Incidence of Side Effects from Levodopa during the Introduction of Treatment

Twenty patients with Parkinsonism were investigated in order to establish whether the gradual introduction of treatment with levodopa allows a higher dose to be tolerated than can be achieved if treatment is introduced rapidly. No indication was obtained that slow introduction of treatment offers an advantage in maximum tolerated dose, and patients aged 65 and over responded similarly in this respect to those under 65. The maximum tolerated dose is slightly lower in the elderly patient. The incidence of the different side effects does not appear to be affected by the rate of increasing the dose of levodopa.     

Long-acting nifedipine versus metoprolol as monotherapy for essential hypertension. A randomized,controlled crossover study.

We assessed the efficacy of long-acting nifedipine as monotherapy in 52 patients with mild to moderate essential hypertension in a randomized, controlled crossover study. Good blood pressure control was achieved in 34 of 40 patients (85%) receiving nifedipine (mean daily dose, 52 mg in 2 divided doses) compared with 23 of 40 patients (58%) receiving metoprolol (mean daily dose, 155 mg in 2 divided doses). After treatment for 4 weeks, the mean blood pressures with nifedipine (149.7 +/- 16.6/88.7 +/- 11.1 mm of mercury) and metoprolol administration (163.9 +/- 23.3/94.2 +/- 10.2 mm of mercury) were significantly lower than with placebo (176.7 +/- 17.3/100.9 +/- 7.1 mm of mercury) (P less than .05). The mean systolic pressure during nifedipine treatment was 14.2 mm of mercury lower (95% confidence interval [CI], 3.9 to 24.5 mm of mercury) and mean diastolic pressure 5.5 mm of mercury (95% CI, 0.3 to 10.7 mm of mercury) lower than with metoprolol therapy. Both drugs were reasonably well tolerated, and intolerance requiring withdrawal was encountered in 3 of 45 (7%) patients receiving nifedipine, compared with 1 of 45 (2%) of those taking metoprolol and placebo, respectively. Adverse effects of nifedipine, most of which were transient, included palpitations, headache, facial flushing, and ankle edema. Long-acting nifedipine is a promising agent when given alone for mild to moderate hypertension and can be safely administered in clinical practice.     

L-Dopa in Parkinsonism and the Influence of Previous Thalamotomy

A double-blind cross-over trial over 24 weeks (10 weeks on the active remedy, 4 weeks off treatment, and 10 weeks on placebo) of the effect of L-dopa on idiopathic Parkinsonism (paralysis agitans) has shown no difference in the response obtained in patients who had undergone previous stereotaxic ventrolateral thalamotomy and in those who had not. Of the 34 patients (18 men and 16 women) in the trial 18 had been operated on (nine unilateral, nine bilateral operations) and 16 had not. All patients entering the trial were taking anticholinergic drugs in stable dosage and these were continued throughout. The only factor which seemed to limit the response to treatment was pre-existing hypertension. Of 31 patients who completed the 10-week treatment period, 12 showed marked improvement, 15 moderate improvement, and 4 and mild or negligible change. It seems that previous ventrolateral thalamotomy affords some protection against the development of L-dopa-induced involuntary limb movements on the side contralateral to the operation. As found by others, maximum benefit was seen in bradykinesia and rigidity and related features but a significant reduction in tremor was also noted during treatment. Side effects (nausea, hypotension, and involuntary movements) were common but rarely limited the therapeutic response.     

Drugs of Dependence Though Not of Abuse: Fenfluramine and Imipramine

Measures of subjective feeling used by five patients indicated that depression of mood occurred about four days after fenfluramine withdrawal. An experiment in which another 11 patients took fenfluramine 80 mg for 28 days confirmed the depression, maximal on the fourth withdrawal day. It also indicated that in the first week of administration there was some mood elevation, but with feelings of impaired ability to concentrate. The drug reduced appetite and weight. A comparison is drawn with imipramine, which was found to induce initial and withdrawal changes of subjective experience (of dreaming) in six volunteers. It is suggested that certain mood-influencing drugs may not be drugs of abuse because of some unpleasant initial effects, though they can be drugs of dependence.     

