Co-dergocrine Mesylate Research Articles

Improvement of sexual function in partial testosterone-deficient ageing men treated with cream containing testosterone and vasoactive agents

Background Erectile dysfunction has multiple causes in older men. Combination therapy may therefore be an attractive option. Methods We conducted a randomized double blind trial over 2 months. We allocated 89 men who had different causes of erectile dysfunction and low testosterone concentrations randomly to two groups. One group received topical therapy with placebo cream and the other received active cream containing testosterone 0.8%, isosorbide dinitrate 0.5% and co-dergocrine mesylate 0.06%. Serum concentrations of total testosterone were measured every 15 days. Response to each therapy was assessed by measurement of tumescence using RigiScan and a sexual questionnaire. Results Serum concentrations of total testosterone increased significantly in all patients ( p < 0.05) after 15 days of treatment with active cream (240 ± 27 ng/dl vs. 360 ± 29 ng/dl). Application of active cream to the penile shaft in the laboratory induced full tumescence in 18% of patients and partial tumescence in 53%. No patient had full tumescence after application of placebo cream. Sexual desire was improved in 70% of patients during treatment with active cream. Analysis of data from the questionnaires showed that 40% of patients reported full erections with successful intercourse, sexual enjoyment and satisfaction and 37% reported partial erections that were insufficient for successful intercourse. No patient experienced a full erection and successful intercourse after placebo cream. No major side effects were reported. Conclusion Topical treatment with cream containing testosterone and vasoactive agents is a new effective treatment for erectile dysfunction associated with low testosterone concentrations, particularly for patients with psychogenic causes.

Age, strain, and semi-chronic hydergine treatment effects on motor activity and neuronal nucleic acid-protein metabolism in male mice

This study was designed to examine the effects of Hydergine (DHET), co-dergocrine mesylate, treatment on motor activity and neuronal nucleoprotein metabolism in several motor areas of the aging rodent brain, specifically the caudate-putamen (CP), the substantia nigra (SN), and the cerebral cortex layer V (CX). Three age groups of two different strains of mice were used which represented two different aging rates: DBA/2 male mice (short lived) and C57BL/6 male mice (long lived). A representative sample of each age group was injected (IP) daily with a single dose of either DHET (1 mg/kg) or vehicle (0.9% saline) solution for one month. Total spontaneous motor activity was measured using a File apparatus to assess the functional ability of the selected brain areas. Histochemical parameters measured included the relative RNA and protein contents from a homogeneous population of neurons within each nuclei. The RNA and protein contents were assessed with a scanning microdensitometer using azure B and Coomassie staining protocols, respectively. The results of this study provide evidence that DHET does have significant effects on neuronal functioning in the motor compartments studied at the behavioral as well as the histochemical level for DBA/2 male mice. The C57BL/6 strain showed parallel, but less significant, changes in the histochemical parameters and no statistical differences in motor activity. In addition, DHET treatment produced no sign of neurotoxicity within any of the brain nuclei in either strain.

