Antagonism by piperidine of levodopa effects in Parkinson disease

The nicotinic cholinergic amine piperidine diminished both the dyskinesia and the symptomatic control in some patients with Parkinson disease receiving levodopa. Since the piperdine configuration is contained in the molecules of the apomorphine and N-propylnoraporphine, it might be responsible for the antagonism of these drugs to some effects of levodopa in Parkinson disease and for the palliation by apomorphine of some dopamine-mediated symptoms in other extrapyramidal disorders.     

Effects of caffeine on levodopa pharmacokinetics and pharmacodynamics in Parkinson disease

The authors studied the acute effect of caffeine on the levodopa pharmacokinetics and pharmacodynamics in 12 patients with idiopathic Parkinson disease. This double-blind, randomized, crossover study revealed that caffeine shortened the maximal plasma concentration of levodopa, decreased the latency to levodopa walking and tapping motor response, and increased the magnitude of walking response. Caffeine administered before levodopa may improve its pharmacokinetics in some parkinsonian patients.     

Postoperative nausea and vomiting

Nausea and vomiting following surgery may either occur as postoperative nausea and vomiting, which is a condition that is mainly related to anesthesia, or as secondary to postoperative ileus, which denotes inhibition of gastrointestinal motility following surgery. Postoperative ileus is a multifactorial event with several contributing mechanisms. Although postoperative nausea and vomiting pathophysiology has been quite well-studied little is known about it. There are multiple targets for treatment, prevention, and its successful empirical management e.g. by 5-HT(3) receptor antagonists. This review describes different aspects of the pathophysiology of postoperative ileus and postoperative nausea and vomiting, their relevance to postoperative care, and the standardized approach to manage postoperative nausea and vomiting that was established by Apfel and coworkers. Despite the recent advances in the understanding and treatment of conditions that trigger nausea and vomiting in the postoperative period, these symptoms remain a significant problem that affects patients' recovery, comfort, and treatment cost.     

Tremor in Parkinson disease: acute response to oral levodopa

A single blind placebo-controlled study has been performed in order to investigate objectively the acute tremorolytic effect of oral L-Dopa in ten parkinsonians chronically treated with L-Dopa. Finger tremor was assessed by means of a computerized accelerometer method, at rest and during maintenance of a fixed posture. Both resting and postural tremor were significantly influenced by L-Dopa. An “acute test” with oral L-Dopa, especially when different tremor components are investigated, may be useful for identifying objectively parkinsonians whose tremor does not respond to drug therapy or shows a deterioration of drug-responsiveness.

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Sommario Uno studio controllato con placebo è stato condotto su 10 pazienti affetti da morbo di Parkinson idiopatico, in trattamento cronico con L-Dopa, allo scopo di valutare in modo obiettivo l'effetto tremorolitico della L-Dopa. Il tremore è stato valutato alle mani mediante una metodica di accelerometria computerizzata, sia in condizioni di riposo che di postura. In entrambe le condizioni l'effetto tremorolitico della L-Dopa si è rivelato significativo. Un “test acuto” con L-Dopa orale, in particolare con l'esplorazione di componenti diverse del tremore, può risultare utile per una valutazione obiettiva di casi di Parkinson che non rispondano alla terapia farmacologica o che manifestino un deterioramento della risposta alla L-Dopa.

     

Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients

Adjunction of the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) to levodopa/carbidopa (LD/CD) improves motor symptoms in patients with Parkinson disease (PD) by a prolonged elimination of LD. But it is not known whether EN addition influences gastric emptying and thus LD pharmacokinetics and pharmacodynamics. Objectives were to simultaneously determine plasma LD elimination, gastric emptying, and clinical response after a single intake of the same LD dosage as LD/CD--or as (LD/CD/EN) formulation on 2 consecutive days. In both groups, PD patients with delayed gastric emptying had significant lower LD plasma concentrations. Addition of EN did not influence gastric emptying but significantly improved motor response, which was not different for patients with delayed gastric emptying. However, with and without EN adjunction gastric emptying distinctly contributes to the variability of plasma LD bioavailability. This may impact LD delivery to the brain and thus motor response in PD patients. Therefore, fine tuning of LD application, which considers gastric emptying, becomes more and more essential in advanced PD stages with a reduced striatal neuronal dopamine capacity, which is responsible for maintenance of motor response in early PD patients.     

Acute levodopa intake and associated cortisol decrease in patients with Parkinson disease

Levodopa application improves motor symptoms in patients with Parkinson disease (PD). Levodopa induces lower cortisol plasma levels and decreases serotonergic activity in certain brain areas of fish. The objectives of this study were to perform repeat cortisol concentration measurements before and after the administration of soluble levodopa/benserazide (dose, 200 mg) in 32 patients with PD during an interval of 150 minutes. The cortisol concentrations significantly decreased after levodopa intake, particularly in the patients with more advanced stage of PD, but not in the less affected patients. There were significantly lower cortisol levels in the patients at the advanced stage of PD compared with those of the earlier patients with PD, particularly at -30, 0, and 90 minutes before/after levodopa application. Significant inverse relations were found between the cortisol levels and the Unified Parkinson Disease Rating Scale total score, particularly at 60 and 90 minutes after levodopa intake. Neurodegeneration occurs in striatal regions and in the brain stem of patients with PD. The 5-HT-containing neuronal terminals of the brain stem hypothetically mediate the cortisol level decrease after levodopa intake because these cells contain an important fraction of amino acid decarboxylase. Therefore, this compartment may be the site of enzymatic conversion of superfluous, exogenous levodopa to dopamine. Consequently, short-term levodopa administration also leads to levodopa uptake in these 5-HT-metabolizing neurons, which interferes with the 5-HT synthesis and may cause a decrease of 5-HT levels. These lower 5-HT levels reduce the hypothalamic function and, via the corticotropin axis, the subsequent peripheral cortisol release. Thus, levodopa-induced cortisol decrease may be related to PD progression.     

