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Biomedical subjects

R Venuto

Publications and source records attributed to R Venuto.

At least 19 recordsLinked to original sources
PubMed2006

Early and severe hyperparathyroidism associated with hypercalcemia after renal transplant treated with cinacalcet.

Bone disease is a common clinical problem following renal transplantation. In renal transplant recipients, multiple underlying factors determine the extent of bone loss and the subsequent risk of fractures. In addition to the well-recognized risk to bone disease posed by steroids, calcineurin inhibitors and pre-existing bone disease, persistent hyperparathyroidism (HPT) contributes to post-transplant bone loss. HPT is usually treated with vitamin D supplements combined with calcium. Patients whose HPT is associated with hypercalcemia pose a difficult therapeutic dilemma which often requires parathyroidectomy. Cinacalcet, a calcium mimetic agent, offers a unique pharmacologic approach to the treatment of patients with post-transplant hypercalcemia and HPT. In this paper, we describe the clinical course and biochemical changes in 10 renal transplant recipients with hypercalcemia and severe HPT early after renal transplantation treated with cinacalcet. Cinacalcet therapy corrected hypercalcemia and decreased parathyroid hormone (PTH) levels in all cases. A transient rise in the level of alkaline phosphatase was noted following initiation of cinacalcet therapy. In this patient population, correction of HPT was not permanent as discontinuing cinacalcet therapy led to a rapid rise in PTH level.

Administration, Oral↗
PubMed2001

Ganciclovir pharmacokinetics and cytokine dynamics in renal transplant recipients with cytomegalovirus infection.

Ganciclovir is considered to be the first-line treatment for cytomegalovirus (CMV) in renal transplant recipients. This infection is also associated with elevations of specific plasma cytokines post-transplantation. To investigate daily cytokine response to therapy and ganciclovir pharmacokinetics, 4 transplant recipients (3 males, 1 female) with stable renal allograft function diagnosed with CMV infection were enrolled less than 4 months post-transplant. A creatinine clearance (ClCr) was generated by the Cockroft-Gault (C-G) equation (range: 42.3-68.5 mL/min) to determine ganciclovir dosing. Blood samples were collected for ganciclovir and cytokine [including interleukin (IL)-1beta, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, TNF-alpha, GM-CSF, and interferon (IFN)-gamma analyses after 7 d of intravenous (i.v.) ganciclovir (dosage range: 165-400 mg daily) therapy and again after 7 d of oral (p.o.) ganciclovir (dosage range: 1000 mg, 2-3 times daily) therapy. Pharmacokinetic ganciclovir was described with a two-compartment model. Total clearance of ganciclovir was consistently greater than ClCr, suggesting tubular secretion. Peak concentrations for i.v. ganciclovir averaged 8.39+/-1.87 microg/mL with minimum concentrations of 0.48+/-0.35 microg/mL. Plasma concentrations were lower but more sustained during a p.o. dosing interval (max=2.12+/-0.58 microg/mL, min=1.15+/-0.34 microg/mL). IL-6, IL-8, IL-10, and TNF-alpha were detectable at multiple times during the study periods while the remainder of the cytokines were only intermittently detectable. Average concentrations (i.v. versus p.o. study period) for TNF-alpha were 40.1+/-17.5 versus 22.1+/-11.2 pg/mL, for IL-8 were 17.1+/-15.6 versus 4.12+/-2.59 pg/mL, and for IL-10 were 7.39+/-5.54 versus 2.64+/-1.06 pg/mL. Concentrations were similar for IL-6 during both studies (9.39+/-5.42 versus 14.7+/-14.8 pg/mL). TNF-alpha, IL-8, and IFN-gamma appeared to correlate with CMV antigenemia. Further investigation of ganciclovir disposition and changes in plasma cytokines in renal transplant recipients during CMV infection may provide insight into variable antiviral responses in renal transplant recipients.