Drug prescribing by physicians in Cambodia

Objective To investigate drug use and prescribing by physicians in Cambodia. Material and methods Ten physicians at the hospital were interviewed. Results Two (20%) physicians prescribed frusemide and digoxin for congestive cardiac failure, two (20%) physicians frusemide, digoxin, nitrate and ACE-inhibitor (angiotensin- converting enzyme), four (40%) frusemide, digoxin and ACE inhibitor, one (10%) frusemide and ACE inhibitor, and one (10%) only ACE inhibitor. Four (40%) physicians prescribed tetracycline and quinine, one (10%) only mefloquine, one (10%) mefloquine, quinine and artemether or artesunate, two (20%) quinine, one (10%) quinine and artemether or artesunate, and one (10%) chloroquine, tetracycline and quinine for malaria due to Plasmodium falciparum. For malaria due to Plasmodium vivax eight (80%) physicians prescribed chloroquine and two (20%) chloroquine and artemether or artesunate. Eight (80%) physicians prescribed 200 mg isoniazide for an adult patient for tuberculosis, one (10%) 300 mg, and one (10%) 100 mg. Eight (80%) physicians prescribed intravenous fluids for ‘tiredness’. Ten (100%) physicians prescribed bisolvone syrup for ‘cough’. Seven (70%) physicians prescribed all intravenous drugs offered: vitamin C, an antispasmodic (phlorglucinol) and calcium (other than for hypocalcaemia), One (10%) prescribed vitamin C and an antispasmodic (phlorglucinol), 1 (10%) prescribed only an antispasmodic (phlorglucinol), and one (10%) vitamin C and calcium. Two (20%) physicians prescribed all intravenous drugs offered: co-dergocrine mesylate (Hydergine), ethamsylate, diazochrome and cimetidine, three (30%) physicians co-dergocrine mesylate and cimetidine, four (40%) co-dergocrine mesylate, ethamsylate and cimetide, and one (10%) cimetide only. Conclusion Cambodian physicians use drugs of unproven efficacy, symptomatic treatment for tiredness and cough, and drug regimen and doses for tuberculosis, malaria and congestive cardiac failure not recommended by national guidelines and standard textbooks. Information about drug therapy and drugs should be provided. Treatment guidelines should be set up by clinicians, scientists and health care planners, for e.g. tuberculosis and malaria, and adherence in clinical practice should be supported. Copyright © 1999 John Wiley & Sons, Ltd.

Drug prescribing by physicians in Cambodia

Objective To investigate drug use and prescribing by physicians in Cambodia. Material and methods Ten physicians at the hospital were interviewed. Results Two (20%) physicians prescribed frusemide and digoxin for congestive cardiac failure, two (20%) physicians frusemide, digoxin, nitrate and ACE-inhibitor (angiotensin- converting enzyme), four (40%) frusemide, digoxin and ACE inhibitor, one (10%) frusemide and ACE inhibitor, and one (10%) only ACE inhibitor. Four (40%) physicians prescribed tetracycline and quinine, one (10%) only mefloquine, one (10%) mefloquine, quinine and artemether or artesunate, two (20%) quinine, one (10%) quinine and artemether or artesunate, and one (10%) chloroquine, tetracycline and quinine for malaria due to Plasmodium falciparum. For malaria due to Plasmodium vivax eight (80%) physicians prescribed chloroquine and two (20%) chloroquine and artemether or artesunate. Eight (80%) physicians prescribed 200 mg isoniazide for an adult patient for tuberculosis, one (10%) 300 mg, and one (10%) 100 mg. Eight (80%) physicians prescribed intravenous fluids for ‘tiredness’. Ten (100%) physicians prescribed bisolvone syrup for ‘cough’. Seven (70%) physicians prescribed all intravenous drugs offered: vitamin C, an antispasmodic (phlorglucinol) and calcium (other than for hypocalcaemia), One (10%) prescribed vitamin C and an antispasmodic (phlorglucinol), 1 (10%) prescribed only an antispasmodic (phlorglucinol), and one (10%) vitamin C and calcium. Two (20%) physicians prescribed all intravenous drugs offered: co-dergocrine mesylate (Hydergine), ethamsylate, diazochrome and cimetidine, three (30%) physicians co-dergocrine mesylate and cimetidine, four (40%) co-dergocrine mesylate, ethamsylate and cimetide, and one (10%) cimetide only. Conclusion Cambodian physicians use drugs of unproven efficacy, symptomatic treatment for tiredness and cough, and drug regimen and doses for tuberculosis, malaria and congestive cardiac failure not recommended by national guidelines and standard textbooks. Information about drug therapy and drugs should be provided. Treatment guidelines should be set up by clinicians, scientists and health care planners, for e.g. tuberculosis and malaria, and adherence in clinical practice should be supported. Copyright © 1999 John Wiley & Sons, Ltd.

