh terapevticheskogo «perenatselivaniya¼.

The review is devoted to the assessment of the pharmacological effects of 3-hydroxypyridine and succinic acid derivatives (emoxipin, reamberin and mexidol) from the standpoint of their dopaminergic activity. A systematic analysis of the data has been performed, allowing us to consider emoxipin, reamberin and mexidol as «normalizers of dopaminergic neurotransmission¼, the dopaminergic action of which in its phenotype corresponds to the effects of partial dopamine receptor agonists. The position that the dopaminergic effect, antioxidant and antidepressant potential of drugs containing 2-ethyl-6-methyl-3-oxypyridine (emoxipine and mexidol) are associated with their inhibitory effect on monoamine oxidase-A (MAO-A) has been substantiated. A direct relationship between the stimulating effect of succinate-containing drugs (reamberin and mexidol) on MAO-B, their prooxidant activity, insulin-potentiating and antidepressant effects was analyzed. A hypothesis has been put forward on the general pathological significance of dopaminergic regulation disorders, the correction of which with the 3-hydroxypyridine and succinic acid derivatives can be considered as a promising strategy for improving the complex therapy of socially significant and common human diseases.

[An effect of 3-oxypyridine and succinic acid derivatives on the time of reduction of anxiety and depression symptoms in alcohol withdrawal treatment]. / Vliyanie proizvodnykh 3-oksipiridina i yantarnoi kisloty na temp kupirovaniya simptomov trevogi i depressii v protsesse lecheniya sindroma otmeny alkogolya.

OBJECTIVE: To compare the effect of 3-oxypyridine and succinic acid derivatives (emoxypine, reamberin, mexidol) on the time of reduction of anxiety and depression symptoms in the standard treatment of alcohol withdrawal syndrome (AWS). MATERIAL AND METHODS: A short-term prospective placebo-controlled double blind randomized study of the effect of emoxypine, reamberin, mexidol on the dynamics of reduction of anxiety and depression clinical symptoms in the course of a 14-day day hospital treatment of AWS was conducted. The severity of anxiety symptoms was assessed on a daily basis by using the Hamilton Anxiety Rating Scale (HARS). Symptoms of depression were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS). Reduction of certain objective anxiety and depression symptoms was noticed at 0 point of the corresponding HARS and MADRS items. On the 1st and 14th day of treatment, the Zung Self-Rating Anxiety Scale (ZSRAS) and the Beck Depression Inventory (BDI) were additionally used. RESULTS AND CONCLUSION: All the studied drugs reduced the duration of certain anxiety and depression symptoms during AWS treatment. The degree of this effect depended on the features of the chemical structure of a drug. Mexidol accelerated the reduction of «dread¼, «respiratory¼ and «cardiovascular¼ anxiety symptoms (HARS) by 25-50%. «Reduced appetite¼ and «concentration difficulty¼ (MADRS) improved by 28.5%. Reamberin reduced the duration of «gastrointestinal¼ and «respiratory¼ anxiety symptoms (HARS) by 17-50% and «inner tension¼ (MADRS) by 7%. Emoxypine accelerated the reduction of «insomnia¼ and «respiratory¼ symptoms (HARS) but did not affect the duration of objective depression symptoms (MADRS). Emoxypine and reamberin reduced the severity of affective and cognitive symptoms (BDI) by 32-37%. None of the drugs affected self-reported anxiety (ZSRAS). The most balanced treatment of depressive symptoms was provided by reamberin, which was the only of the studied drugs that simultaneously reduced both the duration of objective symptoms and the severity of subjective disorders of affective status in alcohol withdrawal.

[Anxiolytic and antidepressant effects of emoxipine, reamberin and mexidol in experimental diabetes mellitus]. / Anksioliticheskoe i antidepressivnoe deistvie émoksipina, reamberina i meksidola pri éksperimental'nom sakharnom diabete.

