Pardoprunox as adjunct therapy to levodopa in patients with Parkinson's disease experiencing motor fluctuations: results of a double-blind, randomized, placebo-controlled, trial.

AIMS: To determine the efficacy and safety of pardoprunox in levodopa-treated patients with Parkinson's disease (PD) experiencing motor fluctuations. METHODS: Patients were randomized to pardoprunox (up to 42 mg/day, n = 150) or placebo (n = 144). Pardoprunox was titrated to an optimal dose over 7 weeks, followed by a 12-week stable dose period. The primary efficacy variable was the change from baseline to study endpoint in total daily OFF time, based on patient diaries. Secondary analyses included the change in ON time without troublesome dyskinesias, UPDRS-ADL + Motor ON, UPDRS-ADL OFF and PDQ-39. Subgroup analyses explored the impact of pardoprunox on dyskinesias (UPDRS items 32 + 33), depression (Hospital Anxiety Depression Scale) and pain (Visual Analogue Scale). RESULTS: Pardoprunox significantly reduced OFF time versus placebo (-1.62 h/day versus -0.92 h/day, respectively, p = 0.0215). Compared to placebo, pardoprunox improved ON time without troublesome dyskinesias (p = 0.0386), UPDRS-ADL + Motor ON (p = 0.0003), and UPDRS-ADL OFF (p < 0.0001), while no significant difference was observed on PDQ-39. A high drop-out rate due to adverse events (AEs) (pardoprunox, 37%; placebo, 12%) suggested that the selected dose range may have been too high, and/or titration was too rapid. CONCLUSIONS: Pardoprunox decreased OFF time and increased ON time without troublesome dyskinesias in levodopa-treated PD patients. The high drop-out rate at the selected doses justifies the investigation of lower doses. The impact of pardoprunox on dyskinesias and non-motor symptoms deserves further investigation.

Safety and tolerability of pardoprunox, a new partial dopamine agonist, in a randomized, controlled study of patients with advanced Parkinson's disease.

AIMS: To investigate the safety and tolerability of pardoprunox (SLV308), a novel partial dopamine agonist, as an adjunct to levodopa in patients with advanced Parkinson's disease, using two titration schedules. METHODS: Patients were randomized to pardoprunox (n = 51) or placebo (n = 11). Pardoprunox was titrated to the highest tolerated dose (range, 0.3-42 mg/day) over 7 weeks, using a gradual dose escalation without intermediate steps (group 1) or with intermediate steps (group 2). RESULTS: The cumulative drop-out rate was greater in group 1 (without intermediate steps, 56.0%) than in group 2 (with intermediate steps, 34.6%), or with placebo (9.1%). In group 2, doses up to 18 mg/day were well tolerated with a cumulative drop-out rate of 7.7% (2/26) and a drop-out rate due to adverse events of 4.0% (1/26). The most common adverse events reported were nausea, vomiting, headache, and dizziness. There was a trend for reduced OFF time (p = 0.054) in the combined pardoprunox group compared to placebo. CONCLUSIONS: The pardoprunox safety and tolerability profile as an adjunct to levodopa was improved using a gradual titration schedule that included intermediate dose steps. Using this titration, doses up to 18 mg/day were well tolerated.

Sarcoidosis-associated hepatitis C virus infection.

Although several reports of sarcoidosis have been reported in hepatitis C virus (HCV)-infected patients treated with interferon-alpha, this association has never been described in nontreated HCV patients. We report two cases of sarcoidosis associated with chronic hepatitis C infection. The patients developed multivisceral sarcoidosis (cutaneous, lungs, nodes) at two and at least six years after the presumed date of infection. One patient obtained remission of sarcoidosis with corticosteroid treatment but the other remained corticodependent. The levels of hepatic enzymes were not significantly modified throughout the course of corticosteroid therapy. In conclusion, these case reports suggest that HCV itself could induce a granulomatous reaction in chronic HCV-infected patients through the stimulation of the cellular immune system. It could be of interest to test for HCV infection all patients diagnosed with sarcoidosis and to watch over every treated or nontreated hepatitis C infected patient for the development of granulomatous lesions.

[Sarcoidosis and comorbidity: retrospective study of 32 cases]. / Sarcoïdose et comorbidité: étude rétrospective de 32 observations.

PURPOSE: A retrospective study was set up to investigate active pathologic processes associated with sarcoidosis diagnosed in 32 patients. METHODS: Eighteen patients had two identified granulomatous localizations (56%) and 14 patients had three localizations or more (27%). Comorbidity was noticed in nine patients (28% of cases). Sarcoidosis was associated with an infectious disease five times (hepatitis C virus [HCV] infection three times, including one case after recombinant interferon alpha therapy, and HIV and HCV co-infection two times). The association of sarcoidosis with a chronic immunologic inflammatory disease was noticed four times (lupus erythematosus two times, myasthenia and primary biliary cirrhosis). Finally, in two cases sarcoidosis was associated with a neoplasia (non-Hodgkin's lymphoma in a co-infected HIV-HCV patient, ovarian cystadenocarcinoma in another patient). Sarcoidosis preceded or revealed the comorbidity four times.