Possible supportive effects of co-dergocrine mesylate on antioxidant enzyme systems in aged rat brain

Free radical damage is implicated in the course of many diseases, including age-related dementias. Oxidative deamination of primary monoamino oxidase (MAO) produces NH 3 and H 2O 2 with established or potential toxicity. MAO activity is increased in aged rat brain and significantly lowered by chronic hydergine (codergocrine mesylate, Sandoz) treatment. The aim of this study was to investigate the effects of hydergine on enzymatic antioxidant defense systems. Hydergine or vehicle was administered systemically to young (3 months) and aged (18 months) Sprague-Dawley rats for 20 days and 24 h after the termination of the treatment, superoxide dismutase (SOD) and catalase (CAT) activities were determined in some brain regions. SOD and CAT activities were higher in the aged animals and were further increased with hydergine treatment. The increase in SOD levels caused by hydergine treatment in the aged animals were the most prominent in the hippocampus and in the corpus striatum. There was no region-specific effect of hydergine treatment on CAT levels in aged animals. The possible causal relationship between increased MAO activity, a generator of free radicals, and increased antioxidant defense in aging brain require further investigation. Decreasing MAO levels and supporting the antioxidant enzymes may underlie the efficacy of hydergine in the treatment of age related cognitive decline.

Effect-kinetics on brain protection of two codergocrine-mesylate preparations (Aramexe retard® and Hydergine®) by EEG mapping and psychometry under hypoxia

In a double-blind, placebo-controlled study the effect-kinetics on brain protection of a new retard formulation of codergocrine-mesylate (CDM) (Aramexe retard®, 5 mg) were investigated and compared with a standard CDM drug (5 mg Hydergine®) utilizing blood gas analysis, EEG mapping and psychometry. A transient, reversible hypoxic hypoxidosis (i.e. impairment of cerebral metabolism due to hypoxia) was experimentally induced by a fixed gas combination of 9.8% oxygen (O 2) and 90.2% nitrogen (N 2) (found at an altitude of 6000 m), which was inhaled for 23 min under normobaric conditions by 18 healthy volunteers. After an adaptation session they received randomized 5 mg Aramexe retard, 5 mg Hydergine and placebo. Evaluation of blood gases, EEG mapping and psychometry was carried out at 0,2, 4,6, and 8 h after oral drug administration — each time under normoxic and hypoxic conditions. Blood gas analysis demonstrated a drop in SaO 2 from 99% under normoxia to 70% under hypoxia, in P o 2 from 100 to 33 mmHg, and in P co 2 from 36 to 31 mmHg, while pH increased from 7.43 to 7.48. Base excess and standard bicarbonate remained stable. Under hypoxia EEG mapping exhibited an increase in δ/θ, a decrease of α and increase of β activity, as well as a slowing of the centroid of the total power spectrum, which reflects deterioration of vigilance. Both CDM preparations significantly attenuated this vigilance decrement, with 5 mg Hydergine showing its encephalotropic peak effect in the second hour, 5 mg Aramexe retard in the sixth and eighth hours. At the behavioral level, hypoxic hypoxidosis induced a deterioration of the noo- and thymopsyche (by 53% under placebo), which was significantly mitigated by both 5 mg Aramexe retard (19%) and Hydergine (32%).

Effects of chronic codergocrine mesylate administration on the brain somatostatinergic system in aged rats

Codergocrine mesylate (dihydroergotoxine; DHET), which is an ergot derivative, has been reported to counteract some age-induced impairments in brain function, but the mechanism of these effects is not known. We examined the effect of chronic DHET administration on the somatostatinergic system in the brains of aged rats. Intraperitoneal injections of DHET (1 mg/kg per day) or of vehicle were given to aged rats for 14 days, and resulted in a significant increase in somatostatin (SOM) receptor binding in all six brain regions examined except the hindbrain. DHET had no effect on SOM receptor binding in the brains of young-adult rats. However, the SOM concentration in aged rats was nearly identical to that in young-adult rats and the SOM concentration in different brain areas did not change after chronic administration of DHET. Thus, the present results suggest that chronic administration of DHET can ameliorate at least one of the age-induced impairments of brain somatostatinergic function.

Co-dergocrine mesylate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in age-related cognitive decline.

