Double-blind,placebo controlled study of acetyl-l-carnitine in patients with Alzheimer's dementia

Summary

A randomized, double-blind, placebo-controlled, parallel-group clinical trial was carried out to compare 24-week periods of treatment with I gacetyl-l-carnitine twice daily and placebo in the treatment of patients with dementia of the Alzheimer type. A total of 36 patients entered the trial, of whom 20 patients (7 active, 13 placebo) completed the full 24 weeks. Whilst several of the efficacy indices showed little change in either group during the trial, there was an apparent trend for more improvement in the acetyl-l-carnitine group in relation to the Names Learning Test and a computerized Digit Recall Test, both related to aspects of short-term memory. Similarly, there was a trend for reaction time in the computerized classification test to show less deterioration in the active treatment group. Changes within groups, and changes between groups, failed to reach statistical significance, at least partially because of the small number of patients available for analysis. Two indices of overall therapeutic benefit showed a trend for less deterioration in the active-treatment group than in the placebo group. Nausea and/or vomiting occurred in 5 patients in the acetyl-l-carnitine group. Laboratocy tests revealed no signs of drug toxicity. The results suggest that acetyl-l-carnitine may have a beneficial effect on some clinical features of Alzheimer-type dementia, particularly those related to short-term memory.     

Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimer's dementia

A randomized, double-blind, placebo-controlled, parallel-group clinical trial was carried out to compare 24-week periods of treatment with 1 g acetyl-l-carnitine twice daily and placebo in the treatment of patients with dementia of the Alzheimer type. A total of 36 patients entered the trial, of whom 20 patients (7 active, 13 placebo) completed the full 24 weeks. Whilst several of the efficacy indices showed little change in either group during the trial, there was an apparent trend for more improvement in the acetyl-l-carnitine group in relation to the Names Learning Test and a computerized Digit Recall Test, both related to aspects of short-term memory. Similarly, there was a trend for reaction time in the computerized classification test to show less deterioration in the active treatment group. Changes within groups, and changes between groups, failed to reach statistical significance, at least partially because of the small number of patients available for analysis. Two indices of overall therapeutic benefit showed a trend for less deterioration in the active-treatment group than in the placebo group. Nausea and/or vomiting occurred in 5 patients in the acetyl-l-carnitine group. Laboratory tests revealed no signs of drug toxicity. The results suggest that acetyl-l-carnitine may have a beneficial effect on some clinical features of Alzheimer-type dementia, particularly those related to short-term memory.     

L-acetylcarnitine in depressed elderly subjects. A cross-over study vs placebo

An open, cross-over study was performed on a population of 24 geriatric patients hospitalized because of depressive syndrome. They were subdivided, according to Hamilton's Scale as modified for the aged, into low- and high-score subgroups. The study period covered 2 months. Half the patients received acetylcarnitine for 1 month and placebo thereafter (Group A); the other half received placebo and acetyl-carnitine thereafter (Group B). Statistical evaluation was twofold: parametrical analysis of variance was carried out on 4 subgroups (A1, A2, B1 and B2) and analysis of the score percentage modifications before and after treatment was performed on Groups A and B. The experimental results showed that acetylcarnitine treatment was highly effective and statistically significant in subgroups A1/B1, A2/B2, A1, B1 and B2. In particular, it should be noted that depressive tendencies were significantly modified in most groups, whereas general somatic symptoms as well as anxiety, asthenia and sleep disturbances proved to be little affected. Clinical evaluation, carried out by calculation of modifications in pre- and post-treatment score percentages, provided clear evidence that acetylcarnitine was particularly effective in patients showing more serious clinical symptoms. The drug caused no side-effects at the doses and regimens used.     

Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms. A double-blind cross-over study.