Adult↗
PubMed1997

Impact of surgery on nitric oxide in rats: evidence for activation of inducible nitric oxide synthase.

We investigated the effect of euvolemic surgical preparation, on chemical indices of activity of the nitric oxide (NO) system, in anesthetized, acutely prepared rats. The urinary excretion of NO2+NO3 (UNOXV) and cGMP (UcGMPV) increased progressively during the experiment. Pretreatment with aminoguanidine or dexamethasone, inhibitors of inducible NO synthase (iNOS), prevented the increase in UNOXV and UcGMPV but had no impact on mean arterial pressure (BP), renal vascular resistance (RVR) or GFR. Since these variables did not change in the conscious rat, the increased UNOXV results from some aspect of the acute surgical preparation. When acutely prepared rats received L-NAME, a non-specific NOS inhibitor, BP and RVR increased but paradoxical increases in UNOXV and UcGMPV were also seen. Nonselective NOS inhibition (+L-NAME) was fatal in 50% of acutely prepared rats, causing cardiac contracture. The same dose of L-NAME produced no deaths in either conscious chronically catheterized rats or in acutely prepared rats, previously subjected to sterile surgery and acute L-NAME in the conscious state. These data indicate that acute, nonsterile surgery induces expression of iNOS, but that the additional NO generated has no obvious cardiovascular/renal actions. Acute UNOXV and UcGMPV do not predict total NO production, or "hemodynamically active" NO. Generalized NO inhibition in rats acutely stressed by surgery/anesthesia can be fatal.

Animals↗
PubMed1997

Gestational resistance to the pulmonary vasoconstrictor effect of the TxA2 mimetic U-46619: possible mechanism.

Pregnancy is associated with the reduction of vascular sensitivity to vasoconstrictor compounds. We have examined whether pregnancy in rabbits induces hyposensitivity of the pulmonary vascular system to U-46619. Anesthetized, mechanically ventilated nonpregnant (NP; n = 7) and late-pregnant (P; n = 7) rabbits were studied. The intravenous injection of 0.03, 0.1, and 0.3 microgram/kg U-46619 led to a dose-dependent elevation of mean pulmonary arterial pressure (MPAP) in NP rabbits from a baseline value of 15 +/- 1 to 22 +/- 1 mgHg. There was no significant MPAP response to intravenous administration of U-46619 in P rabbits. The pulmonary arterial pressure response of isolated, ventilated, and buffer-perfused lungs of P rabbits was also blunted (P < 0.001 vs. NP). Pulmonary arterial membrane binding of [125I]BOP, another thromboxane (Tx)A2 analog, indicated 48 +/- 16 fmol receptors/mg protein in P rabbits and 193 +/- 48 fmol receptors/mg protein in NP samples (P < 0.025). Receptor affinity [1/dissociation constant (KD)] was also lower in the tissue of P rabbits (P < 0.01 vs. NP). The urinary excretion of the stable TxA2 metabolite 11-dehydro-TxB2 was lower in P than in NP rabbits (P < 0.02), which made homologous desensitization an unlikely explanation for the changes of vascular TxA2 receptors. These results show that, in late gestation, rabbit pulmonary vascular sensitivity to U-46619 is reduced simultaneously with, and as a possible consequence of, downregulation of specific receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Monitoring and diagnosis of cytomegalovirus infection in renal transplantation.

