Overview of clinical trials of hydergine in dementia.

OBJECTIVE: To assess the overall effect of Hydergine (a combination drug called ergoloid mesylates) on patients with possible dementia and to investigate potential moderators of an effect. DATA SOURCES: MEDLINE, EMBASE, and two proprietary databases were searched for reports of clinical trials. STUDY SELECTION: Included were randomized, placebo-controlled, double-blind, parallel-group trials in subjects with symptoms consistent with dementia performed with specified outcome instruments and sufficient statistical information to calculate effect sizes. Forty-seven (31%) of 151 trials reviewed met selection criteria. DATA EXTRACTION: Potential moderating variables were extracted from each trial: sample size, inpatient-outpatient status, trial duration, age, gender, medication dose, publication year, and diagnostic grouping. Outcome measures were extracted with their associated statistics. DATA SYNTHESIS: The overall combined treatment effects ("adjusted d") for three types of outcome measures were calculated. Overall, Hydergine was more effective than placebo as assessed by comprehensive ratings (d = 0.47; 95% confidence interval [CI], 0.38 to 0.56; P = .0001), clinical global ratings (d = 0.56; 95% CI, 0.44 to 0.68; P = .0001), and combined neuropsychological measures (d = 0.27; 95% CI, 0.22 to 0.32; P = .0001). Inpatient status, daily doses of 4 mg or more, and vascular dementia were generally associated with larger effects. The effect in patients with possible Alzheimer's dementia was significant only for combined neuropsychological measures in five trials (d = 0.30; 95% CI, 0.16 to 0.44; P = .0001; and with a dose-response, P = .001). CONCLUSIONS: Overall, ergoloid mesylates were more effective than placebo. However, the effect in patients with possible Alzheimer's dementia was very modest at best. The dose-response relation suggests that potentially effective doses may be higher than the currently approved. The circumstances of the efficacy of Hydergine remain inadequately defined.

Inappropriate medication prescribing in homebound older adults.

OBJECTIVES: Little is known about the prescribing of medications in the growing population of homebound older adults. We report on the prevalence and pattern of inappropriate medications in a nursing home-eligible, homebound population. DESIGN: A cross-sectional design. SETTING: A managed care plan for individuals meeting nursing home eligibility. PARTICIPANTS: 2193 homebound people older than age 60. MEASUREMENTS: We reviewed the pharmacy profiles of all older homebound enrollees. We identified the average number of medications per patient and the most commonly prescribed classes of drugs. The medication profiles were also analyzed in the context of the 26 drugs/groups listed as inappropriate by the explicit criteria of Beers [Arch Intern Med 1997; 157:1531-1536]. RESULTS: A total of 2193 people aged 60 to 106 (mean 82.8 +/- 8.8) were taking an average of 5.3 +/- 2.9 drugs (range 0-22). Cardiac drugs and benzodiazepines were the medications most commonly prescribed. We found 1152 of the total 11,689 prescriptions (9.9%) to be inappropriate. Eight hundred seventy-one (39.7%) of these 2193 residents had at least one inappropriate prescription, and 230 (10.4%) had two or more. Of particular concern were 285 people prescribed excessive doses of temazepam and zoldipem, 211 people taking first-generation antihistamines, 115 taking doxepin or amitriptyline, 106 taking an ergoloid, 98 taking dipyridamole, and 85 prescribed a long-acting benzodiazepine. CONCLUSIONS: Our study revealed a high prevalence of psychotropic medications and inappropriate drug use among older homebound residents, a group that is at the highest risk for adverse drug reactions. Because this group is not subject to oversight by regulatory agencies, further interventional studies and provider education will be important.

An ergot alkaloid preparation (Hydergine) in the treatment of dementia: critical review of the clinical literature.

A critical review is presented of 12 clinical trials with Hydergine (a hydrogenated ergot alkaloid preparation) in the treatment of dementia. Qualitative and quantitative comparisons of improvement in symptoms showed that Hydergine consistently produced statistically significant (p less than or equal to 0.05) improvement in 13 symptoms associated with dementia. However, because of the small magnitude of the improvement and the absence of indications of long-term benefit, Hydergine would seem to be of minor value in dementia therapy. Further research with better methodology and design might lead to a different conclusion.

The use of psychoactive drugs in elderly patients with psychiatric disorders: survey conducted in twelve Veterans Administration hospitals.