1. The effect of clomipramine and desipramine on diabetic neuropathy symptoms was examined in a double-blind, randomised, placebo controlled, cross-over study for 2 + 2 + 2 weeks. Drug doses were adjusted according to the sparteine phenotype, i.e. extensive metabolisers were treated with 75 mg clomipramine day-1 and 200 mg desipramine day-1 whereas poor metabolisers were treated with 50 mg day-1 of both drugs. Nineteen patients completed the study. 2. Plasma concentration of clomipramine plus desmethylclomipramine was 70-510 nM in extensive metabolisers, vs 590 and 750 nM in two poor metabolisers. Desipramine levels were 130-910 nM, vs 860 and 880 nM. 3. Both clomipramine and desipramine significantly reduced the symptoms of neuropathy as measured by observer- and self rating in comparison with placebo. Clomipramine tended to be more efficacious than desipramine. Patients with a weak or absent response on clomipramine had lower plasma concentrations (clomipramine plus desmethyl-clomipramine less than 200 nM) than patients with a better response. For desipramine a relationship between plasma concentration and effect was not established. 4. Side effect ratings did not differ for clomipramine and desipramine and on both drugs three patients withdrew due to side effects. 5. Compared with earlier results obtained with imipramine dosed on the basis of plasma level monitoring, clomipramine and desipramine on fixed doses appeared less efficacious whereas the side effect profiles were the same. At least for clomipramine, appropriate dose adjustment on the basis of plasma level monitoring may increase the efficacy.     

Alaproclate: A pharmacokinetic and biochemical study in patients with dementia of Alzheimer type

Alaproclate, a specific inhibitor of neuronal serotonin re-uptake, was given to 12 patients with dementia of Alzheimer type. The drug was rapidly absorbed and an elimination half-life of 7.1 +/- 0.9 h (+/- SD, n = 8) was calculated. Plasma protein binding for alaproclate was 82 +/- 1%. Two weeks of repeated administration produced plasma concentrations of alaproclate similar to those predicted from a single dose. The pharmacological effect of the drug was demonstrated by an inhibition of serotonin uptake in the patients' platelets and a reduction of the serotonin concentration in blood. Global rating of clinical efficacy showed a positive effect of alaproclate in five of the patients, mainly regarding emotional functions.     

Double-blind randomized cross-over trial comparing methylprednisolone with placebo in chemotherapy-induced nausea and vomiting: a study with special reference to efficacy parameters.

Sixty-one patients with breast cancer who received chemotherapy participated in a double-blind randomized cross-over study with methylprednisolone (MP) 250 mg as a single i.v. injection before chemotherapy and placebo as antiemetic treatment. The determining efficacy parameter was preference. Other parameters used were a visual analogue scale for nausea, a categorical four-point nausea intensity scale recorded by a nurse observer, emetic amounts, emetic episodes, acceptance of nausea and vomiting, and global assessments for nausea and vomiting. MP showed a significant antiemetic effect compared with placebo which was most pronounced for moderately emetogenic chemotherapy. The visual analogue scale, emetic amounts, acceptance and global assessments were easy to handle and showed coherence with preference, whereas nausea intensity and emetic episodes were resource demanding to record and showed no coherence with preference. It is concluded that for a precise evaluation of nausea and vomiting the visual analogue scale and emetic amounts are most reliable; for ambulatory patients global assessments seem to be sufficient.     

Senile dementia of the Alzheimer type

The etiology, pathophysiology, neurochemistry, diagnosis, clinical presentation, and management of senile dementia of the Alzheimer type (SDAT) are discussed. The etiology of SDAT is unclear. The pathophysiologic changes in the brain tissue of patients with SDAT are quantitative rather than qualitative in comparison to normal age-matched controls. The number of neuritic plaques and neurofibrillary tangles are positively correlated to the severity of clinical symptoms and cognitive impairment. There is overwhelming evidence that SDAT is associated with a loss of cholinergic function. Reduction of choline acetyltransferase activity, a cholinergic marker, has been significantly correlated to the severity of dementia. The diagnosis of SDAT is one of exclusion and is based upon clinical presentation and neurological, psychological, and laboratory testing. The clinical presentation of SDAT involves the progressive deterioration of intellectual capabilities. Management of SDAT primarily involves supportive care and symptom control. Attempts to treat the disease with cerebral vasodilators, metabolic enhancers, and neurotransmitter manipulation have been largely unsuccessful. Drug therapy aimed at reversing or retarding the progression of the disease is not recommended. Behavioral disturbances represent the main indication for drug use in patients with SDAT. The antipsychotic agents are considered the drugs of choice. SDAT remains an enigma. The successes in the treatment of the disease are few, but as more information is gathered on the neurochemical abnormalities involved, there is hope that early detection can prevent the disease or at least slow its progression.     