AIM: To perform a comparative study of anxiolytic and antidepressant effects of derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin and mexidol) in experimental diabetes mellitus. MATERIAL AND METHODS: An effect of emoxipine, reamberin and mexidol on manifestations of anxiety in 'elevated plus maze' (EPM) and duration of 'desperate behavior' (DB) in Porsolt test in rats with alloxan diabetes during medication course was studied. Alpha-lipoic (thioctic) acid (α-LA) was used as a reference drug. In additional experimental series, an effect of emoxipine, reamberin, mexidol and α-LA on the intensity of hyperglycemia in experimental DM was investigated. RESULTS AND CONCLUSION: All studied medications used in doses equivalent to therapeutic range in humans and administered for 14 days significantly reduced manifestations of anxiety and depression in rats with alloxan diabetes. The most pronounced anxiolytic potential was demonstrated for emoxipine that emerged as the only medication in the study that reduced manifestations of anxiety not only in comparison with 'alloxan diabetes-control' groups but also in comparison to 'intact control'. The intensity of tranquilizing activity of derivatives of 3-oxypyridine and succinic acid was similar to that of α-LA while the thymoanaleptic activity, when the drugs were administered in maximal doses to rats with experimental DM, was higher. Both emoxipine and mexidol as well as α-LA in all studied doses significantly decreased hyperglycemia in alloxan diabetes. Reamberin demonstrated only insignificant tendencies of the same trend.

[The effect of reamberin and alpha-lipoic acid on the tolerance to acute cerebral ischemia in experimental diabetes mellitus]. / Vliyanie reamberina i α-lipoevoi kisloty na ustoichivost' k ostroi tserebral'noi ishemii pri eksperimental'nom sakharnom diabete.

AIM: To study an effect of reamberin and α-lipoic acid (α-LA) on the tolerance of mice with experimental diabetes mellitus (DM) to acute cerebrovascular accident (ACVA) in mice experiments. MATERIAL AND METHODS: The authors studied mice with alloxan diabetes and subtotal and total brain ischemia. In additional experimental series, an effect of reamberin and α-lipoic acid on the tolerance to acute hypoxic hypoxia and intensity of hyperglycemia in experimental DM was studied. RESULTS AND CONCLUSION: The increased vulnerability of animals to ACVA due to hyperglycemia and increased sensitivity to acute hypoxic hypoxia was established. Reamberin and α-lipoic acid administered for 14 days in doses, which are equivalent to therapeutic range in humans, enhance the tolerance to ACVA and acute hypoxic hypoxia in mice with alloxan diabetes. These medications also decrease the intensity of hyperglycemia during concurrent insulin replacement therapy. The increased tolerance to ACVA in mice with alloxan diabetes caused by reamberin and alpha-lipoic acid is associated with an antihypoxic effect of these medications and does not depend on their effect on the intensity of hyperglycemia. Reamberin outperformed α-lipoic acid in the antihypoxic activity, protection against ACVA and the rate of onset of glucose reducing effect in experimental diabetes mellitus.

[ANTIANHEDONIC EFFECT OF 3-OXYPYRIDINE AND SUCCINIC ACID DERIVATIVES].

We performed a comparative study of the effect of original domestic derivatives of 3-oxypyri-dine and succinic acid (emoxipine, reamberin and mexidol) on measures from «sucrose preferen-ce¼ test which is used for assessment of hedonic behavior in rats. а-lipoic acid (а-LA) and amit-riptylin were used as reference medications. For the modeling of anhedonia rats received dexa-methasone (5 mg/kg subcutaneously). We established that threefold administration of emoxipine, reamberin and mexidol in doses that are equivalent to therapeutic range in humans had antianhe-donic effect and increased the measures of «preference¼ and absolute sucrose consumption. This effect was demonstrated in animals that did not receive dexamethasone as well as in rats with dexamethasone-induced anhedonia. Maximal intensity of antianhedonic effect of 3-oxypyridine and succinic acid derivatives was noted after the previous administration of dexamethasone. In rats that did not receive dexamethasone, succinate-containing medications (reamberin and mexidol) exceeded the isolated 3-oxypyridine derivative (emoxipine) in their antianhedonic potential. In case of previous dexamethasone administration 3-oxypyridine and succinic acid derivatives demonstrated equivalent antianhedonic effect that exceeded the effect of reference medications (а-LA and amitriptylin).