Co-dergocrine mesylate is a combination of the mesylated forms of dihydroergocornine, dihydroergocristine, dihydro-alpha-ergocryptine and dihydro-beta-ergocryptine. In animal models and healthy elderly volunteers the compound improves indices of cognitive function such as memory and learning. The mechanism(s) behind such action remains under investigation. Nonetheless, it has been proposed that co-dergocrine mesylate has a dual effect on central monoaminergic neurotransmitter systems, compensating for both hyperactivity and deficits of the adrenergic, serotoninergic and dopaminergic systems. The compound also appears to have a normalising effect on the power of electroencephalogram frequencies, and may improve cerebral metabolism. Results from controlled studies of elderly patients with age-related cognitive decline have established that co-dergocrine mesylate is well tolerated and, in some studies, had statistically significant positive effects on symptoms of cognitive dysfunction. However, there is considerable controversy over the clinical relevance of these results as there was wide variability in the number and type of cognitive and neuropsychological assessments used in individual studies and there may have been considerable overlap in diagnosis of patients with varying degrees of dementia. In addition, the drug has not been compared with most other, more recently developed, centrally active agents. Thus, the specific place of co-dergocrine mesylate in the treatment of age-related cognitive decline remains undetermined, despite many years of clinical use.

Co-dergocrine mesylate inhibits the increase in plasma catecholamines caused by nifedipine in essential hypertension

Co-dergocrine mesylate (Cod), which inhibits norepinephrine secretion by stimulating presynaptic dopamine receptors, and has no known metabolic side effect, has an additive antihypertensive effect to that of Nifedipine (Nif). Plasma norepinephrine, epinephrine, renin activity and aldosterone have been measured after acute administration of Nif and Cod alone and in combination to 18 patients with a diastolic blood pressure greater than 105 mmHg in a cross-over, randomized, double-blind study. Every patient received 4 mg Cod then 20 mg Nif, placebo then 20 mg Nif and 4 mg Cod then placebo. The second treatment was always given 1 h after the first medication. Blood pressure was measured before and every 15 min during the study period. Blood for measurement of catecholamines, aldosterone and renin activity was collected before medication, 1 h after the first dose and 90 min after the second treatment. Blood pressure was significantly lower (P less than 0.05) where Cod preceded Nif. Cod caused a significant decrease in plasma norepinephrine from 293 to 202 pg.ml-1 and in epinephrine from 67 to 55 pg.ml-1. The Nif-induced increase in norepinephrine from a pre-treatment value of 293 pg.ml-1 with preceding Cod to 331 pg.ml-1 was much less than the increase with placebo as premedication, from 284 to 440 pg.ml-1. Nif caused an increase in renin activity but no increase in aldosterone. Nif-related side effects, such as flushing and headache, occurred in 6 patients of whom 5 had no received Cod as premedication.(ABSTRACT TRUNCATED AT 250 WORDS)

Topographic brain mapping of EEG after acute application of ergotalkaloids in the elderly

In a double-blind, placebo-controlled, crossover study the encephalotropic and nootropic effects of single doses of two ergotalkaloids (30 and 60 mg nicergoline and 5 mg co-dergocrine mesylate (CDM)) were investigated in 12 elderly subjects (mean age 67 years), utilizing topographic brain mapping of the EEG. Evaluation of EEG, memory, pulse and blood pressure were carried out at 0, 2, 4, 6 and 8 h. Topographic brain maps demonstrated an augmentation of total power, an acceleration of the centroid of the total activity, a decrease of delta/theta and an increase of beta activity (mostly in the alpha-adjacent frequency bands), as well as an acceleration of the centroid of the delta/theta and a slowing of the beta centroid. These changes are indicative of improvement in vigilance of elderly subjects after ergotalkaloids, which was also reflected in the significant improvement of memory after nicergoline. Topographically, the main effect was found over the frontal, central and temporal regions. Timewise, the pharmacodynamic peak fell into the 4th h, although with 60 mg significant encephalotropic effects could be observed in the 2nd and in the 6th h. The drugs were well tolerated.

