Dopamine excretion and vulnerability to drug-induced Parkinsonism. Schizophrenic patients.

Before and during a standardized course of trifluoperazine therapy, 18 schizophrenic patients underwent repeated examinations for extrapyramidal motor signs, clinical psychopathology, and urinary excretion of free and conjugated forms of dopamine and its metabolites. Patients excreting more free dopamine and metabolites, or showing less complete conjugation, before drug treatment, were much less likely than others to develop parkinsonian akinesia and rigidity during drug treatment. Neither catatonic rigidity nor akinesia before treatment was predictive of a parkinsonian response to trifluoperazine, but pretreatment tremor may have been. The severity of schizophrenic psychopathology was unrelated to dopamine excretion. This study of schizophrenic patients, and our previous research in Parkinson's disease, suggest that urinary dopamine excretion may reflect dopaminergic function of the extrapyramidal motor system in both conditions.

Effects of levodopa on the renin-aldosterone system.

Plasma renin activity and plasma aldosterone, supine and erect, and urinary aldosterone levels were measured in 18 patients on normal sodium diets and 11 patients on low sodium diets, all of whom also were on long-term levodopa therapy. Of the 230 hormone measurements, 185 were normal, 11 were high, and 34 were low. Most of the low levels were in 3 patients who had recently received fludrocortisone for orthostatic hypotension, and the renin-aldosterone systems might have been suppressed by it. In another phase of this study, 4 subjects were maintained on a constant diet for 6 wk, while the effect of gradually increasing dosages of levodopa on mineral balance and renin-aldosterone was determined. In 3 of the 4 patients there was a mild natriuretic effect of levodopa (previously demonstrated for acute levodopa therapy). There were no significant consistent changes in renin or aldosterone levels while levodopa was being administered. These studies indicate that levodopa does not usually suppress the elements of the renin-aldosterone system and that such a mechanism is unlikely to be the cause of orthostatic hypotension during the course of levodopa therapy. Since levodopa may induce natriuresis, in this situation unchanged lvels of renin and aldosterone may, however, represent an inappropriately low set of this hormonal system.

Low urinary dopamine and prediction of phenothiazine-induced Parkinsonism: a preliminary report.

Psychiatric patients who excreted larger amounts of urinary free dopamine before treatment were significantly more likely than patients excreting smaller amounts to develop parkinsonian side effects during moderate-dose trifluoperazine therapy. If this finding is replicated, urinary free dopamine determinations could prove valuable in indicating which patients should receive those antipsychotic drugs least likely to produce extrapyramidal side effects.

Levodopa-induced postural hypotension. Treatment with fludrocortisone.

Six parkinsonian patients with symptomatic postural hypotension secondary to levodopa therapy were treated with 0.05 to 0.2 mg of fludrocortisone acetate daily for six to ten months. Severe orthostatic light-headedness and frequent syncope had previously been alleviated only be reducing the dosage of levodopa to levels producing less than optimal antiparkinsonian benefits. In all six patients, symptoms were alleviated satisfactorily, and supine and upright blood pressures returned to normal levels during treatment with fludrocortisone acetate. There were no adverse reactions. Fludrocortisone acetate is an effective and safe drug for the treatment of severe and otherwise intractable postural hypotension secondary to therapy with levodopa.

Increased dosage of carbidopa in patients with Parkinson's disease receiving low doses of levodopa. A pilot study.

Twenty-one patients with Parkinson's disease were studied because their low maintenance dosages of carbidopa-levodopa in the customary ratio of 1:10 provided less than the daily 75 mg of carbidopa believed necessary to achieve full inhibition of extracerebral dopa decarboxylation. The dosage of carbidopa was increased 2.5 times to between 75 and 150 mg daily, while the mean dosage of levodopa essentially was unchanged. The new carbidopa-levodopa ratio was 1:4. During 15 months, this treatment produced a moderate decrease in the severity of parkinsonism and a marked decrease in peripheral adverse reactions, without a significant increase in the central adverse effects of levodopa. It is concluded that increasing the dosage of carbidopa may be beneficial to patients with Parkinson's disease receiving less than 75 mg of carbidopa and 750 mg of levodopa daily.

