Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease.

Previous studies in the MPTP-lesioned primate model of Parkinson's disease have demonstrated that alpha(2) adrenergic receptor antagonists such as idazoxan, rauwolscine, and yohimbine can alleviate L-dopa-induced dyskinesia and, in the case of idazoxan, enhance the duration of anti-parkinsonian action of L-dopa. Here we describe a novel alpha(2) antagonist, fipamezole (JP-1730), which has high affinity at human alpha(2A) (K(i), 9.2 nM), alpha(2B) (17 nM), and alpha(2C) (55 nM) receptors. In functional assays, the potent antagonist properties of JP-1730 were demonstrated by its ability to reduce adrenaline-induced (35)S-GTPgammaS binding with K(B) values of 8.4 nM, 16 nM, 4.7 nM at human alpha(2A), alpha(2B), and alpha(2C) receptors, respectively. Assessment of the ability of JP-1730 to bind to a range of 30 other binding sites showed that JP-1730 also had moderate affinity at histamine H1 and H3 receptors and the serotonin (5-HT) transporter (IC(50) 100 nM to 1 microM). In the MPTP-lesioned marmoset, JP-1730 (10 mg/kg) significantly reduced L-dopa-induced dyskinesia without compromising the anti-parkinsonian action of L-dopa. The duration of action of the combination of L-dopa and JP-1730 (10 mg/kg) was 66% greater than that of L-dopa alone. These data suggest that JP-1730 is a potent alpha(2) adrenergic receptor antagonist with potential as an anti-dyskinetic agent in the treatment of Parkinson's disease.     

Prolactin releasing peptide has high affinity and efficacy at neuropeptide FF2 receptors

Neuropeptide FF (NPFF) and prolactin-releasing peptide (PrRP) are two members of the RFamide peptide family. In this study we investigated whether these RFamide peptides, which have common structural features in their C-terminal RFamide motif and share several physiologically important functions, could exert their effects through the same set of receptors. The affinity and functional activity of several related RFamide peptides were determined at the human neuropeptide FF receptor subtype 2 (hNPFF2) and the human prolactin-releasing peptide (hPrRP) receptors. The full-length human prolactin releasing peptide 31 (hPrRP31) had significantly higher efficacy compared with NPFF and its stable analog, (1DMe)Y8Fa, at the hNPFF2 receptor. In contrast, NPFF and (1DMe)Y8Fa were not efficacious at the hPrRP receptor. Our study indicated a generally relatively low level of discrimination for RFamide peptides at the NPFF receptor, whereas the hPrRP receptor clearly preferred PrRP or very closely related peptides. The seemingly promiscuous binding of the RFamide peptides to the NPFF receptor was further confirmed by receptor autoradiography. PrRP may thus signal through the NPFF receptors in vivo.     

Hypertension,cardiac state,and the role of volume overload during peritoneal dialysis

The cardiac state and the prevalence of high blood pressure (BP) were analyzed in 21 pediatric patients (mean age 5.3±5.3 years) on chronic peritoneal dialysis (CPD), the aim being to specify the impact of hypervolemia in the etiology of hypertension. C- and N-terminal atrial natriuretic peptide (ANP-C, ANP-N) were measured as possible additional markers of hypervolemia. Baseline investigations were carried out 0.2 years after initiation of PD, and repeated after 0.9±0.2 years. Fifty-two percent of the patients had high BP, and in 40% the nocturnal BP decline was decreased. Left ventricular hypertrophy was present in 45%, but the systolic and diastolic functions of the heart were not impaired. Left ventricular mass correlated significantly with the severity of hypertension and with ANP-N (r=0.79, P<0.01 and r=0.66, P<0.01, Spearman rank correlation). Significant correlations were also found between the severity of hypertension and ANP-N and ANP-C (r=0.82, P<0.01 and r=0.66, P<0.01, Spearman rank correlation). High BP and cardiac impairment were more frequent in the younger and nephrectomized patients in whom volume overload seemed to be the most-important etiological factor. Our results suggest further that an ANP-N over 3.0 nmol/l combined with hypertension is strongly indicative of volume overload in patients on PD. Received: 31 May 2000 / Revised: 22 December 2000 / Accepted: 22 December 2000     

Dental caries and mutans streptococci in the proximal areas of molars affected by the habitual use of xylitol chewing gum.

The relationship between the caries status and the microbiological status [mutans streptococci (MS)] in the proximal areas of lower right and upper left molars was investigated in subjects of the Ylivieska xylitol study in Finland (1982-1985) in a cross-sectional follow-up in 1988. Those children who had used xylitol chewing gum regularly since 1982 showed significantly lower caries indices in 1988, including the proximal caries scores. The presence of MS (expressed in log10 colony-forming units) in the proximal areas studied was significantly lower in habitual xylitol consumers. Carious interproximal areas of all subjects had significantly higher total levels of MS than clinically and radiographically sound interproximal areas. The present study supports the idea of a close association between MS and dental caries, and shows that the total level of MS in the human dentition can be influenced by xylitol. It is likely that the long-term (between 1982 and 1988) habitual xylitol consumption had decreased the prevalence of MS in the interproximal areas of the present subjects and, subsequently, decreased the proximal and overall caries indices.     