EFFECT OF 3-HYDROXYPYRIDINE AND SUCCINIC ACID DERIVATIVES ON BACTERIAL GROWTH IN DISCONTINUOUS CULTURES.

We have studied the effect of domestic derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin, and mexidol) on proliferation of E. coli, S. aureus and E. faecalis in discontinuous cultures (DCs) over a period of 1 or 24 h. It is established that the drugs studied exhibit a biphase effect on the number of bacterial colony-forming units (CFUs) in DCs of E. coli and E.faecalis. This effect is manifested by the initial 1.3 - 3.5-fold decrease in the number of CFUs (after 1-h incubation with drugs) with subsequent return to the control level or 1.8 - 8.8-fold increase over the control level (after 24-h incubation with drugs). In DCs of S. aureus that were incubated with the drugs, we observed 1.1 - 1.95-fold increase in CFU number after I-h incubation and 1.8 - 2.4-fold increase after 24-h incubation. On the whole, the results of our studies demonstrated a positive effect of 3-hydroxypyridine and succinic acid derivatives on bacterial growth in DC. These drugs stimulated increase in CFU number in DCs of test bacterial strains even at concentrations as low as 10⁻9 -10⁻6. The well-known efficiency of 3-hydroxypyridine and succinic acid derivatives in treatment of infectious pathology appears independent of their direct effect on bacterial growth.

[Antidepressant effect of 3-oxypyridine and succinic acid derivatives (experimental study)].

OBJECTIVE: To evaluate antidepressant activity of domestic derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin and mexidol) in rats. MATERIAL AND METHODS: The influence of emoxipine, reamberin and mexidol on duration of desperate behavior of rats in Porsolt forced swim test was studied. Additionally the effect of these substances on the animal's behavior in the open field was evaluated. Amitriptyline and alpha-lipoic acid were used as reference substances. RESULTS: It was established that three administrations of any of the substances in doses corresponding to the therapeutic range in humans reduced the duration of desperate behavior in Porsolt test. Such effect of emoxipine, reamberin, mexidol and alpha-lipoic acid is indicative of their antidepressant activity. Intensity of this activity depends on the effect of these substances on the behavior in the open field. CONCLUSION: Reamberin and alpha-lipoic acid that in maximal doses either had no effect on the orientation behavior in the open field (reamberin) or suppressed it (alpha-lipoic acid) matched amitriptyline in the extent of antidepressant activity. The derivatives of 3-oxypyridine (emoxipine and mexidol) with stimulatory effect on the behavior in the open field demonstrated significantly lower ability to reduce desperate behavior than that of amitriptyline.

Comparative analysis of the anxiolytic effects of 3-hydroxypyridine and succinic acid derivatives.

Threefold administration of 3-hydroxypyridine derivatives emoxipine and mexidol in optimal doses corresponding to the therapeutic dose range for humans produced an anxiolytic effect and stimulated risk behavior in the elevated plus maze test in rats. These effects were most pronounced after injection of 3-hydroxypyridine derivative emoxipine. Combination of 3-hydroxypyridine cation and succinate anion in the mexidol structure led to attenuation of the anxiolytic effect and less pronounced stimulation of the risk behavior. By the anxiolytic effect and induction of risk behavior, emoxipine and mexidol were close to the reference substance amitriptyline. Reamberin, a succinic acid derivative, had no pronounced tranquilizing properties, but risk behavior induction was similar to that produced by mexidol. In contrast to other test agents, the reference substance α-lipoic acid produced anxiogenic effects and suppressed risk behavior. The obtained results suggest that Russian-made 3-hydroxypyridine derivatives emoxipine and mexidol are promising preparations for the treatment of anxiety disorders.

