The role of chemokines in human immunodeficiency virus infection.

Chemokines that bind to human immunodeficiency virus (HIV) co-receptors are potent and selective inhibitors of HIV infection. Therefore, ever since our discovery of this activity, we have proposed their role in controlling HIV infection as a third arm of the immune response, i.e. in concert with humoral and cellular responses. Research carried out in our laboratory, and performed independently by other groups, has recently strengthened this concept. Here, we critically analyze the evidence indicating the positive contribution of chemokines to HIV infection, their involvement with cognate and innate immunity, and the potential for their use in combating HIV infection.

Continuous lisuride effects on central dopaminergic mechanisms in Parkinson's disease.

Effects of the long term, continuous administration of a dopamine agonist on motor response complications attending levodopa therapy were studied in 7 patients with advanced Parkinson's disease under controlled conditions. After a 3-month round-the-clock infusion of lisuride, the duration of antiparkinsonian action of levodopa increased by approximately 90%, and the therapeutic window for the acutely administered dopamine precursor widened by > 300%. These benefits were more than three times greater than those produced by 9 days of continuous levodopa administration. In contrast to the effects on levodopa pharmacodynamics, the continuous infusion of lisuride did not prolong its action, suggesting a lisuride effect on presynaptic as well as postsynaptic dopaminergic mechanisms. These results lend further support to the view that continuous dopamine replacement ameliorates motor fluctuations and peak-dose dyskinesias that complicate standard levodopa regimens. Our findings further suggest that alterations at both presynaptic and postsynaptic levels contributing to these motor complications tend to normalize with the more physiological stimulation afforded by continuous replacement strategies, especially when given chronically.

Partial dopamine agonist therapy of levodopa-induced dyskinesias.

We administered the partial dopamine agonist terguride under controlled conditions to patients with Parkinson's disease (PD), both as monotherapy and in conjunction with intravenous levodopa. Terguride produced a dose-dependent decrease in levodopa-induced dyskinesias (up to 53%) in seven patients without concomitant worsening of parkinsonism, and had no significant antiparkinsonian effect when administered alone. Partial dopamine agonists may hold some promise in the adjuvant therapy of patients with advanced PD.

Opioid peptides in Parkinson's disease: effects of dopamine repletion.

Neurotransmitters other than dopamine, including neuropeptides, could have important pathophysiologic and therapeutic roles in Parkinson's disease. Both Met-enkephalin, the main transmitter of the striatopallidal pathway, and dynorphin, one of the co-transmitters of the striatonigral pathway display complex anatomic and biochemical interactions with the basal ganglionic dopamine system. In this study, the cerebrospinal fluid content of a proenkephalin derivative, Met5 enkephalin-Arg6-Gly7-Leu8 (MERGL), was found in significantly low concentrations in parkinsonian patients following overnight withdrawal of all medications compared with control subjects, and failed to change after at least 16 h of steady-state, optimal doses of levodopa infusion intravenously. MERGL levels increased with advancing age among normal individuals but not among patients with Parkinson's disease. In contrast dynorphin A(1-8) levels were not different between the two study groups, did not change with levodopa therapy, and failed to correlate with age or any indices of disease progression. These observations, consistent with post-mortem studies on Parkinson brains and contrary to findings in animal models of Parkinsonism, suggest that abnormality of the enkephalin system in this disease is due to involvement of these striatal neurons in the primary pathologic process.