Brain protection of nicergoline against hypoxia: EEG brain mapping and psychometry : ∗E. Paulus, B. Saletu, J. Grünberger, L. Linzmayer and P. Anderer. Department of Pharmacopsychiatry, Psychiatric University Clinic of Vienna, Austria

In a double-blind, placebo-controlled study the effect-kinetics on brain protection of a new retard formulation of codergocrine-mesylate (CDM) (Aramexe retard®, 5 mg) were investigated and compared with a standard CDM drug (5 mg Hydergine®) utilizing blood gas analysis, EEG mapping and psychometry. A transient, reversible hypoxic hypoxidosis (i.e. impairment of cerebral metabolism due to hypoxia) was experimentally induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) (found at an altitude of 6000 m), which was inhaled for 23 min under normobaric conditions by 18 healthy volunteers. After an adaptation session they received randomized 5 mg Aramexe retard, 5 mg Hydergine and placebo. Evaluation of blood gases, EEG mapping and psychometry was carried out at 0,2, 4,6, and 8 h after oral drug administration — each time under normoxic and hypoxic conditions. Blood gas analysis demonstrated a drop in SaO2 from 99% under normoxia to 70% under hypoxia, in Po2 from 100 to 33 mmHg, and in Pco2 from 36 to 31 mmHg, while pH increased from 7.43 to 7.48. Base excess and standard bicarbonate remained stable. Under hypoxia EEG mapping exhibited an increase in δ/θ, a decrease of α and increase of β activity, as well as a slowing of the centroid of the total power spectrum, which reflects deterioration of vigilance. Both CDM preparations significantly attenuated this vigilance decrement, with 5 mg Hydergine showing its encephalotropic peak effect in the second hour, 5 mg Aramexe retard in the sixth and eighth hours. At the behavioral level, hypoxic hypoxidosis induced a deterioration of the noo- and thymopsyche (by 53% under placebo), which was significantly mitigated by both 5 mg Aramexe retard (19%) and Hydergine (32%).

Effects of co-dergocrine mesylate (Hydergine) in multi-infarct dementia as evaluated by positron emission tomography.

Three female patients aged from 74 to 79 with multi-infarct dementia were studied using positron emission tomography (PET) to assess the effect of co-dergocrine mesylate (Hydergine) on cerebral glucose metabolism. The cerebral glucose utilization (CMRGlc) of each patient was evaluated by PET scan using 2-deoxy-[18F]-2-fluoro-D-glucose (FDG). Following the first PET study, 0.04 mg/kg of co-dergocrine mesylate was injected intravenously with 250 ml saline solution, and then the second PET study was performed. The CMRGlc was determined from the images of the PET scan and the radioactivity of 18F in the plasma. After the administration of co-dergocrine mesylate, the value of CMRGlc increased significantly in the cerebral cortex (p less than 0.01 and p less than 0.05) and basal ganglia (p less than 0.05) compared with values before the administration, but no significant increase was found in the centrum semiovale. These results suggest that co-dergocrine mesylate stimulates glucose metabolism of neurons in the human brain.

Effects of hydergine on platelet deposition on “active” human carotid artery lesions and platelet function

Effects of co-dergocrine mesylate (Hydergine R), a drug widely used for the therapy of cerebral vascular disease on local platelet accumulation in the carotid artery region was studied by means of the platelet uptake ratio (PUR) and on the systemic platelet-vascular wall interaction as calculated from platelet half-life were investigated. A placebo controlled, double blind, randomised protocol was used, 18 patients were treated with co-dergocrine and compared to placebo (n=18). Co-dergocrine treatment resulted in a significant decrease in platelet deposition, PUR decreased from 1.28 ± 0.05 before treatment to 1.25 ± 0.06 on day 5 of therapy with a statistically significant (p < 0.001) in the paired comparison. In the control group the corresponding changes from 1.29 ± 0.04 before to 1.28 ± 0.04 did not show a p-value of less than 0.05 in paired comparison. Platelet half-life (72 ± 11 before vs. 76 ± 11 hours after 5 days of co-dergocrine treatment) showed a statistically significant (p < 0.001) prolongation, whereas in the placebo group no relevant change of T/2 was observed (71 ± 10 before vs. 72 ± 10 hours on day 5, p > 0.10). No relevant effects on ADP-induced platelet aggregation, platelet-release reaction, platelet aggregate ratio, TXB e plasma levels and thrombin-induced MDA-formation could be detected. These results indicate that co-dergocrine decreased in-vivo platelet residence time to atherosclerotic lesions of the carotid artery. Co-dergocrine may thereby be of benefit in prevention of mural thrombus formation and prevention of transient ischemic attacks, but also of atherosclerosis in man.