In this study, the utility of the cytomegalovirus antigen (CMV-AG) and the shell vial (SV) tests in the diagnosis and monitoring of posttransplant CMV infection were compared. Previous retrospective studies from the authors' center suggested that the CMV-AG test, which uses monoclonal antibodies to detect viral antigen in circulating peripheral blood leukocytes (PBL) may be both a more sensitive and specific test. A cohort of 32 renal transplant recipients was followed-up prospectively with serial CMV-AG testing, as well as conventional culture and SV for blood and urine and tests for immunoglobulin M (IgM) antibody. It was discovered that the CMV-AG test was not only more sensitive than the SV test in detecting CMV infection, but that the degree of antigenemia as expressed by the number of positive cells per 50,000 PBL correlated with the likelihood and degree of symptomatic infection. All patients with a count > 10 positive cells/50,000 PBL developed clinical symptoms; therefore, this threshold could be useful in deciding clinically whether fever is related to CMV infection. Alternatively, if antigenemia were monitored serially after transplant, the same threshold could be used as a trigger for instituting antiviral therapy, because it was often reached prior to the onset of symptoms and had a high specificity for subsequent symptomatic infection. Such an approach could obviate unnecessary treatment of patients not destined to become symptomatic. Based upon the findings in this study, the CMV-AG test is superior to the SV assay because the actual count helps determine the likelihood that symptoms are a result of the virus and the processing time is shorter, it can be used to monitor the response to therapy and as a guide to the institution of preemptive therapy.

Antigens, Viral↗
PubMed1996

The vasoconstrictor effects of L-NAME, a nitric oxide synthase inhibitor, in pregnant rabbits.

1. We have used anaesthetized, acutely instrumented non-pregnant (NP) and late pregnant (P) New Zealand white rabbits to examine the possible role of nitric oxide (NO) in the pregnancy-induced fall of vascular tone and arterial pressure. Systemic, renal and pulmonary vascular resistance, as well as plasma concentrations of cyclic GMP (PcGMP) were compared before and after the inhibition of NO synthesis by N(G)-nitro-L-arginine methyl ester (L-NAME). 2. P rabbits had lower baseline total peripheral resistance (TPR), mean arterial pressure (MAP) and higher PcGMP than NP controls (all P < 0.05 or less). L-NAME (1, 10, 50 mg kg1, i.v.) resulted in dose-dependent elevation of TPR in both groups. However, the absolute, as well as percentage increases in TPR were greater (P < 0.05) in NP than in P rabbits. 3. Cardiac output (CO) was reduced more (P < 0.01) by NO inhibition in NP than P rabbits. Therefore, despite the smaller increase in TPR, the elevation of MAP was greater (P < 0.001) in P than NP rabbits. After L-NAME, NP rabbits developed more severe bradycardia and a greater increase of pulmonary vascular resistance which might have contributed to the more pronounced reduction of CO. 4. PcGMP increased in both groups following L-NAME, but more (P < 0.01) in NP than P rabbits. 5. Infusion of acetylcholine (ACh, 0.02 micromol l-1 kg-1) reduced MAP and TPR more (both P < 0.05) in NP than P rabbits and L-NAME reduced the ACh-induced depressor response only in NP rabbits. 6. These results suggest that the low vascular tone and arterial pressure in pregnant rabbits is not mediated by NO.

Acetylcholine↗
PubMed1995

Acute changes in urinary excretion of nitrite + nitrate do not necessarily predict renal vascular NO production.

NO2 + NO3 (NOx), the stable oxidation products of NO, and cGMP are widely accepted as indices of in vivo NO production. Whether acute changes in urinary excretion of nitrite + nitrate (UNOXV) can be taken to reflect acute changes in renal and/or systemic NO production is not known. The present studies were conducted in the conscious rat to investigate the effect on acute changes in UNOxV, of maneuvers that (a) enhance NO production and (b) act as diuretics. L-arginine (L-arg) and acetylcholine (Ach) produce equivalent NO dependent falls in renal vascular resistance (RVR), but a much greater increase in UNOX V is seen with L-arg. D-arg does not stimulate NO and has no renal vasodilatory effect, but produces a large rise in UNOX V, and SNP lowers BP but not RVR and results in a reduced UNOX V. None of the diuretics employed should stimulate the NO system or lower RVR; however, the proximally acting agents, acetazolamide and D-arg increased UNOx V, while the loop diuretic furosemide had little effect. H2O diuresis (a distal event) led to a fall in UNOx V. These data suggest that NOx is reabsorbed extensively in the proximal tubule and that inhibition of proximal reabsorption leads to an increase in UNOx V. Also, our results show that the relationship between UNOx V and UcGMP V is unpredictable. Therefore, we conclude that measurements of acute changes in UNOxV and/or UcGMP V should be interpreted cautiously, since they may reflect altered tubular handling of NOx rather than the acute activity of the systemic and/or renal NO systems.