[The effect of 3-oxypyridine and succinic acid derivatives on obsessive-compulsive activity of mice in marble-burying test].

The effect of domestic derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin, and mexidol) on obsessive-compulsive behavior of mice was studied in the marble-burying test. Additionally the effect of these drugs on the behavior of animals was assessed in the open field test. Amitriptylin and alpha-lipoic acid were used as reference drugs. It was established that single administration of the investigated drugs in optimal doses, corresponding to therapeutic range in humans, inhibits obsessive-compulsive behavior of mice in the marble-burying test. Amitriptylin and alpha-lipoic acid produced similar effects. It is established that emoxipine stimulates the behavior of mice in the open field after single administration. An increase in the emoxipine dose led to decrease of stimulation and gradual development of sedative effect. Reamberin and mexidol, as well as alpha-lipoic acid and amitriptyline, caused sedation in mice tested in the open field. Inhibiting effect of emoxipine, reamberin, mexidol and alpha-lipoic acid on the obsessive-compulsive behavior in mice directly depended on sedative action of these drugs.

[Anxiolytic and antidepressant effects of 3-oxypiridine and succinic acid derivatives in the acute phase of alloxan-induced diabetes in rats].

The effect of derivatives of 3-oxypyridine and succinic acid (emoxypine, reamberin, and mexidol) on the manifestations of anxiety (according to the criteria of behavior in elevated cross plus maze test) depression (according to the criterian of immobility in the Porsolt test) in the acute phase of alloxan diabetes (96 h after alloxan administration) has been studied in rats. The effectiveness of emoxypine, reamberin, and mexidol was compared with that of alpha-lipoic acid (etalon treatment of diabetic neuropathy). It was established that a single administration of 3-oxypyridine and succinic acid derivatives in doses equivalent to the therapeutic range for humans corrected anxio-depressive disorders in the acute phase of alloxan diabetes, while being not inferior to alpha-lipoic acid with respect to the intensity of anxiolytic and antidepressant action. The correction of affective disorders by emoxypine, reamberin and mexidol did not depend on their effect on hyperglycemia in the acute phase of alloxan diabetes. The most pronounced anxiolytic action was observed upon the administration of emoxypine, while the most pronounced antidepressant effect was observed upon the administration of mexidol.

[Insulin potentiating and antidepressant effects of 3-oxypyridine and succinic acid derivatives].

The dependence of the antidepressant action of 3-oxypyridine and succinic acid derivatives (emoxipine, reamberin, and mexidol) on the insulin potentiating activity of these therapeutic agents has been studied in experiments on rats. Alpha-lipoic acid was used as a reference drug. It was established that single administration of emoxipine, reamberin, mexidol and alpha-lipoic acid in optimal doses, corresponding to the therapeutic range in humans, increased the sensitivity of animals to insulin according to the criterion of insulin coma development. Triple administration of the therapeutic agents studied in the same single dose produced an antidepressant effect according to the criterion of "desperate behavior" in Porsolt forced swimming test. Standardization of obtained data by average difference from the control and further correlation analysis demonstrated that the extent of antidepressant action of emoxipine, reamberin, mexidol and alpha-lipoic acid considerably depends on their insulin potentiating activity (r = 0.762, p = 0.004).

Effects of 3-hydroxypyridine derivatives and succinic acid on endometrial leukocyte infiltration, cytokinemia and related affective symptoms during exacerbation of the chronic inflammation of the uterus and adnexa.

