New rhenium complexes with ciprofloxacin as useful models for understanding the properties of [99mTc]-ciprofloxacin radiopharmaceutical.

Rhenium complexes with the antibiotic ciprofloxacin have been prepared to be studied as models of technetium radiopharmaceuticals. With this aim, the new rhenium complexes 1 {[ReO(Cpf)2]Cl}, 2 {[ReO(CpfH)2]Cl3} and 3 {fac-[Re(CO)3(H2O)(Cpf)]} with ciprofloxacin (CpfH=ciprofloxacin; Cpf=conjugated base of ciprofloxacin) have been synthesised and characterised by elemental analyses, IR, NMR ((1)H, (19)F and (13)C CP-MAS) spectroscopy, as well as MS measurements. All spectroscopic data are consistent with the coordination of ciprofloxacin in all these complexes through the carbonyl and the carboxylate oxygen atoms with the formation of a six member chelate ring. The study of a Tc-ciprofloxacin solution by ESI-MS reveals the presence of [TcO(Cpf)2](+) cations, which agrees with the hypothesis that complexes 1 and 2 can be seen as model rhenium complexes of this radiopharmaceutical. Antimicrobial and DNA gyrase inhibition studies performed with complexes 2 and 3 have shown a very similar behaviour between complex 2 and the free antibiotic, whereas complex 3 exhibit a lower antimicrobial activity. Based on a joint analysis of the data reported in the literature and the chemical and biological results obtained in this study, a tentative proposal to explain some aspects of the behaviour of Tc-ciprofloxacin radiopharmaceutical has been made.

Usefulness of 99mTc-ciprofloxacin scintigraphy in the diagnosis of prosthetic joint infections.

OBJECTIVE: To evaluate the usefulness of 99Tc-ciprofloxacin scintigraphy (CFS) in patients with hip or knee arthroplasty and suspected infection. METHODS: Forty patients (26 women, 14 men) with a mean age of 66±10 years and local pain in the hip (21), knee (16), or shoulder (three) prosthesis were recruited. CFS was performed at 1, 4, and 24 h after intravenous injection of 370 MBq. Anterior and posterior views centered on the affected joint were performed in all patients. A routine bone scan, 99Tc-hexamethylpropyleneamine oxime leukocyte scan, and 99Tc-colloid scan [leukocyte scintigraphy-bone marrow scintigraphy (LS-MS)] were performed. Final diagnosis of infection was confirmed by positive microbiological analysis or macroscopic evidence of purulent material. RESULTS: Diagnosis of arthroplasty infection was established in 16 out 40 cases: coagulase-negative staphylococci (nine), Staphylococcus aureus (three), Enterococcus (one), and macroscopic infection in the remaining three cases. CFS imaging showed the 24-h image to be the best acquisition time-point. The sensitivity, specificity, negative predictive value, and positive predictive value for LS-MS were 75, 92, 86, and 85%, whereas for CFS at 24 h these figures were 88, 71, 67, and 89%. The sensitivity and specificity for LS-MS and for CFS at 24 h for hip were (74, 90, and 88, 85%) and for knee (83, 90 and 100, 50%). CONCLUSION: CFS can be useful in the diagnosis of arthroplasty infection of the hip as a substitute for LS-MS. It is recommended that CFS images be obtained 24 h after injection. The lack of specificity of CFS makes this technique inadequate for knee prostheses in this series.

Assessment of migration of HIV-1-loaded dendritic cells labeled with 111In-oxine used as a therapeutic vaccine in HIV-1-infected patients.

Monocyte-derived dendritic cells (DCs) loaded with heat-inactivated HIV are used in therapeutic immunizations. It is not known whether they migrate in vivo to lymph nodes. We used an (111)In-oxine-labeled DC (ILDC) method to visualize the migration of DCs. The activity, time and incubation medium were investigated to obtain the highest cellular viability and radiolabeling yield. A trypan-blue exclusion test was used to determine the cellular viability. In five patients, 2 x 10(6) ILDCs were injected subcutaneously in the arm. An initial dynamic study was performed during the first 5 min after injection. This was followed by static acquisitions at several time points, using a high-resolution (general electric) gamma-camera and quantifying the activity at regions of interest drawn on the injection point. The sensitivity of the gamma-camera was evaluated. The highest number of viable DCs (>83%) and the best radiolabeling yield (>70%) were obtained with 1.11 MBq (111)In-oxine, after 10 min of incubation at 37 degrees C in sodium chloride solution 0.9%. We did not observe migration of ILDCs to local lymph nodes in any patient. However, focal uptake at the place of injection continued during the study period. We observed a higher than expected loss of activity from the injection point (median A(t)/A(0) = 0.60 at day 2), which correlated with an increase in total cytotoxic T lymphocytes (CD8(+) and granzyme B(+) cells) in the lypmphoid tissue observed after immunization (R(2) = 0.92, p = 0.03). If more than 20,000 ILDCs had migrated, they could have been detected. In future trials, a higher number of DCs or alternative methods should be used to assess the migration of DCs to lymph nodes.