Effect of prolonged co-dergocrine mesylate treatment on choline acetyltransferase levels in rat cerebral cortex after lesioning of the nucleus basalis magnocellularis (of Meynert)

The effects of monolateral lesions of the nucleus basalis magnocellularis (of Meynert) and of 1 or 4 weeks of co-dergocrine mesylate treatment (0.1 or 0.6 mg/kg) on choline acetyltransferase activity in rat frontal, parietal and occipital cortex were studied. According to the literature, ibotenic acid-induced lesions of the nucleus basalis magnocellularis cause a significant decrease in choline acetyltransferase activity in frontal and parietal cortex, but had no effect on enzyme activity in the occipital cortex or cortical areas controlateral to the lesion. Co-dergocrine administration caused, after 4 weeks of treatment, a dose related increase of choline acetyltransferase activity in the frontal and parietal cortex in the lesioned side. In contrast, it had no effect on the enzyme activity in the other cortical regions studied. The possible significance of the increased choline acetyltransferase activity elicited by co-dergocrine mesylate in cerebral cortex areas sensitive to nucleus basalis magnocellularis lesions is discussed.

Use of the whole-embryo culture system in drug safety assessment?

The embryotoxicity and, in particular, the teratogenic potential of three new drug combinations were investigated. The interactions of the single components (all already on the market) in the different drug mixtures were determined by testing the single components in addition to the drug combinations. In order to evaluate the usefulness of these results for safety assessment, the no-effect concentrations (NEC) of the single compounds or the mixed drug preparations, with respect to embryonic growth and differentiation and the presence of anomalies, were compared with human plasma/serum levels during therapeutic use. In addition, in vivo animal data of the single components were used to put into perspective the NEC values after direct in vitro exposure of embryos. Embryotoxicity, measured as a retardation of growth and of differentiation, as well as an increased percentage of cultured embryos with morphological abnormalities, was present at concentrations of 100 μg/ml for the preparation KT 1/300 (ketotifen/theophylline). These effects could be attributed to the component theophylline, as ketotifen was free of an embryotoxic/teratogenic potential in vitro. In the case of the compound mix VKB/BQ, a combination of pindolol, clopamide and endralazine, the in vitro effects of the mixture on embryonic development could also be attributed to one of the compounds (pindolol) in the mixture. In the case of HYCT 4520, the effects of the components hydergine (co-dergocrine mesylate), clopamide and triamterene on embryonic growth, differentiation and anomalies were additive in the drug mixture. None of the compounds was reported to be associated with human teratogenicity. The NEC of the components in the whole-embryo culture system, tested either as a mixture or as individual compounds, were higher than the human peak plasma levels measured during therapeutic use of the compounds. In addition, the single components were reported to be non-teratogenic in in vivo teratogenicity studies up to doses many times higher than the therapeutic dose levels in humans. This study illustrates the usefulness of the whole-embryo culture system as a suitable tool for investigating the embryotoxicity/teratogenicity potential of newly registered drug combinations and the synergistic effects of their single components as part of registration toxicology.

The effect of chronic hydergine treatment on the plasticity of synaptic junctions in the dentate gyrus of aged rats.

