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Biomedical subjects

F Marchini

Publications and source records attributed to F Marchini.

At least 19 recordsLinked to original sources
PubMed2001

Phthalazine PDE4 inhibitors. Part 2: the synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives.

This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described present substituents in position 4 of the phthalazine ring to replace the commonly observed cyclopentyloxy moiety of rolipram analogues. Preliminary evidences of reduced side effects compared to standards and improved pharmacokinetic properties for selected derivatives are also reported.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Alendronate prevents further bone loss in renal transplant recipients.

The aim of this study was to investigate the effects of alendronate, calcitriol, and calcium in bone loss after kidney transplantation. We enrolled 40 patients (27 men and 13 women, aged 44.2 +/- 11.6 years) who had received renal allograft at least 6 months before (time since transplant, 61.2 +/- 44.6 months). At baseline, parathyroid hormone (PTH) was elevated in 53% of the patients and the Z scores for bone alkaline phosphatase (b-ALP) and urinary type I collagen cross-linked N-telopeptide (u-NTX) were higher than expected (p < 0.001). T scores for the lumbar spine (-2.4 +/- 1.0), total femur (-2.0 +/- 0.7), and femoral neck (-2.2 +/- 0.6) were reduced (p < 0.001). After the first observation, patients were advised to adhere to a diet containing 980 mg of calcium daily and their clinical, biochemical, and densitometric parameters were reassessed 1 year later. During this period, bone density decreased at the spine (-2.6 +/- 5.7%;p < 0.01), total femur (-1.4 +/- 4.2%; p < 0.05), and femoral neck (-2.0 +/- 3.0%; p < 0.001). Then, the patients were randomized into two groups: (1) group A-10 mg/day of alendronate, 0.50 microg/day of calcitriol, and 500 mg/day of calcium carbonate; and (2) group B-0.50 microg/day of calcitriol and 500 mg/day of calcium carbonate. A further metabolic and densitometric reevaluation was performed after the 12-month treatment period. At the randomization time, group A and group B patients did not differ as to the main demographic and clinical variables. After treatment, bone turnover markers showed a nonsignificant fall in group B patients, while both b-ALP and u-NTX decreased significantly in alendronate-treated patients. Bone density of the spine (+5.0 +/- 4.4%), femoral neck (+4.5 +/- 4.9%), and total femur (+3.9 +/- 2.8%) increased significantly only in the alendronate-treated patients. However, no trend toward further bone loss was noticed in calcitriol and calcium only treated subjects. No drug-related major adverse effect was recorded in the two groups. We conclude that renal transplanted patients continue to loose bone even in the long-term after the graft. Alendronate normalizes bone turnover and increases bone density. The association of calcitriol to this therapy seems to be advantageous for better controlling the complex abnormalities of skeletal metabolism encountered in these subjects.

Adult↗
PubMed2001

Persistently increased bone turnover and low bone density in long-term survivors to kidney transplantation.

AIMS: There are few data on the long-term outcome of bone health in renal transplant recipients. We wanted to evaluate the prevalence of osteoporosis and related clinical fractures in long-term survivals to kidney transplantation. METHODS: We carried out a cross-sectional study of 80 males and 44 females, aged 45 +/- 1 years, who had undergone kidney transplantation (KTx) 55.6 +/- 4.6 months earlier. Patients were treated according to standard immunosuppressive protocols. RESULTS: High parathyroid hormone levels were observed in 55 out of the 124 patients (44.6%) and the prevalence of secondary hyperparathyroidism (SHPT) remained similar even when subjects were grouped according to the time elapsed since transplant. The Z scores for bone alkaline phosphatase, osteocalcin, urinary N telopeptide and galactosyl-hydroxylysine were increased as compared to normal controls, both in males and females (p < 0.05). Bone formation markers normalized, while bone resorption markers remained elevated in these patients even ten years after transplant. Vertebral and femoral osteoporosis were present in 37% and 56% of the patients, respectively, and no tendency toward a recovery in bone mass was seen even in those patients who had survived the longest time since KTx. Clinical fracture rate was 0.006 and 0.031 patient years, before and after KTx, respectively. The number of fractures was lower in patients taking lower mean daily doses of corticosteroids (p < 0.025). PTH levels positively correlated with bone alkaline phosphatase, osteocalcin and N telopeptide. CONCLUSION: In conclusion, bone density is decreased and bone turnover increased even many years after KTx, with persistent SHPT and corticosteroid use being the main pathogenetic factors.