Effects of propranolol on venous compliance in conscious rats with pre-hepatic portal hypertension.

BACKGROUND/AIMS: The venous system is the primary capacitance region in the body. However, the influence of active changes in the venous system on the hemodynamic alterations of portal hypertension is poorly understood. To investigate venous compliance (VC) in conscious partial portal vein ligated rats (PPVL) and the effect of propranolol on VC. METHODS: Venous compliance was derived from the relationship between changes in mean circulatory filling pressure (MCFP) and changes in blood volume (BV). Measurements were performed before and after i.v. propranolol (7.5 mg/Kg) or placebo in rats with portal hypertension due to PPVL and sham operated controls. RESULTS: PPVL rats had an increased VC when compared to Sham (4.9+/-1.4 vs. 3.7+/-0.9 ml kg-1 mm Hg-1; P<0.02). VC did not change after placebo but was significantly reduced by Propranolol in PPVL (-32.9+/-15.7%; P<0,007). Propranolol did not modify venous compliance in sham operated rats (+10.9+/-13.4%; P=ns). CONCLUSIONS: Venous compliance is increased in portal hypertensive rats, suggesting that the venous system contributes to the profound circulatory changes encountered in portal hypertension. The increased venous compliance is markedly attenuated by propranolol, suggesting that this abnormality is related to increased adrenergic activity.

Systemic hemodynamics, vasoactive systems, and plasma volume in patients with severe Budd-Chiari syndrome.

Budd-Chiari syndrome (BCS) causes postsinusoidal portal hypertension, which leads to complications similar to those observed in cirrhosis. However, no studies have investigated whether patients with BCS develop the hyperdynamic circulatory syndrome present in patients with cirrhosis who have portal hypertension. We evaluated systemic and cardiopulmonary hemodynamics, plasma renin activity, aldosterone and norepinephrine levels, and plasma volume in patients with BCS admitted for complications of portal hypertension. BCS patients had mean systemic and cardiopulmonary pressures and cardiac indices that were within the normal range but were significantly different from those of a group of patients with cirrhosis matched by sex, body surface, and liver function (cardiac index 3.1 +/- 0.7 vs. 4.9 +/- 1.2 L.min(-1).m(-2); P < .001; systemic vascular resistance [SVR] index, 2,189 +/- 736 vs. 1,377 +/- 422 dyne.s.cm(-5).m(-2), P < .001). Despite normal systemic vascular resistance, BCS patients had activation of the neurohumoral vasoactive systems, as evidenced by increased plasma renin activity, aldosterone and norepinephrine levels (15.0 +/- 21.5 ng/mL . h, 76.7 +/- 106.8 ng/dL, 586 +/- 868 pg/mL; respectively) and plasma volume expansion. The analysis of individual BCS patients identified that 7 of the 21 patients actually had reduced SVR index. These patients had the greatest plasma volume expansion. A significant inverse correlation between plasma volume and SVR index was observed. In conclusion, patients with BCS had activation of vasoactive neurohumoral systems and expanded plasma volume. This outcome was observed even though most of these patients did not exhibit systemic vasodilation and cardiac output was not increased, in marked contrast with what is observed in patients with cirrhosis.

Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: changes in glomerular haemodynamics and proteinuria.

BACKGROUND: The study was conducted in order to describe possible intraglomerular haemodynamic changes inducing proteinuria after 14 patients with chronic allograft dysfunction were converted from calcineurin inhibitors (CIs) to sirolimus without changing concomitant immunosuppression or antihypertensive treatment. METHODS: Creatinine, glomerular filtration rate (GFR), proteinuria, renal functional reserve (RFR) and effective renal plasma flow (ERPF) were determined before and 8 months after conversion. Intraglomerular pressure (P(G)), afferent arteriolar resistance (AAR) and efferent arteriolar resistance (EAR) were calculated using Gomez's formula. RESULTS: Creatinine (1.97 vs 2.075 mg/dl; P = 0.270) and GFR (40 vs 43 ml/min; P = 0.505) remained unchanged, proteinuria increased (338 vs 1146 mg/24 h; P = 0.006), RFR decreased (34.84 vs 13.47%; P = 0.019), ERPF (248 vs 310.6 ml/min; P = 0.0625) and P(G) (42.72 vs 46.17 mmHg; P = 0.0625) tendentially increased and AAR tendentially decreased (14.12 vs 10.28 dyne/s/cm(5); P = 0.0625). CONCLUSION: After conversion, P(G) shows a tendency to increase and RFR decreases significantly-characteristics of hyperfiltration, which could possibly partially explain the increase of proteinuria. Therefore, the application of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers seems promising. To avoid hyperfiltration, conversion should be performed early when renal insufficiency is still moderate.

Therapeutic immunization with dendritic cells loaded with heat-inactivated autologous HIV-1 in patients with chronic HIV-1 infection.