Benzodiazepine hypnotics remain effective for 24 weeks.

Ninety-seven poor sleepers aged 40-68 years took capsules nightly for 32 weeks and made daily subjective ratings. The benzodiazepine hypnotics lormetazepam 2 mg and nitrazepam 5 mg appeared still to improve sleep after 24 weeks of intake when compared with continuous placebo intake. The sustained effectiveness was most evident in a significant shortening of the time taken to fall asleep in patients receiving lormetazepam. After weeks, sleep latency and the quality of sleep were significantly worse than baseline values. The impairment was maximal on the second night after withdrawal of lormetazepam and on the fourth night after withdrawal of nitrazepam. It is concluded that benzodiazepines remain effective for at least 24 weeks but that a period of disturbed sleep may be expected after withdrawal.     

Drug treatment of Parkinson's disease.

A wide variety of drugs is available for treating Parkinson''s disease, including anticholinergics, amantadine levodopa, dopamine agonists, and selegiline. In younger patients (less than 50) levodopa is usually delayed provided that adequate relief of symptoms can be achieved with other drugs. In older patients (greater than 70) levodopa should be started as soon as symptom relief is required. Between these ages there is no consensus, but at present most such patients should probably be given controlled release levodopa before a dopamine agonist is added. Fluctuations can often be alleviated by giving controlled release preparations of levodopa, by giving small doses at frequent intervals, by adding selegiline or a long acting oral agonist, or by subcutaneous apomorphine. Dyskinesia can be peak dose, diphasic, or "off period." The diphasic form is hardest to alleviate. Psychiatric side effects should initially be managed by changing the antiparkinsonian treatment before resorting to antipsychotic drugs.     

Withdrawal from long-term benzodiazepine treatment.

Long-term, normal-dose benzodiazepine treatment was discontinued in 16 patients who were suspected of being dependent on their medication. The withdrawal was gradual, placebo-controlled, and double-blind. All the patients experienced some form of withdrawal reaction, which ranged from anxiety and dysphoria to moderate affective and perceptual changes. Symptom ratings rose as the drugs were discontinued, but usually subsided to prewithdrawal levels over the next two to four weeks. Other features of the withdrawal included disturbance of sleep and appetite and noticeable weight loss. Electroencephalography showed appreciable reduction in fast-wave activity as the drugs were withdrawn, and an improvement in psychological performance was recorded by the Digit Symbol Substitution Test. Because of the risk of dependence on benzodiazepines these agents should probably not be given as regular daily treatment for chronic anxiety.     

GluR1 phosphorylation and persistent expression of levodopa-induced motor response alterations in the Hemi-Parkinsonian rat

The phosphorylation of glutamate receptor 1 (GluR1) has been increasingly implicated in the formation and maintenance of plastic responses. To investigate molecular mechanisms that underlie the persisting alterations in motor response occurring with levodopa treatment of parkinsonian patients, we evaluated the time course of these changes in relation to the phosphorylation of GluR1 in 6-hydroxydopamine (6-OHDA) lesioned animals. Three weeks of twice-daily levodopa administration to rats shortened the duration of the rotational responses and increased the peak turning responses, which lasted at least 7 days after withdrawal of chronic levodopa treatment. The shortened response duration and increased peak turning, resembling human wearing-off fluctuations and dyskinesia, were associated with a marked increase in Ser-845 phosphorylated GluR1 (pGluR1S845) immunoreactivity in lesioned striatum in response to levodopa treatment. The time course of changes in GluR1 phosphorylation correlated with the time course of changes in motor behavior after withdrawal of chronic levodopa therapy. Our immunostaining data showed that these changes were confined to parvalbumin-positive neurons where GluR1 are exclusively expressed. Both the altered motor response and the degree of pGluR1S845 were attenuated by the intrastriatal administration of protein kinase A (PKA) inhibitor Rp-cAMPS or GluR1 antisense oligonucleotides. The results suggest that Ser-845 GluR1 phosphorylation within parvalbumin-positive neurons contributes to the persistence of the motor response alterations produced by chronic intermittent dopaminergic stimulation.     

