New olfactometric findings in Parkinson's disease.

OBJECTIVES: To investigate in Parkinson's disease-affected patients a correlation between hyposmia and gastrointestinal dysfunction and their possible identical etiopathogenesis. DESIGN: Retrospective cohort study. SETTING: ENT and neurology departments (Gemelli Hospital, Rome, Italy). PARTICIPANTS: A total of 78 patients with diagnosis of PD according to the UK Brain Bank criteria. INCLUSION CRITERIA: informed consent and olfactory testing executed; exclusion criteria: signs of dementia according to the DSM-IV criteria; Mini Mental State Examination score ≤26; head trauma; central neurological disorders, nasal or systemic diseases potentially affecting olfactory function. Motor condition was assessed by means of Hoehn and Yahr staging and by section III of the Unified PD Rating Scale, performed off and on medications. MAIN OUTCOME MEASURES: The patients underwent olfactory evaluation (TDI score), after rhinomanometry with nasal decongestion. A total of 25 non-motor symptoms were evaluated through an interview. RESULTS: Olfactory dysfunction was objectively found in 91.0% of patients, a percentage higher than the subjective hyposmia reported (55.1%) P = 0.0001. Seven patients (9.0%) were normosmic, 49 (62.8%) hyposmic and 22 (28.2%) anosmic. Subjective hyposmia, constipation, bloating and dyspepsia differed across groups, being higher in anosmic and hyposmic ones than in the normosmic group. P value was ≤0.05 for each symptom. Despite the original results, this study has the limitation of being based on subjective ratings by a relatively limited group of patients. CONCLUSIONS: Hyposmia and gastrointestinal symptoms are correlated, and this would support a possible common origin; the CNS could be reached through two different pathways, both starting in the peripheral nervous system.

Synthesis and anti-HIV-1 activity of new delavirdine analogues carrying arylpyrrole moieties.

In our search for novel anti-human immunodeficiency virus (HIV)-1 agents, 14 delavirdine analogues were synthesized and evaluated as potential anti-HIV-1 agents in cell-based assays. Compound 1Aa exhibited potent and selective anti-HIV-1 activity in acutely infected MT4 cells, with effective concentration (EC50) values in the submicromolar range.

1,5-Benzodiazepines. Part XII. Synthesis and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepine derivatives as nevirapine analogues.

A number of properly substituted 5H-pyrimido[4,5-b][1,5]benzodiazepines (2) and pyrazolo[3,4-b][1,5]benzodiazepines (3 and 4), as well as compounds 5-7, which are derivatives of new tetracyclic systems, were prepared as nevirapine analogues through multistep synthetic routes. The cytotoxic and anti-HIV-1 properties of compounds 2-7 were evaluated in cell-based assays, together with their inhibitory activity against the HIV-1 recombinant reverse transcriptase (rRT) in enzyme assays. The modifications introduced into nevirapine heterocyclic skeleton proved to have a negative effect for the anti-HIV-1 activity. It is worth noting that some of the new derivatives proved to be cytotoxic in the low micromolar range.

Pyrazole related nucleosides 5. Synthesis and biological activity of 2'-deoxy-2',3'-dideoxy- and acyclo-analogues of 4-iodo-1-beta-D-ribofuranosyl-3-carboxymethyl pyrazole (IPCAR).

Continuing our studies on the structure-activity relationships (SAR) of 4-iodo-1-beta-D-ribofuranosyl-3-carboxymethyl pyrazole (IPCAR), the ribofuranosyl moiety has been substituted with acyclic chains, namely 1-[(2-hydroxyethoxy)methyl]- and 1-[(1,3-dihydroxy-2-propoxy)methyl]-pyrazole derivatives (4, 5 and 8, 9 respectively), with the 2'-deoxy-beta-D-ribofuranosyl group (12 and 13) and finally with the 2',3'-dideoxy-D-glycero-pentofuranosyl-moiety (16 and 17). None of the new compounds display any interesting biological activity.

Disoxaril-related 3-(diethylamino)-5-phenylisoxazoles.