Adult↗
PubMed2000

The synthesis and biological evaluation of a novel series of phthalazine PDE4 inhibitors I.

This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described represent conformationally constrained analogues of RP 73401, Piclamilast. Preliminary evidences of reduced side effects of II compared to standards are also reported.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Improved fibrinolytic capacity after withdrawal of steroid immunosuppression in renal transplant recipients.

BACKGROUND: Long-term steroid immunosuppression has been associated with the prothrombotic state observed in renal transplant (RT) patients, in whom both hypercoagulability due to an increase of von Willebrand factor/factor VIII complex, and impaired fibrinolysis due to PAI-1 excess have been demonstrated. Our aim was to investigate the effect of steroid withdrawal on fibrinolytic capacity in a group of RT patients. METHODS: The fibrinolytic study was performed in 28 RT patients under stable immunosuppression therapy with cyclosporine, azathioprine, and methylprednisolone; only 12 of these patients could repeat the study 6 months after steroid withdrawal. Euglobulin lysis time (ELT), tissue plasminogen activator activity (t-PA:act) and antigen (t-PA:Ag), PAI-1 activity (PAI-1:act), and antigen (PAI-1:Ag) were assayed on blood samples drawn before and 20 min after the venous occlusion test (VO). RESULTS: An hypofibrinolytic state due to a significant increase in PAI-1 levels was confirmed in RT patients receiving triple immunosuppression therapy. RT patient who stayed off steroids showed a significant shortening of ELT both before (P=0.01) and 20' after VO (P=0.005) at the 6-month control. Moreover, after steroid withdrawal, PAI-1:Ag levels decreased significantly (P=0.002) and normalized; in a similar manner PAI-1:act levels also showed a significant decrease both before (P=0.001), and after VO (P=0.0001). The prevalence of RT patients with impaired fibrinolytic capacity was as high as 83.3% during steroid treatment, and dropped to 16.7% after steroid withdrawal. CONCLUSIONS: Our findings confirm that steroid withdrawal may normalize impaired fibrinolytic capacity in RT patients; this improvement may further contribute to reduce the thrombotic risk associated with renal transplantation.

Adult↗
PubMed2000

Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients.

BACKGROUND: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS: We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS: Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.

Allopurinol↗
PubMed2000

The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; a primary protective role for bradykinin.

The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. A 1 h infusion of Z13752A (128 microgram kg(-1) min(-1) intravenously) decreased arterial blood pressure (by 11+/-3%; P<0. 05) and increased coronary blood flow (by 12+/-4%, P<0.05). There were no other significant haemodynamic changes. Z13752A inhibited both NEP and ACE enzymes both in dog plasma and in tissue (lung ACE; kidney NEP). Pressor responses to angiotensin I in vivo were inhibited and systemic vasodilator responses to bradykinin were potentiated. When the left anterior descending coronary artery was occluded for 25 min, Z13752A markedly reduced the severity of the resultant ventricular arrhythmias. No ventricular fibrillation (VF) occurred (compared to 7/16 in the controls; P<0.05), and ventricular tachycardia (VT) was reduced (VT in 2/9 dogs treated with Z13752A cp. 16/16 of controls; episodes of VT 0.2+/-0.1 c.p. 10.7+/-3.3; P<0. 05). Reperfusion of the ischaemic myocardium led to VF in all control dogs but occurred less frequently in dogs given Z13752A (survival from the combined ischaemia-reperfusion insult 67% c.p. 0% in controls; P<0.05). Z13752A reduced two other indices of ischaemia severity; epicardial ST-segment elevation and inhomogeneity of electrical activation. These protective effects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg(-1), i.v.) a selective antagonist of bradykinin at B(2) receptors; the ischaemic changes in dogs given both icatibant and Z13752A were similar to those in the controls. We conclude that this ACE/NEP inhibitor is effective at reducing the consequences of coronary artery occlusion in this canine model and that this protection is primarily due to potentiation of released bradykinin. British Journal of Pharmacology (2000) 129, 671 - 680