Double-blind placebo cross-over study of long-acting (chlordesmethyldiazepam) versus short-acting (lorazepam) benzodiazepines in generalized anxiety disorders

Chlordesmethyldiazepam a long-acting benzodiazepine was compared with lorazepam a short-acting one in a double-blind placebo cross-over study against generalized anxiety disorders. Chlordesmethyldiazepam therapy was more effective than lorazepam. Clinical efficacy, drowsiness and insomnia seem well correlated with pharmacokinetic properties of these two benzodiazepines. These results further support the use of a long-acting benzodiazepine rather than a short-acting one as an anti-anxiety agent.     

Drug persistency of cholinesterase inhibitors for patients with dementia of Alzheimer type in Korea

Archives of Pharmacal Research - This study examined 1-year persistency with cholinesterase inhibitors (ChEIs) for the treatment of elderly Alzheimer’s dementia (AD) patients in Korea. Korean...     

Pharmacological treatment strategies in Alzheimer type dementia

Substitution of cholinergic drugs in the treatment of Alzheimer type dementia (AD/SDAT) has hitherto not been very successful. Accumulating data indicate that monoamines are disturbed in AD/SDAT patients. The selective 5-hydroxytryptamine re-uptake blocker, Citalopram, has proven effective in reducing overactivity in the hypothalamic-pituitary-adrenal axis and in improving emotional disturbances in patients with dementia. Efforts to substitute the dopaminergic system have hitherto been negative. Neither has treatment with neuropeptides made any breakthrough in the treatment of demented patients. Nootropics are drugs like Piracetam that are assumed to activate the metabolism of the neurons. Although these drugs have proven effects on the CNS in animal experiments these effects cannot be reproduced in man to the same extent. A subgroup of patients with late onset dementia has reduced concentrations of vitamin B12 and atrophic gastritis. Whether the vitamin B12 deficiency or deficiency of other essential nutrients, is of importance for the brain dysfunction is not clarified. Treatment trials with vitamin B12, folic acid, S-adenosylmethionine and acetyl L-carnitine are in progress. GM1 has proven effect in peripheral nerve damage. GM1 seems not to penetrate the blood brain barrier. If the effect of GM1 and eventually nerve growth factors should be tested in patients with dementia the administration must obviously be directly into the ventricular space.     

Comparative kinetics of oxiracetam in serum and CSF of patients with dementia of Alzheimer type

The purpose of the study was to determine whether oxiracetam crosses the human blood-brain barrier and to evaluate its comparative kinetics in serum and in cerebro-spinal fluid (CSF). Six DAT patients, undergoing CSF collection for diagnostic purposes, received 2 g oxiracetam daily, by a 60 min i.v. infusion, for 7 days. On the last day, in four patients blood samples were collected at time 0, 30, 60 and 120 min, and lumbar drainage was performed at the end of infusion: at this time mean CSF concentration was 3.5 micrograms/ml, i.e. 4.0% of the serum one, demonstrating that oxiracetam crosses the blood-brain barrier. In two patients, blood samples were collected at time 0, 60, 120 and 240 min, and lumbar drainage was performed 60 min after the end of infusion: at this time mean CSF concentration was 2.8 micrograms/ml, i.e. 5.3% of the serum one, indicating a persistence of oxiracetam within this deep compartment. These results provide the first evidence in humans that oxiracetam penetrates the central nervous system and contribute to the understanding of its long-lasting pharmacodynamic effect in man.     