Speed and quality in Coronary Artery Bypass Graft (CABG) surgery: is there a connection?

In this paper we study the connection between coronary artery bypass graft (CABG) operation time and quality. Our quality metric was the improvement in health related quality of life (HRQoL) survey score in a sample of 432 patients admitted to Kuopio University Hospital. Patients were interviewed with a structured questionnaire a day before the procedure and the follow-up questionnaires were mailed 6 and 12 months after the surgery. However, the HRQoL metric used did not have high retest reliability. Subsequently, we did not find any connection between CAGB operation times and HRQoL. Likewise, we did not find the speed of the surgeon to have any connection to HRQoL improvement.     

Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops

BACKGROUND: To investigate the pharmacological basis of systemic side effects of ophthalmic timolol, we estimated the systemic bioavailability of 0.5% timolol eyedrops and compared cardiopulmonary effects of intravenous and ophthalmic timolol. METHODS: In a randomized crossover study we administered 0.2 mg timolol either intravenously or ocularly to eight healthy volunteers. After drug administration we measured heart rate, arterial blood pressure, forced expiratory volume in 1s, forced vital capacity, and intraocular pressure (IOP). Plasma timolol concentrations were determined using a beta-adrenoceptor binding assay. RESULTS: The peak concentration of ophthalmic timolol in plasma, (C(max)=1.14+/-0.34 ng/ml, mean+/-SD, n=8) was measured in most subjects within 15 min after drug administration. The mean area under the curve from zero to infinitum (AUC(0-)(infinity)) was 6.46+/-2.49 ng/ml per hour after intravenous and 4.78+/-1.90 ng/ml per hour (means+/-SD, n=8) after ocular administration. The systemic bioavailability (F) of the eyedrop was 78.0+/-24.5% (mean+/-SD, n=8). Heart rate, arterial blood pressure, and pulmonary functions were similar after intravenous and ocular timolol administration, whereas IOP was lowered more effectively by the ophthalmic than the intravenous dose. CONCLUSIONS: Ophthalmic timolol resembled intravenous timolol in terms of systemic bioavailability, plasma kinetics, and cardiopulmonary effects. Clinicians should pay attention to the high systemic bioavailability of ophthalmic timolol, because intensive systemic beta-blockade can be highly hazardous to aged patients suffering from cardiopulmonary diseases.     

Effect of xylitol consumption on the plaque-saliva distribution of mutans streptococci and the occurrence and long-term survival of xylitol-resistant strains.

Since the exposure of mutans streptococci to xylitol is known to select for xylitol-resistant (XR) natural mutants, the occurrence and long-term survival of such xylitol-resistant strains was evaluated in a cross-sectional sampling of participants of the Ylivieska xylitol study four years after the original two-year experimental period. Paraffin-stimulated whole saliva was first collected, and then plaque was collected and pooled. The salivary and dental plaque mutans streptococci were enumerated after growth on TSY20B agar. The proportion of XR strains was determined by autoradiography with 14C-xylitol. A strong and significant correlation (r = 0.645 and p = 0.005) between the number of mutans streptococci in saliva and in dental plaque was observed in non-consumers of xylitol. Such a correlation totally disappeared (r = 0.098 and p = 0.612) in xylitol-exposed consumers (habitual and former xylitol-consumers). The proportion of the salivary XR mutants (35%) in non-consumers (n = 16) was significantly lower than in the xylitol-exposed consumers (79%) (n = 27), (p = 0.0001) or in former consumers (75%) (n = 13), (p = 0.0008) or in the habitual consumers (83%) (n = 14), (p = 0.004). The proportion of XR mutants in dental plaque was, on the average, much lower than in the corresponding saliva. The proportion of XR in the plaque of xylitol non-consumers was half of that of the xylitol-exposed group, but the difference was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enantiomers of neuroactive steroids support a specific interaction with the GABA-C receptor as the mechanism of steroid action

Neuroactive steroids can either potentiate or inhibit a variety of membrane channels. Most studies have suggested that the effects are mediated by specific association of the steroid with the affected channel. However, a recent study of the rho1 (GABA-C) receptor (Mol Pharmacol 66:56-69, 2004) concluded that the actions were consistent with an action of the steroid in the lipid bilayer to alter the lateral pressure profile in the membrane. The enantiomers of an optically active compound are expected to have identical physical properties, including interactions with hydrophobic portions of the cell membrane. We have used two pairs of enantiomers (pregnanolone and ent-pregnanolone, allopregnanolone and ent-allopregnanolone) and show that the ability to potentiate (allopregnanolone) or inhibit (pregnanolone) the rho1 receptor is enantioselective. Therefore, these results strongly suggest that the actions of these neuroactive steroids are mediated by interactions with chiral regions of the target protein, rather than by a change in membrane properties (including lateral pressure).