Previous research has shown that 3-(dialkylamino)-5-phenylisoxazoles possessing a compact structure were active against HRV-2 and, consequently, presented a type B activity. In this paper, 3-(diethylamino)-5-phenylisoxazoles, which are structurally more elongated and related to Disoxaril, were synthesized in view to attempt type A activity against HRV-14. Unfortunately, all tested compounds were devoid of activity against HRV-14 (and HIV-1) or exhibited great toxicity.

d(CH2)5Tyr(Me)-[Orn8]vasotocin, a potent oxytocin antagonist, antagonizes penile erection and yawning induced by oxytocin and apomorphine, but not by ACTH-(1-24).

Intraventricular (i.c.v.) injection of d(CH2)5-Tyr(Me)-[Orn8]vasotocin, a potent oxytocin antagonist, antagonized in a dose-dependent manner (10-100 ng) penile erection and yawning induced by the systemic injection of apomorphine (80 micrograms/kg s.c.) or by the i.c.v. injection of oxytocin (30 ng). In contrast, the oxytocin antagonist, even at the dose of 10 micrograms, did not modify penile erection and yawning induced by the i.c.v. injection of ACTH-(1-24). These results suggest that apomorphine, but not ACTH-(1-24), induce penile erection and yawning by releasing oxytocin in some brain area.

Low doses of ethanol activate dopaminergic neurons in the ventral tegmental area.

In unanesthetized rats the intravenous administration of low doses of ethanol (0.125-0.5 g/kg) produced a dose-dependent increase (30-80%) in the firing rate of dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA). In agreement with previous observations, a dose range between 0.5 and 2 g/mg of ethanol was needed to produce comparable stimulant responses in DA neurons of the Substantia Nigra Pars Compacta. However, in anesthetized rats, doses of ethanol up to 1 g/kg failed to activate VTA-DA neurons. The high sensitivity of VTA-DA neurons to ethanol activation suggests that they might be involved in the reinforcing properties of the drug.

Stimulation of "regulatory" dopamine receptors by bromocriptine (CB-154).

Bromocriptine produces long-lasting hypomotility and decreases brain dihydroxyphenylacetic acid (DOPAC) in mice. These effects are obtained with doses much lower than those which produce hypermotility. The decrease of brain DOPAC is correlated to the hypomotility both on a dose and on a time basis. Potent DA receptor blockers as pimozide, benzperidol and droperidol antagonize the hypomotility and the decrease of brain DOPAC produced by bromocriptine. These effects are obtained with very low doses (0.05-0.3 mg/kg) of neuroleptics which per se do not affect motility or brain DOPAC. The maximal decrease of brain DOPAC produced by bromocriptine is similar to that produced by apomorphine and the combination of these drugs does not result in a further decrease. On the basis of these results it is postulated that bromocriptine decreases DA turnover and produces hypomotility by acting on "regulatory" DA receptors different from the postsynaptic ones of the "terminal" dopaminergic areas.

Evidence for selective and long-lasting stimulation of "regulatory" dopamine-receptors by bromocriptine (CB 154).

Bromocriptine, an ergot-derivate with DA-receptor stimulating properties in vivo, produces long-lasting hypomotility in mice not accustomed to the motility cage and decreases brain DOPAC and HVA without affecting brain DA. These effects are obtained with doses 25 times lower than those which produce hypermotility. The decrease of brain DOPAC is correlated to the hypomotility both on a dose- and on a time-basis. Potent neuroleptics as pimozide, benzperidol and droperidol, which are considered to be fairly specific DA-receptor blockers, antagonize the hypomotility and the decrease of brain DOPAC produced by bromocriptine. These effects are obtained with very low doses (0.05--0.3 mg/kg) of neuroleptics which per se do not affect motility or brain DOPAC. The maximal decrease of brain DOPAC and HVA produced by bromocriptine is similar to that produced by apomorphine and the combination of these drugs does not result in a further decrease of brain DOPAC or HVA. On the basis of these results it is postulated that bromocriptine decreases brain DA-turnover and produces hypomotility by acting on "regulatory" DA-receptors different from the post-synaptic ones of the "terminal" dopaminergic areas.