Nicotine and tetrahydroaminoacradine: Evidence for improved attention in patients with dementia of the Alzheimer type

A placebo-controlled, single-blind study investigated the effects of administering three acute doses of nicotine (0.4, 0.6, and 0.8 mg) to a group of patients suffering from dementia of the Alzheimer type (DAT), and to young and aged normal controls. Performance on objective computerised tests provided evidence for improvements in attentional function rather than memory, in patients with mild to moderate DAT. Despite the lack of drug effect on mnemonic ability, these results demonstrate that DAT patients have significant attentional deficits which can be remediated by nicotine administration. They add to the growing body of evidence that the cholinergic system is involved in the control of attentional processes; and are substantiated by the findings of a second study examining the use of a chronic dose of the cholinesterase inhibitor THA, as a treatment for DAT. In this study, effects on both subjective clinical rating scales and objective computerised tests were assessed. In regard to the former, analysis of the three main clinical outcome measures showed statistically significant effects of the drug on the Mini-Mental State Examination (MMSE) and the Abbreviated Mental Test Score (AMTS), but not on the Activities of Daily Living scale (ADL). Using objective computerised CANTAB tests, sensitive to specific aspects of memory and attention, evidence was found for improvements in attentional function rather than memory, in patients with mild to moderate DAT. These data will clearly provide important comparative data for future investigations of putative cognitive enhancing drugs in DAT sufferers. © 1994 Wiley-Liss, Inc.     

Single-dose and steady-state pharmacokinetics of sabeluzole in senile dementia of Alzheimer type patients

Summary The single- and repeated-dose pharmacokinetics of sabeluzole have been determined in six elderly patients with [senile] dementia of the Alzheimer type.After a single oral dose of 10 mg sabeluzole, the peak plasma concentration was attained at 1 to 4 h; it averaged 42 ng·ml^–1. On repeated dosing (10 mg b. d.), steady-state was virtually attained after 3 days of treatment. Steadystate mean trough and peak plasma concentrations fluctuated between 53 and 94 ng·ml^–1. The mean terminal half-life after a single dose and at steady-state was of the order of 33 h.Sabeluzole was well tolerated and at the end of treatment, no systematic changes in blood haematology, biochemistry or urinalysis were seen.     

盐酸溴己新葡萄糖注射液致严重不良反应1例

对盐酸溴己新注射液中特有的未知杂质进行结构鉴定、合成和分析,并作为已知杂质控制。

通过二维液相色谱串联质谱推导了未知杂质的结构,根据产品的处方工艺推导出了杂质来源,分析杂质产生机制,采用定向合成的方式获得杂质单体,并采用二维液相色谱串联质谱、核磁共振等技术确证杂质的结构,最后采用HPLC对杂质进行分析方法验证。

确证该类杂质为溴己新与辅料葡萄糖反应生成,2个杂质与盐酸溴己新的校正因子分别为2.2和2.4,分析方法专属性和重现性良好。

将该2个注射液特有杂质分别命名为杂质1和杂质2,并作为已知杂质定入标准,按照自身对照加校正因子法计算杂质含量。本研究对指导盐酸溴己新注射液的杂质控制以及辅料葡萄糖筛选有着重要的意义。

     

Double-blind placebo controlled clinical trial of almitrine bismesylate in patients with chronic respiratory insufficiency

Summary The efficacy and safety of almitrine bismesylate, a new respiratory stimulant, in patients with the hypoxaemic form of chronic respiratory insufficiency caused by chronic bronchitis and emphysema has been assessed. The multicentre trial of 12 weeks duration was double-blind and placebo controlled, with individual and group comparisons. Twenty three patients received almitrine 50 mg b.d. p.o. and 17 took placebo. In the almitrine group a significant increase in P_aO₂ was achieved (control value 54.4 mm Hg, rising to 59.1 mm Hg after 6 weeks, and to 59.4 mm Hg after 12 weeks). There was also a significant decrease in P_aCO₂ in the almitrine group after 12 weeks. No correlation was found between the plasma almitrine concentration, P_aO₂ and P_aCO₂. Lung function (FVC, FEV₁, FEV₁/FVC, Raw, TLC, RV, FRC) did not change in either group, but the degree of dyspnoea and performance in the 6 min walking test were significantly improved in the almitrine group.Adverse reactions appeared in 6 out of 23 patients on almitrine bismesylate (headache, urticaria, breathlessness, diarrhoea, chest pain, nausea and vomiting), causing drop out of 4 patients.Thus, almitrine bismesylate can be considered useful in the treatment of patients with chronic respiratory insufficiency.