Acetylcholine↗
PubMed1995

24-hour immunologic assessment of CD4+ and CD8+ lymphocytes in renal transplant recipients receiving chronic methylprednisolone.

Glucocorticoids are commonly prescribed in the post transplant period as a component of combination immunosuppressive regimens. However, the daily 24-hour pattern of helper lymphocytes (CD4+) and suppressor cells (CD8+) during chronic methylprednisolone therapy has not been examined in renal transplant recipients in relation to glucocorticoid exposure and time post-transplant. The response of total lymphocytes, CD4+ and CD8+ lymphocytes was examined in 23 stable renal transplant recipients who received methylprednisolone for at least 8 months post-transplant. The patient's prescribed oral methylprednisolone dose (mean daily dose = 9.7 +/- 2.6 mg) was given intravenously and whole blood was sampled periodically over 24 h for lymphocyte counts and methylprednisolone concentrations. A complete blood count with differential was determined via an automated hemocytometer with CD4+ and CD8+ lymphocytes determined using flow cytometry. Methylprednisolone area under the concentration versus time curve (AUC) was determined and normalized for each patient's respective dose. A general lymphopenia resulted in all patients with a mean decrease of 61 +/- 15% and an average nadir time occurring at 6 h. The decline from baseline was 76 +/- 17% for absolute number of CD4+ and 59 +/- 18% for CD8+ lymphocytes with an average nadir time at 6 h. Twelve patients exhibited a baseline CD4+ count to be less than 688 cells/mm3 (the low end of the reference range) and the lymphocyte count of all the patients fell below this value at the nadir. Six patients had a CD8+ lymphocyte count below 380 cells/mm3 (low end of the reference range) at baseline with 21 of the 23 patients exhibiting less than 380 cells/mm3 at the nadir time. At the time of nadir, the mean CD4+ and CD8+ counts were 156 +/- 105 cells/mm3 and 256 +/- 270 cells/mm3, respectively. In 17 of the 23 patients, the CD4+ count was below 200 cells/mm3 at the time of nadir. The dose-normalized AUC of methylprednisolone ranged from 22.6 to 113.5 ng.h/ml with 48% of patients exhibiting morning cortisol concentrations greater than 60 ng/ml. No correlation was noted between daily methylprednisolone exposure and the extent of lymphocyte decline. Lymphocyte response patterns are not clinically recognized in renal transplant recipients, as a means of monitoring immunosuppression. The absolute CD4+ and CD8+ lymphocyte count and the timing of these sample collections post-steroid administration, may have clinical relevance when serially assessed as is done in other immunologic diseases. Prospective evaluation of lymphocyte subset patterns and correlation with susceptibility to overimmunosuppressive (i.e. opportunistic infections) is necessary to help determine if these complications can be minimized by more individualized steroid dose modification.

Adult↗
PubMed1993

The effect of pregnancy on the response to the TxA2/PGH2 analogue U-46619 in rabbits.