Therapeutic immunization with autologous monocyte-derived dendritic cells (DCs) loaded with heat-inactivated autologous human immunodeficiency virus type 1 (HIV-1) in 12 patients with chronic HIV-1 infection who were receiving highly active antiretroviral therapy (HAART) was feasible, safe, and well tolerated. Virus was obtained during an initial interruption of HAART (hereafter, "stop 1") so that DCs could be pulsed. After immunization and a second interruption of HAART (hereafter, "stop 2"), set-point plasma viral load (PVL; 24 weeks after stop 2) decreased > or =0.5 log(10) copies/mL relative to baseline PVL in 4 of 12 patients. We observed a significant lengthening in mean doubling time of PVL rebound and significant decreases in the area under the curve and the mean peak of PVL rebound after stop 2, compared with those after stop 1. This response was associated with changes in HIV-1-specific CD4(+) lymphoproliferative and CD8(+) T cell responses. These changes were not observed in a group of nonimmunized control patients.

Effects of contrast media on renal function in patients with cirrhosis: a prospective study.

Patients with cirrhosis are frequently submitted to radiological procedures that require the administration of contrast media. Contrast media is a well-known cause of renal failure, particularly in the presence of some predisposing conditions. However, it is not known whether cirrhosis constitutes a risk factor for contrast media-induced renal failure. The aim of this study was to assess the possible nephrotoxicity of contrast media in patients with cirrhosis. In a first protocol, renal function was evaluated with sensitive methods (glomerular filtration rate using iothalamate I 125 clearance and renal plasma flow using iodohippurate I 131 clearance) before and 48 hours after the administration of contrast media in 31 patients with cirrhosis (20 with ascites, 5 with renal failure). Solute-free water clearance, urine sodium, prostaglandins, and markers of tubular damage were also measured. The administration of contrast media was not associated with significant changes in renal function tests, neither in the whole group of patients nor in patients with ascites or renal failure. Urinary prostaglandin E2 and N-acetyl-beta-D-glucosaminidase increased significantly, but sodium and solute-free water excretion remained unchanged. In a second protocol, a different series of 60 patients with cirrhosis and renal failure were examined prospectively. No patient had renal failure due to contrast media. Only in 1 patient with septic shock was contrast media a possible contributing factor. In conclusion, the administration of contrast media is not associated with adverse effects on renal function in patients with cirrhosis. Cirrhosis does not appear to be a risk factor for the development of contrast media-induced nephrotoxicity.

Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis.

Short-term carvedilol administration is more powerful than propranolol in decreasing hepatic venous pressure gradient (HVPG) in cirrhotic patients, but induces arterial hypotension that may prevent its long-term use in portal hypertensive patients. This study compared the HVPG reduction and safety of long-term carvedilol and propranolol. Fifty-one cirrhotic patients were randomly assigned to receive carvedilol (n = 26) and propranolol (n = 25). Hemodynamic measurements and renal function were assessed at baseline and after 11.1 +/- 4.1 weeks. Carvedilol caused a greater decrease in HVPG than popranolol (-19 +/- 2% vs. -12 +/- 2%; P <.001). The proportion of patients achieving an HVPG reduction >/=20% or

Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-beta(1) plasma levels in a crossover trial in renal transplant recipients.

Hypertension and hyperfiltration are two important risk factors for the development of chronic allograft nephropathy. Transforming growth factor-beta(1) (TGF-beta(1)) is the main cytokine involved in the fibrotic process that is involved in chronic rejection. Angiotensin II upregulates TGF-beta(1) production. Angiotensin II receptor antagonists therefore could not only control BP but also reduce TGF-beta(1) production in renal transplant patients. The aim of this study was to compare the effects of losartan and amlodipine on renal hemodynamics, as well as TGF-beta(1) and endothelin-1 (ET-1) plasma levels in a group of renal transplant patients who had normal renal function and who were treated with cyclosporine. Seventeen renal transplant patients who were receiving cyclosporine and who had normal graft function were included in a random 2 x 2 crossover trial with amlodipine and losartan (6 wk with each therapy). Three studies were performed (at baseline and at the end of both treatment periods) to determine renal hemodynamics, TGF-beta(1), and ET-1. Both treatments controlled BP to a similar degree, but only amlodipine increased GFR through an increase in the estimated glomerular hydrostatic pressure and filtration fraction. In contrast, losartan maintained GFR and reduced estimated glomerular hydrostatic pressure and filtration fraction significantly. Losartan and amlodipine had opposite effects on TGF-beta(1). Amlodipine did not affect TGF-beta(1) concentrations. In contrast, losartan reduced the plasma levels of TGF-beta(1) by approximately by 50% (from baseline, 5.2 to 2.6 ng/ml; P: = 0.01); the majority of the patients reached normal levels of TGF-beta(1). ET-1 concentrations were significantly higher during amlodipine compared with losartan treatment. The present study documents that with similar control of BP, losartan and amlodipine have opposite effects on renal hemodynamics and on TGF-beta1 concentrations. These differences could be important for the management of chronic allograft nephropathy.