A survey conducted at 12 VA hospitals included the collection of detailed information on the use of psychoactive drugs in 1,276 elderly psychiatric patients. On the day of the survey, 61 per cent of the patients were receiving psychoactive drugs. Prescription practices relating to the choice of drugs, prevalence of drug use, dosage, combination drug preparations, and antiparkinson agents are discussed in terms of such factors as the patient's age and the diagnosis. Also discussed is the literature on psychoactive drugs, particularly as it pertains to elderly populations.

Mental decline in the elderly: pharmacotherapy (ergot alkaloids versus papaverine).

This is the first double-blind study in outpatients to evaluate the effectiveness of dihydrogenated ergot alkaloids (DEA) (Hydergine) versus papaverine in the treatment of selected symptoms associated with mental aging. In addition, this is the first study comparing these two pharmacologic agents in relatively young geriatric patients, with a mean age in the mid-sixties. After twelve weeks of treatment, ratings of overall clinical condition and global change showed that the 26 patients given DEA improved more than twice as much as the 27 patients given papaverine. Of the 14 individual symptoms rated, 13 improved significantly more in the DEA group than in the papaverine group. These symptoms included confusion, dizziness, unsociability, depressive mood, and mental alertness. Other data confirmed the generally superior results with DEA. In view of its demonstrated beneficial clinical actions and of its notable scarcity of contraindications or side effects, DEA appears to represent a significant pharmacologic contribution to the care of elderly persons showing selected symptoms of mental and functional decline.

The effect of topically applied vasoactive agents and testosterone versus testosterone in the treatment of erectile dysfunction in aged men with low sexual interest.

The objective was to evaluate the efficacy and safety of topically applied cream containing testosterone, isosorbide dinitrate and co-dergocrine mesylate compared to testosterone cream in the treatment of erectile dysfunction in aged men with low sexual interest. A randomised double-blind crossover trial was performed over two months. The subjects were 42 men with erectile dysfunction and low normal or slightly depressed testosterone level randomly allocated to two equal groups. Polypharmacy cream containing testosterone 0.8%, isosorbide dinitrate 0.5% and co-dergocrine mesylate 0.06% was applied for one month, and testosterone 0.8% cream for another month. The serum level of total testosterone was measured before and after each phase of treatment. Response to each therapy was assessed by a sexual questionnaire, measurement of tumescence and repeat penile duplex ultrasonography. Twenty-eight patients reported full erection and satisfactory intercourse with the polypharmacy cream. Thirteen men reported full erection and satisfactory intercourse with either cream. Polypharmacy cream increased penile arterial flow (P<0.001) and induced tumescence in 34 patients in lab. No patient in either phase of the study has tumescence or a significant increase in cavernous arterial peak systolic velocities after the application of testosterone cream. Serum level of total testosterone increased in all patients (P<0.05). Sexual desire was improved in 85% and 62% of patients during the treatment with polypharmacy cream and testosterone cream, respectively. No marked side effects were reported after either of them. Topical treatment with cream containing testosterone and vasoactive agents may represent a new effective treatment for erectile dysfunction associating with aging.

Drug treatment of Alzheimer's disease. Effects on caregiver burden and patient quality of life.

Alzheimer's disease is a devastating illness that will become more common as the population ages. Although clinical diagnosis of the illness is not certain without histological examination of the brain, and misdiagnosis may occur, broad working criteria to help diagnose the likely presence of Alzheimer's disease are available. Thoughtful clinical evaluation improves diagnostic accuracy, and appropriately diagnosed patients are critical for involvement in research into new antidementia agents. Essential to the discovery of new drugs is careful measurement of illness response. A variety of scales--some aimed at patients, others at their caregivers, and yet others for clinicians--assess Alzheimer's disease severity, progression, symptom response, and quality of life. Of note, patient response is not the only measurement of treatment benefit today. Growing interest is also being placed on tracking the possible amelioration of caregiver 'burden'. This burden refers to the psychological, physical, and material costs of providing care for an Alzheimer's patient over long periods of time. A number of scales and questionnaires have been developed and are occasionally used. Many drugs have been tried in Alzheimer's disease, but very few have produced any benefit, and this is often modest. Ergoloid mesylates, initially thought to be effective, are now considered of little value. The cholinomimetic drugs, especially the acetylcholinesterase inhibitor tacrine, have provided a very modest benefit, slowing the progression of the illness for a number of months. No cognitive improvement has been noted with the various nootropic agents such as piracetam. Early studies with levacecarnine (acetyl-L-carnitine), a substance that facilitates the use of fatty acids, memantidine, the dimethyl derivative of amantidine, and the calcium channel blocker nimodipine, have shown some promise, but require larger, more rigorous studies. As mentioned above, documenting effects in individual patients is crucial; examining for potential benefit to caregivers is a growing part of research design. Current treatment efforts will become more sophisticated as a deeper understanding of the neurobiology of Alzheimer's disease develops. For the immediate future, the goal is not cure but slowing of the disease process. Achieving this limited goal would have a substantial impact on the financial and human costs of the illness.