Adrenergic beta-Antagonists↗
PubMed2000

New immunosuppressive treatment in kidney transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) has been successfully introduced into clinical practice with evident benefits for renal transplant recipients. SUBJECTS AND METHODS: To evaluate some clinical results of MMF introduction, two groups of subjects underwent cadaveric renal transplants over the last 3 years and were retrospectively investigated. The first group (AZA group) contained 40 subjects (26 males and 14 females) on triple-drug therapy with steroids, cyclosporine and azathioprine (AZA). The second group (MMF group) contained 25 patients ( 19 males and 6 females) on the same regime with steroids and cyclosporine but MMF was administered as a third drug instead of AZA. The AZA group received renal transplant after a mean dialytic time of 32 +/- 19 months and the AZA group's dialytic time was 39.9 +/- 17 months. Clinical data, collected after a minimum 12 months observational period included a crude mortality rate and survival analysis recognized by Kaplan-Meyer curve, creatinine, creatinine clearance, rejection episodes and major clinical events such as infections and acute tubular necrosis. RESULTS: One subject died in each group. For kidney graft survival, Kaplan Meyer survival analysis showed a mean survival time of 1170.04 days in the AZA group vs 845 in the MMF group without statistical significance. Graft survival demonstrated 5:40 (12.5%) graft losses in the AZA group vs no kidney transplant loss in the MMF group (the only deceased patient had a well functioning kidney). The curve of graft cumulative proportion survival analysis demonstrated a more improved survival in the MMF group, but this difference did not reach a statistical significance (p = 0.07). Acute rejection episodes in the AZA group were 37.5% vs. 20% in the MMF group. In both groups, CMV infection was successfully treated with specific antiviral agents. CONCLUSIONS: MMF represents an important step towards induction and maintenance of immunosuppression. Our experience in a relatively small cohort investigated in a single center, demonstrates encouraging results regarding graft survival in comparison to those detected in conventional triple drug therapy. Surprisingly, in spite of stronger immunosuppressive treatment, the prevalence of CMV infections was not statistically different in the MMF versus the AZA group.

Adult↗
PubMed2000

Mycophenolate mofetil (MMF) versus azathioprine (AZA) in pancreas transplantation: a single-center experience.

AIM: Advances in immunosuppression and careful monitoring for rejection are largely responsible for improved results in pancreas transplantation. We conducted a retrospective study to establish the effectiveness of immunosuppressive therapy with mycophenolate mofetil (MMF) instead of azatioprine (AZA) in pancreas transplantation and to assess adverse effects in the two different immunosuppressive regimes. SUBJECTS AND METHODS: Since 1991, 27 pancreas transplantations were performed in 25 patients at our Institute. For induction therapy, immunosuppressant protocol consisted of quadruple immunosuppressive therapy with cyclosporine, steroids, antilymphocyte globulin and AZA in 13 patients or MMF in 12 patients respectively. RESULTS: Acute rejection occurred in 76% of patients in the AZA group compared with 53% in the MMF group. Steroid-resistant rejection was observed in 7% in the MMF group compared to 38% of patients on AZA (p < 0.01). Two kidney grafts were lost due to acute rejection in the AZA group, one pancreas was lost due to acute rejection and one to chronic rejection in the MMF group. There were no significant differences in CMV infection. Severe fungal infections were noted in 2 patients treated with MMF. Malignancy occurred in 1 patient (pancreas graft lymphoma) in MMF. CONCLUSIONS: In conclusion, patients treated with MMF required less frequent and less intensive treatment for acute rejection. However, its short- and long-term side effects should be further investigated.

Adult↗
PubMed1998

The effect duration of selective phosphodiesterase inhibitors in the guinea pig.

The beta-adrenoceptor agonists, isoprenaline, salbutamol and salmeterol, the non-selective phosphodiesterase (PDE) isoenzyme inhibitors, theophylline, trequinsin; the PDE3 isoenzyme inhibitor, milrinone; the PDE3/4 isoenzyme inhibitor, benzafentrine; and the PDE4 isoenzyme inhibitors, denbufylline, nitraquazone, RP 73401, Ro-20-1724, rolipram and tibenelast all induced concentration-dependent reversal of prostaglandin F2alpha-induced contraction of guinea-pig superfused trachea in vitro. The relaxant response of the non-selective PDE isoenzyme inhibitor trequinsin was slow in onset and demonstrated very slow recovery, similar to that observed with the long-acting beta2-adrenoceptor agonist, salmeterol and the PDE4 inhibitor, RP 73401. The relaxant agonists also significantly reversed bombesin-induced bronchospasm in anaesthetised guinea-pigs and there was a highly significant correlation between the ability of drugs to reverse PGF2alpha-induced contraction of guinea-pig isolated trachea in vitro and bombesin-induced bronchoconstriction in vivo. Furthermore, both salmeterol and trequinsin demonstrated long lasting bronchodilator responses consistent with the in vitro data. These results show that PDE isoenzyme inhibitors demonstrate different pharmacodynamic profiles that is not determined by PDE4 inhibitory potency and indicate that other factors may be important in this regard.