Sympathetic modulation by levodopa reduces vascular risk factors in Parkinson disease

BackgroundSympathetic nervous system hyperactivity promotes vascular disorders by its catabolic effects and by increasing arterial blood pressure. Levodopa-derived dopamine modulates sympathetic overactivity and is known to reduce blood pressure, but its effects on glucose and lipid metabolism have not been studied in large series of patients.MethodsWe retrospectively examined 483 consecutive parkinsonian patients, admitted to a single institute between 1970 and 1987, before statins were available. We compared risk factors for vascular disease in the 305 who were on levodopa with the 178 who had never received the drug.ResultsOn admission levodopa-treated patients had significantly lower plasma levels of triglycerides, total cholesterol and lipids, and lower frequency of diabetes and hypertension than untreated patients. Mean body mass index, resting blood pressure, fasting plasma glucose, and smoking did not differ between the groups. A year after enrolment 160 patients were re-hospitalized; of these 63 had started levodopa during first hospitalization. In these new levodopa users total cholesterol, triglycerides and lipids had reduced to levels comparable with those of longer-term levodopa users.ConclusionLevodopa use in parkinsonian patients is associated with reduced vascular risk factors. In causal terms this finding might be attributed to the inhibitory action of levodopa-derived dopamine on the sympathetic nervous system.     

Optimising levodopa therapy for the management of Parkinson’s disease

Journal of Neurology - Levodopa remains unrivalled in providing symptomatic benefit for the treatment of Parkinson’s disease (PD). However, wearing-off and dyskinesia have been associated...     

Pavlovian conditioning of nausea and vomiting

Cancer patients undergoing cytotoxic drug treatment often experience side-effects, the most distressing being nausea and vomiting. Despite antiemetic drugs, 25-30% of the chemotherapy patients report these side-effects when being re-exposed to the stimuli that usually signal the chemotherapy session and its drug infusion. These symptoms are called anticipatory nausea and anticipatory vomiting. The present paper summarizes the evidence that anticipatory vomiting is acquired by Pavlovian conditioning, and, consequently, may be alleviated by conditioning techniques. To explore the mechanisms that induce and alleviate conditioned nausea and vomiting further, a conditioned nausea model was established in healthy humans using body rotation as the nausea-inducing treatment. The validity of this motion sickness model to examine conditioning mechanisms in the acquisition and alleviation of conditioned nausea was demonstrated. Cortisol and tumor-necrosis factor-alpha were elevated as endocrine and immunological correlates of nausea. Data in the rotation-induced motion sickness model indicated that gender is an important moderator variable to be considered in further studies. The paper concludes with a review of applications of the demonstrated conditioning principles as interventions to ameliorate distressing anticipatory nausea or anticipatory vomiting in cancer patients undergoing chemotherapy.     

Pathomechanism of dyskinesia associated with treatment of Parkinson disease with levodopa

The 5-HIAA/HVA ratio was determined in the cerebrospinal fluid in 5 patients with Parkinson's disease with L-DOPA preparations in which drug-induced dyskineses developed, in 5 patients treated with L-DOPA without dyskineses, and 10 controls. A decrease in the 5-HIAA/HVA ratio was observed in the group with dyskineses as compared with patients without dyskineses and in controls. The directions of further investigations on hte pathomechanism of drug-induced dyskineses are discussed.     

Intrajejunal levodopa versus conventional therapy in Parkinson disease: motor and nonmotor effects

ABSTRACT: Seventeen patients with advanced Parkinson disease (PD) were treated with intrajejunal L-dopa infusion (IJL) and compared with a matched group of 9 patients (termed comparator [C]) not given IJL because of funding restriction by primary care trusts (PCTs) in the UK, although considered to be clinically eligible for IJL. Assessments were baseline and follow-up (6 months) with Hoehn and Yahr staging, unified PD rating scale (UPDRS-III and UPDRS-IV), Parkinson disease questionnaire (PDQ-8, quality of life [QoL]) and nonmotor symptom scale (NMSS).Baseline characteristics were comparable between the groups. The IJL-treated group showed highly significant improvements in UPDRS-III (P = 0.005), UPDRS-IV (P = 0.0004), total NMSS score (P = 0.004), and QoL (P = 0.01), whereas the C group showed no change in these parameters. A large effect size of IJL was seen in treated patients for UPDRS-III (1.13), UPDRS-IV (1.52), NMSS score (0.82), and QoL (1.12), whereas continuing conventional treatment registered no effect in C.This study confirms the robust effect of IJL on motor and, in particular, nonmotor symptoms and QoL in advanced PD as described in open-label studies but additionally points to the need for such treatment in those denied this therapy because of centrally dictated funding policies leading to inequalities in health care.