We compared the hemodynamic actions of U-46619, a stable thromboxane A2 (TxA2) prostaglandin H2 (PGH2) analogue, in nonpregnant (NP) rabbits with those observed in late pregnant (P) rabbits. An intravenous injection of U-46619 (10 micrograms) to each of eight NP chronically instrumented rabbits (mean body weight 3.4 kg) induced an immediate (1 min) and reversible fall of cardiac output (CO, 66%) and mean arterial pressure (MAP, 41%, both P < 0.01). P rabbits (n = 6, mean body weight 3.8 kg), however, responded with an elevation of MAP (5%, P < 0.02) upon intravenous injection of the drug (10 micrograms), while CO remained unchanged. The fall of CO in NP rabbits was associated with the temporary disappearance of a fraction of circulating platelets between the superior vena cava and the aortic arch. The number of platelets at 30 and 60 s after U-46619 was reduced (P < 0.05) by 14 and 20% respectively in the aortic blood, whereas caval platelet counts were unchanged until 90 s (-6%, P < 0.05). In contrast, intraaortic administration of this drug (10 micrograms) to NP rabbits resulted in neither thrombocytopenia nor hypotension. U-46619 (10-30 micrograms i.v.) caused no decrease in platelet count in the aorta of P rabbits. In vitro, U-46619-induced aggregation of platelets harvested from P rabbits was also blunted (P < 0.001). This could not be attributed to reduced affinity or number of platelet thromboxane receptors. The data indicate that U-46619 induces a fall of arterial pressure simultaneous with intravascular platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Metabolic activity of the lung during cardiopulmonary bypass.

Metabolic functions of the lung were examined in sixty patients undergoing coronary artery bypass surgery employing a method to separate right and left heart flow during surgery. Six study groups were employed to investigate the activity of normal serum electrolytes, minerals, enzymes and vasoactive prostanoids as they pass through the pulmonary vasculature. Various sample sites were employed to represent isolated segments of the vascular tree: pump (systemic) and right atrium (myocardium), aortic (bronchial flow). LDH, Ca++, phosphate and SGOT were documented to vary with passage through the pulmonary circulation while alkaline phosphatase, bilirubin, creatinine, urate, cholesterol, albumin and BUN remained essentially unchanged. Bronchial flow was calculated and directly related to temperature and pump flow with an average range of 15 ml/min +/- 6 ml/min. The stress of surgery produced elevated PGE2 in bronchial flow and urine that caused reproducible hypotension when rapidly reinfused into the patient. PGE2 production, though decreased with Indomethacin block, could be rapidly reversed with the stress of surgery.

Blood Pressure↗
PubMed1985

Hemodynamic consequences of bronchial flow during cardiopulmonary bypass.

Nine patients (seven men and two women) were studied while undergoing coronary artery bypass on cardiopulmonary bypass. Selective bronchial flow samples were obtained and analyzed for prostaglandin E2 levels, and the hemodynamic effects of this vasodilator were studied. Bronchial flow collection and measurements were performed during hypothermic cardioplegic arrest while the peripheral anastomosis was being completed, as described previously. This collected sample was reinfused abruptly to the pump circuit, but samples were also analyzed for specific radioimmunoassay antiserum for prostaglandin E2 levels. Urine levels were obtained both with and without indomethacin block. All nine patients were studied for the hemodynamic effects of rapidly reinfused bronchial flow. A 34% +/- 8.8% mean drop of blood pressure and peripheral vascular resistance were recorded (p less than 0.002). Three study groups were established: In Group I, serum prostaglandin assay was performed on six patients. Prostaglandin E2 levels showed an average of increase of 159% compared to the baseline (p less than 0.02). In Group II, urine prostaglandin was measured. Nine assays were performed on six patients. Analysis of the total urine production while on cardiopulmonary bypass showed an average increase in prostaglandin E2 of 300% (p less than 0.02). In Group III, combined serum and urine prostaglandin levels were measured in three patients before and after indomethacin block (50 mg four times a day for 48 hours before the operation). All of these patients demonstrated the same hypotensive phenomena with reinfusion of the bronchial flow. The urinary prostaglandin E2 output and serum prostaglandin E2 levels in bronchial flow were elevated. Overall, this group manifested a 50% reduction in prostaglandin E2 production over baseline values with indomethacin block (p less than 0.02) and a 300% increase in production during cardiopulmonary bypass (p less than 0.02). Our data suggest that significant amounts of prostaglandin E2 are released in the lung during the stress of cardiac operations. Rapid reinfusion of bronchial flow is responsible for hypotension during cardiopulmonary bypass. Pretreatment with indomethacin will not completely block prostaglandin E2 release in the lung during stress.