Comparative Effects of Acute or Chronic Administration of Levodopa to 6-OHDA-lesioned Rats on the Expression and Phosphorylation of <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">d</Emphasis>-aspartate Receptor NR1 Subunits in the Striatum

N-methyl-d-aspartate receptor (NMDA) has been increasingly implicated in the formation and maintenance of various forms of behavioral and synaptic plasticity. Recent evidence has linked striatal NMDA function to the adverse effects of long-term dopaminergic treatment in Parkinson’s disease. The subcellular distribution and phosphorylation of NMDA subunit, NR1, reflects NMDA receptor activity. To elucidate molecular mechanisms that underlie the persisting alterations in motor response occurring with levodopa treatment of parkinsonian patients, we evaluated the effects of unilateral nigrostriatal depletion with 6-hydroxydopamine and subsequent levodopa treatment on motor responses and NR1 alterations. Three weeks of levodopa administration to rats shortened the rotational duration and increased the peak turning responses, which lasted after withdrawal of chronic levodopa treatment. We found a significant reduction in the abundance of both phosphorylated NR1 on serine residues 890 and 896 (pNR1S890 and pNR1S896) and NR1 in the cell plasma membrane of lesioned striatum. Chronic treatment of lesioned rats with levodopa markedly upregulated pNR1S890, pNR1S896, and pNR1S897 in lesioned striatum with a concomitant normalization of the plasma membrane NR1 abundance. The magnitude of increased pNR1S890, pNR1S896, and pNR1S897 is dependent on the number of levodopa injections and is paralleled by a sensitization of the rotational response. Our data indicate that glutamate signaling is triggered during the levodopa administration. Activated NMDA receptor NR1-mediated mechanisms are involved in the persistent expression of the motor response alterations that appear during chronic levodopa therapy of parkinsonian rats and continue after treatment withdrawal. M. Kong and M. Ba are contributed equally to this work.     

Withdrawal Depression in Obese Patients after Fenfluramine Treatment

Measurements of subjective feeling in 20 patients receiving fenfluramine alternating with placebo and in 19 patients receiving phentermine alternating with placebo indicated that depression of mood occurred four days after fenfluramine withdrawal but no such depression was seen with phentermine.     

Cognitive effects of olanzapine treatment in schizophrenia

Improvement in some but not all domains of cognition during treatment with the atypical antipsychotic drugs clozapine, quetiapine, olanzapine, and risperidone has been reported in some but not all studies. It has been recently suggested that these reports are an artifact, related to lessening of the impairment due to typical neuroleptic drugs and anticholinergic agents. The purpose of this study was to further test the hypothesis that olanzapine, an atypical antipsychotic drug reported to have anticholinergic properties, improves cognition in patients with schizophrenia, including domains of cognition related closely to work and social function (ie, verbal learning and memory) and that this improvement is independent of improvement in psychopathology. Thirty-four patients with schizophrenia who were partial responders to typical antipsychotic drug treatment were evaluated with a comprehensive neurocognitive battery, including measures of executive functioning; verbal and visual learning and memory; working memory; immediate, selective, and sustained attention; perceptual/motor processing; and motor skills prior to and following treatment with olanzapine for 6 weeks. The Brief Psychiatric Rating Scale (BPRS) was used to assess psychopathology in patients treated with typical antipsychotic drugs. Subjects were switched to olanzapine (average dose 13.4 mg, range 5-20 mg) and reassessed following 6 weeks and 6 months of treatment. Significant improvement was noted in 9 of 19 cognitive tests, including measures of selective attention, verbal learning and memory, and verbal fluency. No cognitive test was worsened by olanzapine treatment. Improvements in the BPRS Total and Positive Symptom Subscale scores were noted. Improvements in verbal learning and memory, sustained attention, and psychomotor tracking were independent of improvement in psychopathology. These data suggest that olanzapine improved some but not all cognitive deficits in schizophrenia, including verbal memory, a cognitive domain impaired by anticholinergic drugs. The basis for the improvement in cognitive scores, which should lead to improvement in role functioning if real, is discussed.     