Adrenergic beta-Agonists↗
PubMed1998

Pharmacological evidence for the presence of a peripheral postjunctional D2-like dopamine receptor in rabbit splenic artery.

1. This study was designed to investigate the involvement of postjunctional D2-like receptors in a rabbit vasculature model used to evaluate the D1-like agonist activity. Dopamine, epinine and (-)-DP-5,6-ADTN, three mixed D1/D2-like agonists, fenoldopam and SKF 82958, two selective D1-like agonists and SKF 89124, a selective D2-like agonist, were administered cumulatively in precontracted and alpha/beta-blocked rabbit splenic artery rings in order to evaluate their D1-like-mediated vasorelaxant activity before and after pretreatment with the selective D2-like antagonist YM 09151-2 (1 nM). 2. Dopamine (pD2=6.35+/-0.09), epinine (pD2=6.73+/-0.13), (-)-DP-5,6-ADTN (pD2=7.56+/-0.09) and SKF 82958 (pD2=8.55+/-0.10) reversed completely the U46619-induced contracture whereas SKF 89124 was inactive up to 10 microM and fenoldopam acted like a partial agonist (pD2=8.31+/-0.09, alpha=0.62). The selective D2-like dopamine receptor antagonist YM 09151-2 (1 nM) significantly (P<0.05) potentiated the vasorelaxant activity of dopamine (pD2=7.01+/-0.07), epinine (pD2=7.14+/-0.08), (-)-DP-5,6-ADTN (pD2=8.19+/-0.09) and SKF 89124 (40% relaxation at 10 microM), whereas it did not alter the effects of fenoldopam (pD2=8.40+/-0.09, alpha=0.68) and SKF 82958 (pD2=8.58+/-0.08). 3. The D2-like antagonist YM 09151-2 induced the same degree of effect with all the substances tested in both endothelium-denuded and endothelium-intact preparations. 4. The selective D2-like dopamine receptor agonist SKF 89124 did not produce any intrinsic effect on the splenic artery, but was able to produce a rightward shift of the forskolin-induced relaxation. 5. The results of these experiments support the existence of a non-endothelial postjunctional D2-like dopamine receptor counteracting the D1-like-mediated vasodilatation in rabbit splenic artery, probably by the inhibition of adenylate cyclase.

Animals↗
PubMed1998

Short-term outcome of diabetic patients in renal replacement therapy.

BACKGROUND: Diabetic nephropathy or diabetes-related nephropathies represents one of the most relevant causes of renal failure in recent years. This complex pathological picture becomes particularly severe as time elapses and after starting renal replacement therapy (RRT). METHODS: In an attempt to investigate the evolution of the major clinical features, a retrospective study was carried out on a cohort of 76 diabetic patients on RRT. Sixty-five have been treated by haemodialysis (HD) and 11 by peritoneal dialysis (CAPD), for at least 1 year. In these patients change in modality of treatment, metabolic control, cardiovascular, and ophthalmological complications, peripheral neuropathy, state of vascular access, and intradialytic complications were surveyed at initiation and after 1 year of treatment. A modified Karnofski's score was utilized, to evaluate the degree of rehabilitation. The comparison of prevalence was evaluated, using Student's t-test for paired samples. RESULTS: After 1 year, 11 patients on CAPD remained on the same type of treatment. Out of 65 patients on standard bicarbonate HD, 11 were moved to acetate free biofiltration, two to paired filtration dialysis and one to haemofiltration. A worsening in arrhythmias was recorded with an increased prevalence from 25.0 to 35.0% (n.s.), and one more patient (15 vs 16 and 19 vs 20 respectively) experienced ischaemic cardiomyopathy and cerebrovascular insufficiency. Hypertension showed a significant improvement (72 vs 42, P<0.01). Nausea and vomiting, hypotensive episodes, and muscular cramps were more frequently observed. A worsening in patient's welfare was also recorded but without statistical significance. CONCLUSIONS: This clinical evaluation even if retrospective and lasting 1 year, may suggest that RRT does not per se represent a cause of the development and progression of the major complications related to diabetic disease.

Adult↗