Mineral metabolism disturbances start early in the course of CKD. The first alterations to take place are a 1,25-dihydroxyvitamin D decrease, a 24 h urine phosphate decrease and a PTH elevation, which show significant level variation when the glomerular filtration rate falls below 60 ml/min. K/DOQI recommended levels for mineral metabolism parameters are difficult to accomplish, in particular for PTH levels.

Dietary intervention, phosphate (P) removal during dialysis and, especially, phosphate binders are current methods for the management of hyperphosphataemia. Ideally, the amount of P absorbed from the diet should equal the amount of P removed during dialysis, and this must occur in the context of an adequate protein intake. We evaluated the relationship between P intake and protein intake in 60 stable chronic uraemic patients (mean age 55+/-15 years, 25% diabetics, 68% males) on standard 4 h haemodialysis. The dietary counselling was relatively free for protein and calories. Nutrient intake was recorded during a 5 day period, and average daily ingestion of P and proteins was calculated using a computerized diet analysis system. A highly significant correlation was observed between protein and P intake. The mean daily ingestion of P and proteins was 998+/-316 mg and 64+/-19 g (1+/-0.4 g/kg/day), respectively. For an optimal protein diet of 1-1.2 g/kg/day, the P intake was 778-1444 mg. The amount of P removed by haemodialysis, extrapolated to an average week, is 250-300 mg/day. Since approximately 40% of P ingested is absorbed from the gut by uraemic patients treated with intestinal P binders, 750 mg of P intake should be the critical value above which a positive balance of P may occur. This value corresponds to a protein intake of 45-50 g per day (>0.8 g/kg body weight/day for a 60 kg patient). In patients undergoing standard chronic haemodialysis, a neutral P balance is difficult to achieve, despite phosphate binder therapy, when protein intake is >50 g. Additional protein restriction, in order to obtain a neutral balance, may impose the risk of protein malnutrition.

No abstract

The vasorelaxant profile of quercetin 3,7-dimethyl ether, a flavonoid isolated from Croton schiedeanus Schlecht (Euphorbiaceae), was assessed in aortic rings isolated from Wistar rats. To gain insight into its structure-activity relationship, we compared this substance with quercetin 3,4',7-trimethyl ether (ayanin), another flavonoid isolated from this plant, quercetin 3,3',4',7-tetramethyl ether, a flavonoid synthesized by us, and quercetin. In addition we examined the interaction of quercetin 3,7-dimethyl ether with the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. According to their pEC50 values (concentration producing a 50% inhibition of the maximal contractile response) to phenylephrine-induced precontraction in rat isolated aorta, the potency order was quercetin 3,7-dimethyl ether > quercetin > quercetin 3,4',7-trimethyl ether > quercetin 3,3',4',7-tetramethyl ether (4.70+/-0.18; 3.96+/-0.07; 3.64+/-0.02; 3.11+/-0.16). The relaxant effect of quercetin 3,7-dimethyl ether was significantly decreased by the removal of endothelium as well as by methylene blue, an inhibitor of guanylyl cyclase, and by N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME), an NO-synthase inhibitor. Therefore, quercetin 3,7-dimethyl ether has a NO/cGMP pathway-related profile, with increased vasorelaxant activity due to hydroxylation at positions 3 and 4 of the B ring. In addition, methylation at positions 3 and 7 with respect to quercetin of the C and A rings, respectively, seems to further enhance the vasorelaxant activity of quercetin 3,7-dimethyl ether.