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.

Hydergine for dementia.

BACKGROUND: Currently hydergine is used almost exclusively for treating patients with either dementia, or 'age-related' cognitive symptoms. Since the early eighties there have been over a dozen more clinical trials, yet hydergine's efficacy remains uncertain. Although previous reviews offer generally favorable support for hydergine's efficacy, they were, however, limited by a bias with respect to the particular clinical studies chosen (eg, the inclusion of case reports, and uncontrolled trials), and by authors' impressionistic assessments of results. Not surprisingly, there has been a lack of consensus among reviewers with regard to the efficacy of hydergine. In 1994, a meta-analysis was published by the present reviewers who reported that overall, hydergine was more effective than placebo. However they also observed that the statistical evidence for efficacy in 'possible or probable Alzheimer's disease' patients was so modest that one additional statistically non-significant trial would have reduced the results to non significance. OBJECTIVES: Because of uncertainty surrounding the efficacy of hydergine, the goals of this overview were to assess its overall effect in patients with possible dementia, and to investigate potential moderators of an effect. SEARCH STRATEGY: The Cochrane Dementia Group Register of Clinical Trials was searched using the terms 'hydergine', 'ergoloids,' 'ergoloid mesylates,' 'dihydroergocristine,' 'dihydroergocryptine,' 'dihydroergotoxine,' and 'dihydroergocornine. MEDLINE, EMBASE, and two proprietary databases were searched also. Published reviews were inspected for further sources. SELECTION CRITERIA: Trials to be included must be randomized, double-blind, parallel-group, and unconfounded comparisons of hydergine with placebo for a treatment duration of greater than 1 week in subjects with dementia or symptoms consistent with dementia. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers, pooled where appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used. Outcomes of interest included clinical global impressions of change and comprehensive rating scales. Potential moderating variables of a treatment effect included: inpatient/outpatient status, trial duration, age, sex, medication dose, publication year, and diagnostic grouping. MAIN RESULTS: There were a total of nineteen trials that met inclusion criteria and that had data sufficient for analysis. Thirteen trials reported sufficient information to use a global rating of improvement and nine trials provided information on a comprehensive rating scale. Three trials provided both outcome measures. It was not possible to use many of the published results in a combined analysis owing to the lack of sufficient data to perform statistical analyses. For the twelve trials that used global ratings, there was a significant effect favoring hydergine (OR 3.78, 95%CI, 2.72-5.27). For the nine trials that used comprehensive ratings, there was a significant mean difference favoring hydergine (WMD 0.96, 95%CI, 0. 54-1.37). Hydergine was well tolerated in these trials, with 78% of randomized subjects available for data analyses. Greater effect sizes on global ratings were associated with younger age, and possibly higher dose, although most of the subgroup analyses were statistically insignificant. REVIEWER'S CONCLUSIONS: As in an earlier systematic review, we found hydergine to show significant treatment effects when assessed by either global ratings or comprehensive rating scales (based here on a smaller set of trials than in the earlier published systematic review because trials were required to have data that could conform with MetaView, the Cochrane Collaboration statistics software). The small number of trials available for analysis, however, limited the ability of subgroup analyses to identify statistically significant modera

Hydergine for dementia.