Dynorphin modulates dopamine D1-receptor mediated turning behavior in 6-hydroxydopamine-lesioned rats.

We investigated if the potentiated turning response to a challenge with the partial dopamine D1 receptor agonist SKF-38393, as seen after priming with L-dihydroxyphenylalanine (DOPA) of unilaterally 6-hydroxydopamine-lesioned rats, can be modulated by infusion of dynorphin A (1-17) in the striatum. Seventeen days after the 6-hydroxydopamine lesion, rats received intrastriatal dynorphin (0. 08 or 3.85 microg) followed by L-DOPA (50 mg/kg i.p.) and were challenged 3 days later with SKF-38393 (3.0 mg/kg s.c.). Compared to controls, the lower dose of dynorphin caused an earlier onset of turning, while the higher dose decreased the response to SKF-38393. These findings suggest a dose-dependent modulatory role for striatal dynorphin in L-DOPA-priming of a D1-mediated behavioral response.

Acute effects of etidronate on glucocorticoid-induced bone degradation.

OBJECTIVES: To study the acute short-term effects on the biochemical parameters of calcium and bone homeostasis in post-menopausal women treated with a high dose of prednisone alone or with additional etidronate, before and during 5 days of treatment. METHODS: Serum calcium, phosphorus, creatinine, alkaline phosphatase activity, osteocalcin, carboxy-terminal propeptide of type I procollagen (PICP), cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), parathyroid hormone (PTH), 25-hydroxyvitamin D and urinary excretion of calcium over 24 h were measured before and during 5 days of treatment in 14 post-menopausal women treated with a high dose of prednisone (60 mg/day) alone (group A) or combined with cyclical etidronate (group B). RESULTS: Significant differences from baseline were found in osteocalcin and urinary excretion of calcium in both groups and for ICTP in group B. Significant differences between groups were calculated at day 5 of the study for osteocalcin, ICTP and 24 h urine calcium excretion (P < 0.01). Urinary excretion of calcium over 24 h increased in group A (+14.7%; P < 0.05) and decreased in group B (-22.1%; P < 0.01). Osteocalcin levels decreased in group A (- 38.1%) and increased in group B (+27.4%; both P < 0.01). ICTP decreased only in group B (-19.4%; P < 0.01). CONCLUSIONS: The results are consistent with the fact that etidronate is acutely able to prevent bone resorption due to corticosteroids. The increase in osteocalcin in the etidronate-treated group is a new feature. A direct or indirect (PTH, 1,25 vitamin D?) stimulatory effect of etidronate on the osteoblast cannot be excluded.

Priming with L-DOPA differently affects dynorphin and substance P mRNA levels in the striatum of 6-hydroxydopamine-lesioned rats after challenge with dopamine D1-receptor agonist.

In unilaterally 6-hydroxydopamine-lesioned rats, potentiation of D1-agonist-induced turning behavior by priming with l-DOPA was correlated with changes in striatal neuropeptide mRNA levels. In non-primed rats, administration of the D1-agonist SKF-38393 markedly increased dynorphin and substance P mRNA levels in the lesioned striatum. Priming with l-DOPA dissociated the response of the two neuropeptides to the D1-agonist, with higher dynorphin and reduced substance P mRNA levels.

Serotonin and carbachol induced suppression of synaptic excitability in rat CA1 hippocampal area: effects of corticosteroid receptor activation.

Serotonin (5HT) and the cholinergic analogue carbachol (CCh) act on neurons in the hippocampal CA1 area through pre- and post-synaptic receptors. Previously, it was shown that post-synaptic actions of 5HT and CCh are affected by corticosteroids: predominant activation of high affinity mineralocorticoid receptors resulted in small hyperpolarizing responses to 5HT and small depolarizing responses to CCh; additional activation of low affinity glucocorticoid receptors led to increased 5HT and CCh responses. In the present study, we examined the consequences of steroid modulation of these post-synaptic membrane effects and/or possible pre-synaptic effects by 5HT and CCh for the excitability in the CA1 area, using extracellular field potential or intracellular recordings from individual pyramidal neurons. Steroid treatment by itself did not affect the amplitude or paired pulse properties of synaptic responses. In slices from adrenally intact rats, both 5HT (3-30 microM) and CCh (1-10 microM) induced a dose-dependent suppression of the synaptic field responses evoked in the CA1 area by stimulation of the Schaffer collaterals. No changes in these transmitter effects were observed after adrenalectomy. The 5HT induced suppression of the population spike amplitude was, however, reduced after selective occupation of mineralocorticoid receptors. Intracellularly, no significant steroid dependent modulation of (pre-synaptic) 5HT evoked changes in synaptic responses was observed. These data suggest that the steroids modulate post-synaptic but not pre-synaptic 5HT effects and that this modulation is reflected in the excitability of the CA1 region. The CCh induced suppression of the population spike was not affected by corticosteroid receptor activation, indicating that the previously found steroid modulation of post-synaptic CCh effects has no clear consequences for the CA1 excitability.