No abstract

In the novel agent era, the role of double autologous transplantation (ASCT) as up-front therapy for MM still remains undefined. Recently, several European cooperative groups prospectively compared bortezomib-based vs non-bortezomib-based induction regimens before ASCT for newly diagnosed myeloma (MM). By study design, patients enrolled into these trials were prospectively assigned to receive either a single or double ASCT. A multivariate regression analysis revealed that the leading factors independently associated with shorter PFS and OS were ISS 3, presence of high-risk cytogenetic abnormalities (hr-cyto), including t(4;14) and/or del(17p) by FISH, failure to achieve CR after induction therapy and assignment to receive a single ASCT. In comparison with patients for whom a single ASCT was planned by study design, those who were assigned to receive a double ASCT had significantly longer PFS (median: 38 vs 50 months, p<0.001) and OS (5-years estimates: 63% vs 75%, p=0.002). To evaluate the impact of double vs single ASCT on outcomes, an integrated analysis of patient-level data from these studies was performed. The intent-to-treat (ITT) population included 606 patients who were randomized to bortezomib-based induction regimens and for whom a single (n=254) or double (n=352) ASCT was planned at time of study entry. Based on the presence or absence of one, two or three adverse prognostic variables (ISS 3, hr-cyto and failure to achieve CR after induction therapy), four groups of patients with different risk of progression and/or death were identified. In group 0 were included patients with ISS 1-2 MM, lack of hr-cyto and who achieved CR after induction therapy; these patients represented 13% of the overall population. Patients in group 1 (61%) were identified by the presence of a single adverse variable. Group 2 included patients (23%) with two adverse variables. Patients in group 3 (3%) were identified by the presence of all the three adverse variables. These groups of patients had different clinical outcomes in terms of PFS and OS, and differently benefited from double ASCT. Median PFS was 61 months for patients in group 0, 56 months for group 1, 36 months for group 2 and 26 months for group 3 (p<0.001). A Cox regression analysis adjusted for the number of preplanned ASCT(s) showed the following hazard ratio (HR) values for PFS when group 1 (HR=1.7, p=0.02), group 2 (HR=3.2, p<0.001) and group 3 (HR=6.6, p<0.001) were compared with group 0. In comparison with a single ASCT, prospective assignment to receive a double ASCT was associated with longer PFS for patients with a single (group 1) or two (group 2) adverse prognostic variables (median, 54 vs 43 months; HR=0.70, p=0.006). The greatest PFS benefit with double vs single ASCT was seen for patients in group 2 who had two adverse prognostic variables (median, 41 vs 20 months; HR=0.52; p=0.003), in particular for those with a hr-cyto profile at baseline and who failed CR after bortezomib-based induction regimens (median: 42 vs 21 months with a single ASCT; HR=0.41, p=0.006) (Fig.1). The Cox proportional hazards model for the ITT population confirmed that the presence of two (HR=4.8, p<0.001) or three (HR=9.0, p<0.001) adverse prognostic variables conferred a progressively shorter OS compared to the lack of all the three adverse variables (group 0). Consistently with results of PFS analysis, patients in group 2 who had two adverse variables and by study design were assigned to receive a double ASCT had significantly longer OS in comparison with the same group of patients for whom a single ASCT was planned (median, 67 vs 31.5 months; HR=0.32, p<0.001). OS benefit with double ASCT was particularly relevant for patients who failed CR after bortezomib-based induction therapies and who presented with hr-cyto (5-year estimates: 70% vs 17% with a single ASCT; HR=0.22, p<0.001) (Fig.2) or ISS 3 MM (HR=0.42, p=0.033). To the best of our knowledge, this is the first analysis so far reported comparing double vs single ASCT applied after the gold standard, bortezomib-based, induction regimens. Results suggested a possible beneficial role of double ASCT in improving outcomes for newly diagnosed MM patients with poor prognosis, in particular for those who failed CR after exposure to bortezomib as part of induction therapy and who had a hr-cyto profile. These data need to be confirmed by prospective phase III clinical studies which are currently ongoing. Disclosures: Cavo: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Salwender:Janssen and Celgene: Honoraria. Rosiñol:Janssen and Celgene.: Honoraria. Moreau:Janssen and Millennium: Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria. Petrucci:Janssen and Celgene: Honoraria. Bladé:Janssen and Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx and Glaxo-Smith-Kline (GSK): Membership on an entity’s Board of Directors or advisory committees; Janssen: Grant, Grant Other. Attal:Celgene and Janssen: Membership on an entity’s Board of Directors or advisory committees. Weisel:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. San Miguel:Jansen, Celgene, Onyx, Novartis, Millenium: Membership on an entity’s Board of Directors or advisory committees. Lahuerta:Janssen and Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Facon:Janssen and Celgene: Speakers Bureau; Millennium, Onyx, Novartis, BMS, Amgen: Membership on an entity’s Board of Directors or advisory committees. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Goldschmidt:Celgene and Janssen: Membership on an entity’s Board of Directors or advisory committees.

No abstract

1 A study was made of the e ects of 5-carboxamidotryptamine (5-CT) on pressor responses induced in vivo by electrical stimulation of the sympathetic out¯ow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Sympathetic stimulation (0.1, 0.5, 1 and 5 Hz) resulted in frequencydependent increases in blood pressure. Intravenous infusion of 5-CT at doses of 0.01, 0.1 and 1 mg kg 71 min 71 reduced the pressor e ects obtained by electrical stimulation. The inhibitory e ect of 5-CT was signi®cantly more pronounced at lower frequencies of stimulation. In the present study we characterized the pharmacological pro®le of the receptors mediating the above inhibitory e ect of 5-CT. 6 These results suggest that the presynaptic inhibitory action of 5-CT on the electrically-induced pressor response is mediated by both r-5-HT 1D and 5-HT 1A receptors.