BACKGROUND: Currently hydergine is used almost exclusively for treating patients with either dementia, or 'age-related' cognitive symptoms. Since the early eighties there have been over a dozen more clinical trials, yet hydergine's efficacy remains uncertain. Although previous reviews offer generally favorable support for hydergine's efficacy, they were, however, limited by a bias with respect to the particular clinical studies chosen (eg, the inclusion of case reports, and uncontrolled trials), and by authors' impressionistic assessments of results. Not surprisingly, there has been a lack of consensus among reviewers with regard to the efficacy of hydergine. In 1994, a meta-analysis was published by the present reviewers who reported that overall, hydergine was more effective than placebo. However they also observed that the statistical evidence for efficacy in 'possible or probable Alzheimer's disease' patients was so modest that one additional statistically non-significant trial would have reduced the results to non significance. OBJECTIVES: Because of uncertainty surrounding the efficacy of hydergine, the goals of this overview were to assess its overall effect in patients with possible dementia, and to investigate potential moderators of an effect. SEARCH STRATEGY: The trials were identified from a search of the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group on 15 November 2000 using the terms hydergin*, ergoloid* and dihydroergo*. Two proprietary databases were searched also. Published reviews were inspected for further sources. SELECTION CRITERIA: Trials to be included must be randomized, double-blind, parallel-group, and unconfounded comparisons of hydergine with placebo for a treatment duration of greater than 1 week in subjects with dementia or symptoms consistent with dementia. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers, pooled where appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used. Outcomes of interest included clinical global impressions of change and comprehensive rating scales. Potential moderating variables of a treatment effect included: inpatient/outpatient status, trial duration, age, sex, medication dose, publication year, and diagnostic grouping. MAIN RESULTS: There were a total of nineteen trials that met inclusion criteria and that had data sufficient for analysis. Thirteen trials reported sufficient information to use a global rating of improvement and nine trials provided information on a comprehensive rating scale. Three trials provided both outcome measures. It was not possible to use many of the published results in a combined analysis owing to the lack of sufficient data to perform statistical analyses. For the twelve trials that used global ratings, there was a significant effect favoring hydergine (OR 3.78, 95%CI, 2.72-5.27). For the nine trials that used comprehensive ratings, there was a significant mean difference favoring hydergine (WMD 0.96, 95%CI, 0.54-1.37). Hydergine was well tolerated in these trials, with 78% of randomized subjects available for data analyses. Greater effect sizes on global ratings were associated with younger age, and possibly higher dose, although most of the subgroup analyses were statistically insignificant. REVIEWER'S CONCLUSIONS: As in an earlier systematic review, we found hydergine to show significant treatment effects when assessed by either global ratings or comprehensive rating scales (based here on a smaller set of trials than in the earlier published systematic review because trials were required to have data that could conform with MetaView, the Cochrane Collaboration statistics software). The small number of trials available for analysis, however, limited the ability of subgroup analyses to identify statistically significant moderating effects. Unfortunately, most of the randomized, double-blind, and placebo-controlled trials of hydergine were conducted and published before the advent of consensus-based diagnostic standards of dementia in 1984; therefore diagnostic criteria were less specific. As a result, uncertainty remains regarding hydergine's efficacy in dementia.

Alpha-dihydroergocryptine and predictive factors in migraine prophylaxis.

OBJECTIVE: A double-blind, crossover study was carried out to compare the efficacy of alpha-dihydroergocryptine mesylate (10 mg twice daily) vs propranolol (40 mg twice daily) in the prophylaxis of migraine without aura, and to identify possible predictors of therapeutic response by evaluating the symptomatological profile of individual migraine attacks and the autonomic cardiovascular response to noradrenergic and dopaminergic (cold pressor, bromocriptine) tests. PATIENTS AND METHODS: Forty migraineurs (10 males, 30 females) were randomized according to a two-period (3-month), two-treatment, crossover design. Efficacy was assessed using quantitative data recorded in the patient's headache diary. Data were evaluated using the Wallenstein's method. RESULTS: Both drugs showed a significant reduction in all the efficacy variables (headache attacks, days with headache, analgesic consumption) with no difference between treatments. Neither a bromocriptine test, nor a cold pressor test nor the symptomatological profile of individual migraine attacks differed between the two groups of migraine patients. Ten patients experienced at least one adverse drug reaction during the first period of the crossover design, 5 being treated with alpha-dihydroergocryptine and 5 with propranolol. CONCLUSIONS: It is concluded that alpha-dihydroergocryptine is an effective medication for migraine prophylaxis. The biochemical tests and the type of psychological profile cannot be used to predict drug response.

Ergoloids and ischaemic strokes; efficacy and mechanism of action.

In this double-blind, randomized study the efficacy of the ergoloid compounds, co-dergocrine mesylate and nicergoline, in the rehabilitation of patients with ischaemic stroke was investigated. A group of 30 patients was treated daily with 60 mg nicergoline, orally, and a second group of 27 patients was given 1.8-6 mg co-dergocrine mesylate, orally or intramuscularly, daily (depending on the time since the initial ischaemic insult) for 6 months. Outcome measures included: motoricity index (limb function); Sandoz Clinical Assessment Geriatric (SCAG) scale; psychometric tests to assess functions such as attention, psychomotor performance, perception and sensory and short-term memory; conventional and computerized electroencephalography; and P300 and reaction time measures. The results showed improvements in some aspects such as limb function (P < 0.05), SCAG score (P < 0.01) and some electrophysiological parameters (P < 0.01) after treatment with both drugs. Though statistically significant most of the changes were not large. The efficacy of both drugs was qualitatively similar. The quantitative difference in some aspects in favour of nicergoline could be attributed to differences in the mechanisms of action of the two drugs, although it is also possible that the difference may reflect the dosages used. Nootropic drugs may induce a condition that facilitates the effects of cognitive training.