We studied the effects of original Russian derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) on the time course of endometrial leukocyte infiltration, blood levels of inflammatory cytokines (IL-1ß and TNF-α), and indicators of affective status in women with exacerbation of the chronic inflammation of the uterus and adnexa. It was found that emoxipine, reamberin, and mexidol included in the complex therapy corrects anxiety and depressive disorders depending on the degree of reduction of endometrial leukocyte infiltration and blood levels of inflammatory cytokines. Derivatives of 3-hydroxypyridine (emoxipine and mexidol) exhibited efficiency, which were superior to derivative of succinic acid (reamberin) in the degree of reduction in endometrial leukocyte and neutrophyl infiltration and in severity of anxiety and depressive disorders. Mexidol, a 3-hydroxypyridine and succinic acid derivative, was most effective and surpassed emoxipine by the degree of reduction of inflammatory cytokine level in the blood and the severity of affective anxiety symptoms in women with exacerbation of the chronic inflammation of the uterus and adnexa.

[Protective effect of 3-oxypyridine and succinic acid derivatives under conditions of acute alloxan-induced intoxication in mice].

Protective action of 3-oxypiridine and succinic acid derivatives (emoxipin, reamberin and mexidol) was studied in mice under acute alloxan-induced intoxication conditions. All these drugs exhibited protective action with respect to hyperglycemia and hyperglycemia-connected elongation of desperate behavior in the tail-suspension test and reduced activity level on the open field test. Mexidol exceeded emoxipin in the dose range of protecting action with respect to alloxan-induced hyperglycemia and was superior to reamberin in the treatment of desperate behavior in the tail-suspension test.

[The effect of 3-oxypyridine and succinic acid derivatives on the resistance to acute cerebral ischemia].

OBJECTIVE: The effect of original domestic derivatives of 3-oxypiridine and succinic acid (emoxipine, reamberin and mexidol) on the resistance to acute brain ischemia was studied in an experimental mouse models. MATERIAL AND METHODS: We used 260 adult outbred mice. The drugs were introduced intraperitoneally 30 min before the modeling of acute brain ischemia. Each drug was used in 3 three doses: 1/2 of the calculated equivalent of mean treatment dose (EMTD), EMTD and double EMTD. A strangulation model with the assessment of mouse mortality latency and decapitation model with the assessment of agonal respiration (gasping) were used. The efficacy of the drugs was determined by comparison against alpha-lipoic acid that was used as a reference substance in previous studies of antihypoxic activity of emoxipine, reamberin and mexidol. RESULTS AND CONCLUSION: It was established that the derivatives of 3-oxipiridine and succinic acid protected against subtotal ischemia of rostral brain segments (of cerebral hemispheres) as evidenced by the increase in longevity. Emoxipine demonstrated the maximal effect thereby surpassing reamberin and mexidol in the intensity of antiischemic activity. Antiischemic effect of alpha-lipoic acid was comparable to emoxipine. In the model of total brain ischemia, the derivatives of 3-oxipiridine and succinic acid caused the opposite (proischemic) action on the bulbar respiratory center as evidenced by the reduction in duration of gasping. Alpha-lipoic acid did not affect the duration of gasping.

[Clinical and immunological study of the relationship of the digestive system chronic diseases and atherosclerosis in the basin of the abdominal aorta in elderly patients].

Paper describes clinical and immunological study about the relationship between chronic diseases of the digestive system and atherosclerosis in the basin of the abdominal aorta in patients of elderly and senile age. There were revealed the structural and clinical features of the gastrointestinal tract diseases, depending on the extent of atherosclerosis in the basin of the abdominal aorta. Evaluation of the immune status included the determination of lymphocyte subpopulation composition, the functional state of neutrophils and cytokine levels. It is found that the progression of atherosclerosis in the basin of the abdominal aorta in patients of elderly and senile age with chronic diseases of the digestive system was accompanied by the activation of pro-inflammatory mechanisms of the immune system and the accompanying intensification of oxidative stress.

[Experimental study of 3-oxypiridine and succinic acid derivates antidepressant activity in mice].