Low dosages of bromocriptine added to levodopa in Parkinson's disease.

Thirty-six patients with Parkinson's disease, on levodopa, were admitted to a double-blind, parallel, 40-week study of adjunct bromocriptine in dosages increased by 2.5 mg every 4 weeks. A 37% improvement of the mean neurologic deficit score was obtained at the maximal daily dosage of 20 mg. Improvement was greatest in patients with mild disease. The wearing-off effect, off-dose abnormal involuntary movements, and leg pains, associated with levodopa, improved in over 70% of patients at an average dosage of 13 mg. Only 15% of patients had adverse reactions severe enough to necessitate discontinuance of the drug. Abnormalities of mental state were less severe than expected, but two patients had exacerbations of angina pectoris.

Acute overdose with levodopa. Clinical and biochemical consequences.

A 61-year-old parkinsonian patient ingested up to 100 gm of levodopa during a period of 12 hours. Signs of parkinsonism were completely alleviated. Adverse effects included initial hypertension followed rapidly by hypotension of a few hours' duration, prolonged symptomatic postural hypotension, sinus tachycardia, mental confusion, insomnia, and anorexia. The effects of the overdose gradually subsided over 1 week. Analyses of serum and urine for dopa and its metabolites confirmed the overdose, which biochemically resulted in apparent saturation of two enzymatic pathways that inactivate dopamine: conjugation with sulfuric acid and O-methylation.

Spinal myoclonus.

The focal involuntary muscular contractions of spinal myoclonus have been associated with neoplastic, infectious, traumatic, and degenerative lesions of the spinal cord. Four patients are described here. In two, the myoclonus is associated with severe cervical spondylitis. One patient had herpes zoster. In the fourth, a segment of thoracic spinal cord is narrow and probably atrophic. Both tetrabenazine and clonazepam were therapeutically effective.

Effect of age at onset on progression and mortality in Parkinson's disease.

We examined longitudinal disability scores in 54 patients with Parkinson's disease followed for 6 years at UCLA. We sorted data into 3 groups based on age at onset of symptoms: group A, onset under 50 years; group B, 50 to 59 years; group C, 60 years or older. There were no significant differences between groups initially. All 3 groups improved dramatically when levodopa was given, but group A showed significantly less disability in years 4, 5, and 6 than did group C. The groups did not differ with respect to side effects. To determine if age at onset affected mortality, we sorted records from 4 geographically diverse centers into the same 3 groups. Results on 359 patients followed for 3,314 person-years, covering a period of 17 years after onset of symptoms, showed that group A had the most favorable observed-to-expected mortality ratio, 1.82, compared with 2.17 and 2.20 for groups B and C respectively, but the difference was not statistically significant. Results from the disability analyses indicate that patients with onset of Parkinson's disease under 50 years of age may have a more favorable prognosis than those whose symptoms begin in later years.

An examination of male-female differences in progression and mortality of Parkinson's disease.

We conducted disability and mortality studies to determine if the male preponderance usually found in Parkinson's disease (PD) was reflected in different courses of the diseases in the 2 sexes. We analyzed longitudinal disability score in 47 men and 23 women with PD followed for 6 years at UCLA. We found no significant differences between the sexes in mean disability scores in any of the 6 years. Mean dopa dosage was significantly higher in men, possibly reflecting their generally larger body mass. Choreoathetosis, dementia, or other side effects did not differ between the 2 groups. We obtained observed to expected mortality ratios in 239 men and 132 women followed for 3,831 person-years from records of 4 medical centers. Using the sex-specific US Life Tables to calculate expected mortality, we found the observed to expected ratio for the men was 1.7457 and for the women 2.4740, a significantly greater excess in female mortality. Analyses of mortality using tables which are not sex-specific will fail to uncover the decreased longevity in women with PD. We conclude that, despite the male preponderance in PD, men and women acquire it at the same age, have the same progression and duration of disease, and die at the same age; whereas, in the general population, women have a longer life expectancy than men. It is not known what factors protect women from incurring PD and what lowers their life expectancy to that of men when they do have the disease.