Amiodarone for refractory cardiac arrhythmias: 10-year study.

Over a 10-year period 130 patients with drug-resistant cardiac arrhythmias associated mainly with coronary artery disease and its complications were treated with amiodarone. The drug controlled all the tachyarrhythmias associated with the Wolff-Parkinson-White syndrome, 95% of the ventricular arrhythmias, including recurrent ventricular tachycardia and fibrillation, and 92% of the supraventricular arrhythmias. The maximum duration of therapy was 111 months and the mean 34 months. Side effects occurred in 34% of the patients, and there was one withdrawal from therapy per 15.3 patient-years of treatment. The commonest cause of withdrawal was nausea, which was significantly related (p less than 0.01) to a drug interaction with digoxin and diuretics. Reversible neurologic complications occurred in eight patients (6%), and acute myositis was recognized for the first time. Pulmonary infiltration developed in four patients (3%), who were receiving 600 mg of amiodarone per day. The rates of side effects and of withdrawal from therapy differed significantly between the patients whose maintenance doses were 600 and 200 mg/d, at 59% v. 6% (p less than 0.01) and 32% v. 0% (p less than 0.05) respectively. Thus, amiodarone is a very effective antiarrhythmic that can be administered over long periods with acceptable rates of side effects and withdrawal provided the minimal effective dose is used; 400 mg/d or less is desirable.     

Is there a place in the United Kingdom for intensive antacid treatment for chronic peptic ulceration?

Sixty nine patients with chronic duodenal or juxtapyloric ulceration were studied in a prospective double blind randomised trial to compare the efficacy of antacid and placebo at high (30 ml seven times daily) and low (10 ml as required) doses. After four weeks ulcers had healed in 12 out of 18 patients (67%) receiving "low dose" antacid compared with in six out of 17 patients (35%) receiving low dose placebo; ulcers had also healed in six out of 19 patients (32%) receiving "high dose" antacid compared with in two out of 15 patients (13%) receiving high dose placebo. Overall, the effect of antacid was superior to that of placebo in healing ulcers (p less than 0.05) and the effect of low dose treatment was superior to that of high dose treatment (p less than 0.01). There were no significant differences between antacid and placebo at eight weeks. Antacid was better than placebo in relieving pain, but the difference was not significant. Poor compliance and high incidence of diarrhoea made high dose antacid an impractical treatment. Low dose antacid was associated with a significantly better rate of healing than high dose antacid and was far better tolerated. This low dosage of antacid should be considered to be an active treatment in trials of ulcer healing.     

One year's treatment with propranolol after myocardial infarction: preliminary report of Norwegian multicentre trial.

A prospective, randomised, double-blind study was performed to compare the effects of propranolol and placebo on sudden cardiac death in a high-risk group of patients who survived acute myocardial infarction. Altogether 4929 patients with definite acute myocardial infarction were screened for inclusion: 574 (11.6%) died before randomisation, and 3795 (77%) were excluded. Five hundred and sixty patients aged 35 to 70 years were stratified into two risk groups and randomly assigned treatment with propranolol 40 mg four times a day or placebo. Treatment started four to six days after the infarction. By one year there had been 11 sudden deaths in the propranolol group and 23 in the placebo group (p less than 0.038, two-tailed test analysed according to the "intention-to-treat" principle). Altogether there were 25 deaths in the propranolol group and 37 in the placebo group (P less than 0.12), with 16 and 21 non-fatal reinfarctions respectively. A quarter of the patients were withdrawn from each group. Withdrawal because of heart failure during the first two weeks of treatment was significantly more common among propranolol-treated patients than among the controls, but thereafter the withdrawal rate was the same. The significant reduction in sudden death was comparable with that after alprenolol, practolol, and timolol, which suggests that the mechanism of prevention is beta-blockade rather than any other pharmacological property of the individual drugs.     

Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early,mild Parkinson's disease. Parkinson's Disease Research Group of the United Kingdom.

OBJECTIVE: To compare effectiveness of levodopa and levodopa combined with selegiline in treating early, mild Parkinson''s disease. DESIGN: Open, long term, prospective randomised trial. SETTING: 93 hospitals throughout United Kingdom. SUBJECTS: 520 patients with early Parkinson''s disease who were not receiving dopaminergic treatment. INTERVENTIONS: Treatment with levodopa and dopa decarboxylase inhibitor (arm 1) or levodopa and decarboxylase inhibitor in combination with selegiline (arm 2). MAIN OUTCOME MEASURES: Assessments of serial disability, frequency and severity of adverse events, and deaths from all causes. RESULTS: After average of 5-6 years'' follow up, mortality ratio in arm 2 compared with arm 1 was 1.57 (95% confidence interval 1.09 to 2.30), and difference in survival between the two arms was significant (log rank test, P = 0.015). Hazard ratio adjusted for age and sex was 1.49 (1.02 to 2.16), and after adjustment for other baseline factors it increased to 1.57 (1.07 to 2.31). Patients in arm 1 had slightly worse disability scores than those in arm 2, but differences were not significant. Functionally disabling peak dose dyskinesias and on/off fluctuations were more frequent in arm 2 than arm 1. During the trial the dose of levodopa required to produce optimum motor control steadily increased in arm 1 (median daily dose 375 mg at 1 year and 625 mg at 4 years), but median dose in arm 2 did not change (375 mg). CONCLUSIONS: Levodopa in combination with selegiline seemed to confer no clinical benefit over levodopa alone in treating early, mild Parkinson''s disease. Moreover mortality was significantly higher with combination treatment, casting doubts on its chronic use in Parkinson''s disease.     

Predictive value of ambulatory blood pressure shortly after withdrawal of antihypertensive drugs in primary care patients.

OBJECTIVE: To determine whether ambulatory blood pressure eight weeks after withdrawal of antihypertensive medication is a more sensitive measure than seated blood pressure to predict blood pressure in the long term. DESIGN: Patients with previously untreated diastolic hypertension were treated with antihypertensive drugs for one year; these were withdrawn in patients with well controlled blood pressure, who were then followed for one year. SETTING: Primary care. SUBJECTS: 29 patients fulfilling the criteria for withdrawal of antihypertensive drugs. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive value of seated and ambulatory blood pressure eight weeks after withdrawal of antihypertensive drugs. RESULTS: Eight weeks after withdrawal of medication, mean diastolic blood pressure returned to the pretreatment level on ambulatory measurements but not on seated measurements. One year after withdrawal of medication, mean diastolic blood pressure had returned to the pretreatment level both for seated and ambulatory blood pressure. For ambulatory blood pressure, the sensitivity and the positive predictive value eight weeks after withdrawal of medication were superior to those for seated blood pressure; specificity and negative predictive value were comparable for both types of measurement. Receiver operating characteristic curves showed that the results were not dependent on the cut off values that were used. CONCLUSION: Ambulatory blood pressure eight weeks after withdrawal of antihypertensive drugs predicts long term blood pressure better than measurements made when the patient is seated.     

Short term effect of withdrawal of diuretic drugs prescribed for ankle oedema.