The number of synapses (Nv), the surface density of contact zones (Sv) as well as the average size (S) of E-PTA stained synapses in the supragranular layer of the dentate gyrus from adult (12 months), old (30 month), and Hydergine-treated old (30 months) rats were measured by using quantitative morphometric techniques. In old animals, Nv and Sv were significantly reduced, whereas S was significantly increased as compared with the values in adult rats. Hydergine (Codergocrine mesylate) treatment of old animals (3 mg/Kg/day for 4 weeks) influenced these three parameters, differentially. The Sv in aged animals receiving Hydergine, relative to that in untreated old rats, was significantly increased; the number and size of synapses in the treated old rats were significantly higher and smaller, respectively, than that in old controls. We interpret the present findings to indicate a modulating effect of Hydergine on the morphological plasticity of synaptic junctions in the dentate gyrus of aged rats.

Pentoxifylline

Pentoxifylline (oxpentifylline) is an orally active haemorheological agent for the treatment of peripheral vascular disease, cerebrovascular disease and a number of other conditions involving a defective regional microcirculation. Pentoxifylline acts primarily by increasing red blood cell deformability, by reducing blood viscosity and by decreasing the potential for platelet aggregation and thrombus formation. Extensive open and placebo-controlled studies have shown that pentoxifylline 600 to 1200 mg/day for at least 6 weeks is associated with subjective and objective improvements in 60 to 100% of patients with peripheral vascular disease. The most commonly assessed clinical parameter, walking distance, is usually improved by about 100%, although much greater improvements have also been documented. Other parameters which have been clearly improved include lower limb rest pain, paraesthesia, muscle blood flow, cramps and leg ulcers. Pentoxifylline has produced consistently better results than placebo, and in those studies using comparative drugs, better results than nylidrin, adenosine and naftidrofuryl. In patients with cerebrovascular disorders, open studies with pentoxifylline, usually at a dosage of 600 to 1200 mg/day (300 to 600 mg/day in Japan), have shown marked overall clinical improvements in about 85% of patients. Symptomatic improvements in rehabilitation psychometric tests, neuromotor and speech deficits and other subjective symptoms have accompanied increased cerebral blood flow, particularly to ischaemic areas. Pentoxifylline would appear to be useful in most types of cerebrovascular disease including transient ischaemic attacks, sequelae of cerebral thrombosis and haemorrhage, and chronic ischaemic disorders. In patients with chronic cerebrovascular disease pentoxifylline 600 to 1200 mg/day conferred significant clinical benefit compared with placebo and in isolated studies proved to be superior to drugs such as co-dergocrine mesylate, adenosine and pyrithioxine. Preliminary studies indicate that pentoxifylline may also prove useful in vaso-occlusive crises of sickle cell disease, some hearing disorders, disorders of eye circulation, high altitude sickness and asthenozoospermia. Pentoxifylline is usually well tolerated when administered as the conventional controlled release formulation, gastrointestinal symptoms (about 3%) being the most common complaint, although these and other adverse effects have not occurred to a significantly greater extent than with placebo. Thus, pentoxifylline offers a well-tolerated and effective alternative to the treatment options available for patients with peripheral vascular disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Proof of antihypoxidotic properties of tenilsetam in man by EEG and psychometric analyses under an experimental hypoxic hypoxidosis