Hypothalamic atrophy.

A patient, who has been followed for thirteen years, developed the first symptoms of progressive hypothalamic atrophy at the age of 39. The diagnosis was confirmed by pneumoencephalography five years after onset. Hypothalamic dysfunction was manifested clinically by loss of libido, impotence, obesity, polydypsia, somnolence, and rage attacks. Assessment of endocrinologic function demonstrated low serum levels of testosterone, FSH, and LH, a diabetic glucose tolerance curve, decreased basal and hypoglycemic stimulated levels of HGH, and progressively increasing levels of serum prolactin. Repeated pneumoencephalography revealed an initial, and then progressive, enlargement of the third ventricle which was later associated with generalized, but proportionately less severe, atrophy of the cerebellum and cerebral hemispheres. Analysis of the physiologic and endocrinologic mechanisms underlying these abnormalities suggests diffuse hypothalamic damage, especially in the ventromedial area. The decreased somnolence and increased libido and potency which accompanied therapy with levodopa suggest damage to dopaminergic and noradrenergic pathways. Slowly progressive hypothalamic atrophy, confirmed by pneumoencephalography, but without specific etiology, has not been reported previously. This article describes such a patient followed over thirteen years, and the efficacy of therapy with levodopa in ameliorating certain aspects of his disease.

Age distribution of patients with Parkinsonism.

The modal age at onset of the parkinsonian syndrome during the past thrity years is less than a decade higher than it was in the late 19th and early 20th centuries, suggesting that the same disease entity is affecting parkinsonian patients now as then. The evidence points to the existence of two distinct clinical entities: 1) parkinsonism secondary to encephalitis lethargica, which had its greatest influence on the epidemiology of parkinsonism between 1920 and 1945; and 2) classic parkinsonism, which has undergone little change in the past hundred years.

Bromocriptine and its use in Parkinsonism.

Bromocriptine is a potent dopamine agonist which directly stimulates dopamine receptors. In the corpus striatum, this action results in alleviation of many of the signs and symptoms of parkinsonism. The effectiveness of bromocriptine may persist for at least one to two years; results of more prolonged treatment are not available. Adverse reactions are common and often severe, but safety in dosages up to 100 mg daily for one to two years has been adequately established. Bromocriptine is qualitatively and quantitatively similar to levodopa in both beneficial and adverse effect. However, because of variations in individual response, bromocriptine sometimes ameliorates the problems of prolonged levodopa therapy, i.e., declining efficacy, fluctuations in therapeutic response, and the development of disabling abnormal involuntary movements, Thus bromocriptine is a valuable adjunct in the treatment of parkinsonism.

A trial of antilymphocyte globulin in the treatment of chronic progressive multiple sclerosis.

Twenty-three patients with chronic progressive multiple sclerosis (MS), resistant to steroid therapy, were treated with antilymphocyte globulin (ALG) and prednisone (30 mg by mouth daily). Twelve patients completed a full course of therapy (2 ml ALG i.m. daily for 2 weeks and 2 ml i.m. on alternate days for 2 weeks) and 6 others completed at least 2 weeks of daily injections. Six patients experienced an overall improvement of at least 15% using a comprehensive neurological scoring system. Three other patients had limited, but functionally useful improvement in specific neurologic functions. Six months after the completion of therapy, no patient had deteriorated to a level of function below that noted prior to treatment. Adverse reactions, which often necessitated stopping treatment, included fever, local inflammatory reactions, local rash, general malaise, mild anaphylactoid reactions, and enlargement and tenderness of regional lymph nodes. Because of the short duration of immunosuppression and the toxic side effects of ALG, we do not feel that ALG treatment yet deserves to be intorduced as a standard treatment in clinical practice. However, the improvement or arrest of progression seen in these patients who were deteriorating progressively despite steroid therapy would seem to justify a continued search for a safer method of suppressing immunity in MS patients.

Parkinsonism treated with levodopa: progression and mortality.