[Effect of hydrogenated ergot alkaloids on cerebral metabolism of the patients with neurological deficits after subarachnoid hemorrhage (author's transl)].

Cerebral blood flow and metabolism were measured in 9 patients with neurological deficits after subarachnoid hemorrhage using the 133Xe intra carotid injection methods. Regional cerebral blood flow (r-CBF) values were calculated with initial slope method (2 minutes flow index), their values were compared with the blood flow response to arterial PCO2 and to administration of hydrogenated ergot alkaloids (HEA). In case of repeated examination after short interval CBF values were corrected using the rate of reproducibility. The content of oxygen, glucose, lactate, and pyruvate in the arterial and the internal jugular blood were measured , and CMRO2, CMR glucose, CMR lactate, values were calculated: 1st step: The measurement of r-CBF was performed immediately after the infusion of 1.5 mg HEA for 15 minutes. The focal ischemic lesions decreased, mean CBF value increased by 8% significantly, arterio-venous difference of oxygen value increased by 20% significantly and CMRO2 value increased by 26% significantly after HEA administration. 2nd step: 1.8 mg HEA was infused for one week. EEG findings were improved after administration of HEA. The pressure and the lactate levels of cerebrospinal fluid decreased, but the effect of HEA must be carefully distinguished from natural recovery. Administration of HEA increased the CMRO2 values and consequently increased the mean CBF values.

[Clinical study on effect of yuantong capsule in treating vascular dementia].

OBJECTIVE: To observe the clinical effect of Yuantong Capsule (YTC) in treating vascular dementia (VD). METHODS: Eighty-three patients of VD were randomized on ratio of 2:1 into two groups, the 54 patients in the treated group were treated with YTC orally administered, 3 times a day, 1 capsule in each time. The remaining 29 patients in the control group were treated with Hydergine orally, 3 times a day, 2 mg in each time. The therapeutic course for both groups was 2 months. RESULTS: The therapeutic effect in the treated group was significantly better than that in the control group, significant difference (P < 0.05 or P < 0.01) was shown in comparison of the two groups in terms of the mini-mental state examination (MMSE) and activity of daily living (ADL) test, symptoms scoring, total effective rate, and laboratory indexes findings. CONCLUSION: The therapeutic effect of YTC in treating VD was obvious.

[Redergin treatment of hypertensive menopausal women]. / Opyt primeneniia redergina u bol'nykh arterial'noi gipertoniei klimaktericheskogo perioda.

AIM: To assess a hypotensive effect of redergin (dihydroergotoxin)--agonist of dopaminergic receptors--in monotherapy (4.5-6 mg/day) and in combination with enalapril and amlodipin (10 mg/day). MATERIAL AND METHODS: Redergin in monotherapy or combined therapy was given to 106 hypertensive women in pre- or postmenopause and 24 hypertensive women of reproductive age. Antihypertensive effect was assessed by changes in arterial pressure, frequency and severity of hypertensive crises, diuresis, clinical symptoms of menopausal syndrome. RESULTS: A significant fall in arterial pressure, intensive diuresis, less frequent or absent hypertensive crises, relief of menopausal symptoms were observed on day 10-14 of redergin monotherapy of menopausal patients with mild hypertension and in combined treatment of menopausal women with moderate and severe hypertension. CONCLUSION: Antihypertensive and diuretic effect of redergin confirm a pathogenetic role of deficient dopaminergic activity in development of menopausal hypertension.

[Pathogenetic basis for using prodectin and teonicol, redergin and aescuzan in complex treatment of chronic gastritis]. / Patogeneticheskie osnovy primeneniia prodektina i teonikola, redergina i éskuzana pri kompleksnom lechenii khronicheskogo gastrita.

The study of the microvessels in bioptates of gastric mucosa and micro haemocirculation in the conjunctiva of 254 patients with chronic gastritis revealed that exacerbation of the gastric process is going on the background of hard terminal bloodstream disorders. They have the generalized character and picture of the typical chronic relapsing trombohaemorrhagic syndrome. The use of Prodectin (250 mg), Teonicolum (150 mg), Redergin (1 tab.) and Aescuzan (25 dr.) 4 times per day during 3 weeks helps to eliminate the microcirculatory disorders and exacerbation of the chronic gastritis.