AbstractProof of the protective properties against cerebral hypoxic hypoxidosis of a new potentially nootropic drug, tenilsetam (TEN), were studied as compared with 5 mg co‐dergocrine mesylate (CDM) in a double‐blnd, placebo‐controlled trial. Hypoxic hypoxidosis was induced by a fixed gas combination of 9.8% oxygen and 90.2% N2, equivalent to 6,000 m altitude, which was inhaled for 23 min under normobaric conditions by 15 healthy volunteers. They received randomized after an adapation session placebo, 150 mg, 300 mg, and 900 mg TEN and 5 mg CDM. Blood gases, quantitative EEG, and psychometric measures were obtained under normoxic (21% O2) and hypoxic (9.8% O2) conditions before as well as 2,4,6, and 8 hr after oral drug administration. Blood gas analysis demonstrated under hypoxia a drop in PO2 from 91 to 37 mm Hg and in PCO2 from 38 to 33 mm Hg, while pH increased from 7.41 to 7.47. Under these hypoxic conditions, computer‐assisted spectral analysis of the EEG showed an increase of delta/theta, decrease of alpha, and increase of superimposed fast beta activity indicative of deterioration in vigilance. The latter was documented at the behavioral level by deterioration of intellectual and mnestic functions, psychomotor activity, performance in a reaction time task, mood, and wakefulness. Both TEN and CDM attenuated this brain dysfunction, although in a different manner. Whereas TEN induced an increase in alpha and decrease of fast beta activity as compared with placebo, 5 mg CDM attenuated delta/theta and increased alpha‐adjacent beta activity. Multivariate analysis based on changes in all EEG‐variables exhibited the highest dosage TEN and the reference substance significantly different from placebo. Psychometric data added—despite high variance—further evidence for antihypoxidotic/nootropic properties of both drugs, as psychometric performance under hypoxia deteriorated by 45% after placebo, while after 5 mg CDM, 150 mg, 300 mg, and 900 mg TEN only by 25, 27, 39, and 22%, respectively. Based on changes in all 12 psychometric variables obtained at all times, 900 mg, but also 150 mg TEN as well as 5 mg CDM, were significantly different from placebo. Under normoxic conditions, multivariate analyses did not show any significant differences to placebo, and only singular neurophysiological and behavioral changes were observed.

Effects of prolonged co-dergocrine mesylate (Hydergine®) treatment on local cerebral glucose uptake in aged Fischer 344 rats

Hydergine® (co-dergocrine mesylate) was administered orally for 4 weeks to adult (10–12 months old) and aged (28 months old) Fischer 344 rats at dosages ranging from 0.1 mg to 4.0 mg/kg daily, in order to investigate its effect on 14C-deoxyglucose (DOG) uptake by the brain and the dose-effect relation. In the aged rats the dose-effect curve was bell-shaped, with maximal increases in DOG uptake at 0.6 mg/kg co-dergocrine. These were particularly pronounced in the caudoputamen (+47%), nucleus ventralis thalami (+32%), nucleus ventromedialis hypothalami (+57%) and the nucleus suprachiasmaticus (+39%), while the nucleus ambiguus, nucleus dorsalis nervi vagi, nucleus cuneatus and nucleus loci coeruleus also showed increases in DOG utilisation of between 23% and 29%. The dose-effect curve for the adult rats was similar in shape to that for the aged rats, but the peak was much lower and occurred at the lowest dosage (0.1 mg/kg). Cerebral DOG uptake responded considerably more sensitively in the adult rats than in the aged rats, so that the higher dosages were associated with a fall in DOG uptake. Parallels may be detected between the pharmacological effects exerted by co-dergocrine and its effects on DOG uptake in the nuclei of the extrapyramidal system (dopaminergic stimulation), in the hypothalamus (autonomic and neuroendocrine effects, regulation of body temperature and sleep) and in the alpha-receptor nuclei (alpha-blockade, cardiovascular regulation).

Comparative randomized study of cerebral blood flow after long-term administration of pentoxifylline and co-dergocrine mesylate in patients with chronic cerebrovascular disease

The behaviour of regional cerebral blood flow was studied in 90 patients with vascular type dementia. Patients were divided at random into three groups of 30 and treated 3-times daily over a period of 8 weeks with either 400 mg pentoxifylline ('Trental' 400) or 2 mg co-dergocrine mesylate, or remained untreated (control group). Measurements of regional cerebral blood flow were made before and after 4 and 8 weeks of the study using an atraumatic inhalative 133Xenon clearance technique and assessments made in 16 regions of interest per hemisphere (grey matter perfusion). A statistically significant increase over baseline in mean regional cerebral blood flow was found in patients on pentoxifylline medication at Weeks 4 and 8. At Week 8, the change from baseline was +16.4% in the pentoxifylline group whereas the respective values for the other two groups were +0.4% for co-dergocrine mesylate, -2.4% for the controls. Hypoemic regions showed the most pronounced regional cerebral blood flow changes with pentoxifylline (+40%), the corresponding values for the co-dergocrine mesylate and control group being +10.8% and +0.4%, respectively.