Patients with Parkinson's disease treated with levodopa over the past 15 years were compared, by parallel statistical methods, to a group of similar patients followed for 15 years before the levodopa era. The duration of illness at each Stage of disease was longer in the treated group, and, at each duration of illness, there was less disability and death. The prevalence of peak-dose dyskinesias increased with increased duration of treatment, but seldom out-weighed the benefits of treatment. Although extreme fluctuations of therapeutic response were not seen during the first 2 years of treatment, their prevalence was otherwise uninfluenced either by the duration of treatment or by postponing treatment. There is, however, some evidence that the postponement of treatment is accompanied by an increased proportion of patients who become "unresponsive" to levodopa. The age at death was 4.5 years older than in the untreated group, and the mortality rate equal to that of the general population. There is ample evidence that treatment with levodopa improves the quality and length of life, and no real evidence that delaying therapy confers benefits in the future.

Parkinson's disease: progression and mortality.

Patients with Parkinson's disease were compared during two 15-year periods before and after the introduction of levodopa. With levodopa treatment: The duration of illness at each stage of severity was 3 to 5 years longer; at every duration of illness, death and disability were reduced 1.5- to 3-fold, except in patients whose treatment had been delayed; abnormal involuntary movements that interfered with function occurred in 24% of patients; severe fluctuations that required rescheduling of activities occurred in 29% of patients; severe AIMs and fluctuations were rare during the first 3 years of treatment, but remained constant thereafter, without progressive increase; prevalence of severe fluctuations was related only to age of onset of disease: If under 50, severe fluctuations developed in 66%, if age 50 to 59 at onset, they developed in 30%, if over age 60, in only 6%; average age at death was 6 years older; and observed/expected mortality was 1.2, not significantly different from the unaffected population.

The natural history of Parkinson's disease in the pre-levodopa and post-levodopa eras.

Since Parkinson's disease was first described by James Parkinson in 1817, the natural history has been confounded by various treatment modalities: the replenishment of deficient dopamine, the addition of the dopamine agonists, and the more recent addition of drugs whose putative action may slow the natural history of the disease. Nevertheless it remains a disease that is slowly and inexorably progressive over several decades. The quality of life during this progression can be improved, and the duration of life before inanition produces life-threatening complications can be extended. New approaches to identifying the disease before the overt symptoms appear and to slowing the progression of the underlying pathophysiology are being explored but to date have not produced significant changes in the prognosis for the individual patient.

Chronic levodopa and renal function.

Renal function studies were performed in seventeen patients, under metabolic ward conditions, before the initiation of therapy with levodopa. These studies were repeated during the first two to three weeks of treatment and, again, after one to two years of chronic therapy. There were no significant differences between the results of pre- and post-therapy studies, except that the blood urea nitrogen was slightly, but significantly, elevated in the nine patients who had been on the drug for one to two years. During the early weeks of treatment, there was an insignificant trend towards hypotension and increased excretion of sodium. This did not persist in those patients followed for one to two years after the initiation of treatment. Glomerular filtration rate, as measured by an endogenous method, was unchanged by chronic therapy with levodopa. These results are in contrast to the acutely increased glomerular filtration rate, as measured by an exogenous method, and the increased sodium excretion following a single dose of levodopa or dopamine.

The discovery, fermentation, isolation, and structure of antibiotic A33853 and its tetraacetyl derivative.

The structure of antibiotic A33853, isolated from the culture broth of Streptomyces sp., NRRL 12068, is reported. The structure was deduced from an X-ray crystallographic study of its tetraacetyl derivative. Tetraacetyl A33853 is unique because it contains an anhydride moiety, an unexpected product from the reaction of A33853 with acetic anhydride and pyridine.

A30641, a new epidithiodiketopiperazine with antifungal activity.

A new antibiotic, designated A30641, having in vitro activity against Gram-positive bacteria and fungi has been isolated from a strain of Aspergillus tamarii. Chemical and physical characterization indicate that it is a member of the class of antibiotics containing the epidithiodiketopiperazine moiety.