OBJECTIVE--To determine the effect of withdrawing diuretic drugs on oedema in patients prescribed them for only ankle oedema, excluding patients with cardiac, hepatic, or renal failure. DESIGN--Randomised controlled trial. SETTING--15 general practices in the Netherlands. PATIENTS--1202 patients aged 65 years or older and taking diuretic drugs, 63 of whom were eligible for the trial. MAIN OUTCOME MEASURE--Change in volumetrically determined ankle oedema (oedema index) over six weeks. RESULTS--34 patients were randomised to stop diuretics and 29 to the control group. In eight patients diuretics had to be restarted. Among patients who had diuretics withdrawn successfully, rebound oedema caused a temporary increase in mean oedema index. The peak level (3.5% (95% confidence interval 1.5% to 5.2%) was reached in the third week, after which the oedema seemed to be returning to the baseline level. CONCLUSION--Few patients who have been prescribed diuretics for only ankle oedema clearly have no contraindications to withdrawing diuretics. If patients are unlikely to have cardiac insufficiency and careful monitoring is provided, withdrawal of diuretics seems to be feasible, though moderate rebound oedema may occur for a short time.     

Diazepam withdrawal syndrome: its prolonged and changing nature.

The diazepam withdrawal syndrome was studied in 10 patients who had abused the drug for 3 to 14 years. In the previous 6 months their consumption of diazepam had ranged from 60 to 120 mg daily; none had used other drugs during this period. The withdrawal period lasted about 6 weeks. The intensity of the symptoms and signs was high initially, fell during the first 2 weeks, then rose again in the third week, before finally declining. Three groups of symptoms and signs were identified. Group A symptoms occurred throughout withdrawal and included tremor, anorexia, insomnia and myoclonus. Group B symptoms and signs were largely confined to the first 10 days and were those of a toxic psychosis. Group C symptoms reached a peak in the third and fourth weeks of withdrawal and were characterized by sense perceptions that were either heightened or lowered. The symptom groups, the presence of tremor and myoclonus, and the relief of symptoms by a test dose permit diazepam withdrawal to be distinguished from anxiety. The biphasic course of the symptoms is probably related to the pharmacokinetics of diazepam.     

Steroid-sparing effect of wormwood (Artemisia absinthium) in Crohn's disease: a double-blind placebo-controlled study.

In this double-blind study carried out at five sites in Germany, 40 patients suffering from Crohn's disease receiving a stable daily dose of steroids at an equivalent of 40 mg or less of prednisone for at least 3 weeks were administered a herbal blend containing wormwood herb (3×500 mg/day) or a placebo for 10 weeks. Besides steroids, 5-aminosalicylates, if dose remained constant for at least 4 weeks prior to entering the trial and/or azathioprine, stable dose for at least 8 weeks, or methotrexate, stable dose for at least 6 weeks, were permitted as concomitant medications. The recruited 40 patients – 20 in each treatment group, were evaluated with the help of a Crohn's Disease Activity Index (CDAI) questionnaire, an Inflammatory Bowel Disease Questionnaire (IBDQ), the 21-item Hamilton Depression Scale (HAMD) and an 8-item Visual Analogue Scale (VA-Scale) in 2-week intervals during the first 10 study weeks, and then at week 12, 16 and 20, which were the trial-medication free observation periods. The initial stable dose of steroids was maintained until week 2, after that a defined tapering schedule was started so that at the start of week 10 all the patients were free of steroids. At the end of week 10 the trial medication was also discontinued. The concomitant medications were maintained at the same dose levels till the end of the observation period that was the end of week 20.There was a steady improvement in CD symptoms in 18 patients (90%) who received wormwood in spite of tapering of steroids as shown by CDA-Index, IBDQ, HAMD, and VAS. After 8 weeks of treatment with wormwood there was almost complete remission of symptoms in 13 (65%) patients in this group as compared to none in the placebo group. This remission persisted till the end of the observation period that was week 20, and the addition of steroids was not necessary. In two (10%) patients did the re-starting of corticoids become necessary? On the other hand, the CD conditions of the patients who received the placebo deteriorated after the tapering of steroids, and re-starting steroids became necessary in 16 (80%) patients in this group after week 10. These results strongly suggest that wormwood has a steroid sparing effect. The improvements in HAMD scores indicate that wormwood also has an effect on the mood and quality of life of CD patients, which is not achieved by other standard medications.