Effect of Russian 3-oxypiridine and succinic acid derivatives (emoxipin, reamberin and mexidol) on duration of behavioral despair in mice in forced swimming test (by Porsolot) and tail suspension test (by Steru) was investigated. In addition impact assessment of studied medicinal products (MP) on animals' behavior in open field test was performed. Amitriptyline and alpha-lipoic acid were used as reference drugs. It was determined that single delivery of all studied drugs in optimal doses eqvivalent to therapeutic range for human reduces lasting of behavioral despair in Porsolot and Steru tests. This effect of reamberin, mexidol and alpha-lipoic acid indicates their antidepressant action unrelated to stimulatory activity, as far as these MPs like amitriptyline show sedative action in open field test. Reduction of behavioral despair due to effect of emoxipin in relative low doses was associated with increase of mice activity in open field test and so it can't be considered to be antidepressant action per se. Increase of emoxipin dose leads to progressive decrease of its stimulatory effect impact in behavioral despair reduction and induce antidepressant effect in the setting of sedation.

[Stating the need of surgical treatment of the infiltrative lung tuberculosis].

To reveal predictors of demand formation in phthisiosurgical care during standard treatment of infiltrative pulmonary tuberculosis. Clinical, radiological, laboratory and psychological examination of 103 patients with new-onset infiltrative pulmonary tuberculosis in exsolved phase (ICD-10 A15. and A16.) before standard therapy were done. All patients were divided into two groups (with indications to phthisiosurgical treatment and without indications to transthoracic operation) based on prospective 12-months follow-up results. Predictors of demand formation in phthisiosurgical care were revealed based on results of intergroup comparison and stepwise logistic regression. It was established that demand formation in phthisiosurgical care during conservative treatment of infiltrative pulmonary tuberculosis linked with M. tuberculosis presence in sputum and relative increasing sizes of tuberculous infiltrates, content of erythrocytes in blood, thymol test, atherogenic index and circulating ceruleoplasmin concentration at a time when depressive soreness and asthenia relatively decreased. Integrate algorithm of demand in phthisiosurgical care prognosis was formed by dint of stepwise logistic regression. This algorithm is based on consideration of integrated index of clinical symptoms severity, hidrosis, number of destruction in tuberculous infiltrate and its sizes, HDL concentration, total protein and serum beta-globuline percentage. Algorithm formed with logistic regression offers the possibility to make a prognosis of demand in phthisiosurgical care with 72,7% responsiveness and 80% specificity.

[Cerebroprotective effect of 3-oxypyridine and succinic acid derivatives in experimental diabetes mellitus].

We studied an effect of original domestic derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin and mexidol) on changes in the cellular composition of cortical and diencephalic structures in the rat brain in relation to the hyperglycemia severity in rats with alloxan diabetes. The effect of 3-oxypyridine and succinic acid derivatives was compared with the results of alpha-lipoic acid treatment. We determined that administration of 14 optimal doses of any medication in this study prevented the decrease in neuronal count in the primary somatosensory cortex (Par1 field). This effect was particularly evident after treatment with 3-oxypyridine derivatives (emoxipine and mexidol). Additionally, a two-week administration of emoxipine and mexidol led to a decreased percentage of lipofuscin-positive neurons in the neocortex and field CA1 of the hippocampus. Concurrently, emoxipine and mexidol increased the number of basket neurons as well as oligodendrocytes and microglia in the studied structure of the Ammon's horn. Moreover, these two substances prevented the decrease in the number of astrocytes in the somatosensory cortex and the paraventricular nucleus of the hypothalamus. The cerebroprotective activity of reamberin and alpha-lipoic acid in alloxan diabetes was less effective than that of 3-oxypyridine derivatives. Also, reamberin and alpha-lipoic acid induced undesirable side-effects manifested in the decreased number of pyramid neurons in field CA1 in the hippocampus and the increased number of lipofuscin-positive neurons in the somatosensory cortex and the paraventricular nucleus of the hypothalamus. Changes in the cellular composition of cortical and diencephalic structures resulting from administration of medications used in this study did not depend on the ability of these substances to restrain the hyperglycemia in alloxan diabetes.