Aged↗
PubMed1984

Blood pressure control in pregnant rabbits: norepinephrine and prostaglandin interactions.

The relationship between norepinephrine (NE) and prostaglandins in the regulation of systemic blood pressure during pregnancy was examined in conscious rabbits. The arterial prostaglandin E2 (PGE2) concentration was higher in pregnant than in nonpregnant rabbits. Resting blood pressure was slightly lower in the gravid animals. The pressor response to incremental doses of intravenous NE was blunted in the pregnant rabbits. Meclofenamate, a cyclooxygenase inhibitor, failed to alter the resting blood pressure in either group of animals, although it reduced PGE2 levels more than 60% in the pregnant rabbits. The pressor response to NE was significantly increased only in the pregnant rabbits when the NE infusion was repeated following meclofenamate. Pregnant rabbits could also be differentiated from nonpregnant by their higher peripheral blood levels of NE and their uniform hypotensive response to alpha-adrenergic blockade. These observations define an altered responsiveness to both endogenous and exogenous NE in pregnant rabbits that appears to be related to an increase in vasodilator prostaglandins.

Animals↗
PubMed1982

Uterine and peripheral blood concentrations of vasodilator prostaglandins in conscious pregnant rabbits.

The concentrations of prostaglandin E2 (PGE2) and prostacyclin (PGI2) were estimated in blood obtained from the uterine venous effluent and a peripheral artery of conscious pregnant and nonpregnant rabbits. The blood was analyzed both with a superfusion bioassay and radioimmunoassays. PGE2, but not PGI2, was detected in a very high concentration in the uterine venous effluent of the pregnant rabbit. The peripheral blood of pregnant animals also revealed increased levels of only PGE2. The results of both assay techniques correlated closely. These studies suggest that the uteroplacental unit is the source of the increased peripheral level of the potent vasodilator PGE2. In contrast, these data fail to support the notion that PGI2 is the primary systemic-acting vasodepressor prostaglandin in rabbit pregnancy.

Animals↗
PubMed1982

Angiotensin-induced sodium excretion patterns in cirrhosis: role of renal prostaglandins.

Changes in renal hemodynamics and sodium excretion induced by an angiotensin II (AII) infusion were correlated with urinary prostaglandin E2 (PGE2) excretion in 15 patients with cirrhosis and ascites. All induced natriuretic responses in 47% and antinatriuretic responses in 53% of the patients. Natriuresis was accompanied by an increase; antinatriuresis by a decrease in PGE2 excretion. Although there was no change in GFR (CIn), renal blood flow (CPAH) decreased. Patients were clinically indistinguishable. Antinatriuretic responders tended, however, to have higher baseline PGE2 excretion rates, were more sensitive to effects of prostaglandin blockade, and were less sensitive to the pressor effect of AII. Following partial inhibition of renal prostaglandin synthesis by indomethacin, AII-induced natriuretic responses were accentuated. GFR, RBF, and urine flow rate markedly decreased in both groups. There was no difference in pressor sensitivity to AII following prostaglandin synthesis blockade. We conclude that in patients with hepatic cirrhosis, the sodium excretion pattern induced by an exogenous AII challenge may depend on the prior state of intrarenal prostaglandin activity. Our findings also support the hypothesis that renal hemodynamic parameters in patients with cirrhosis and ascites are crucially dependent on renal prostaglandins.

Angiotensin II↗
PubMed1978

Histology of human tubulo-interstitial nephritis associated with antibodies to renal basement membranes.

Twenty-seven patients with diffuse "crescentic" glomerulonephritis (CSGN) were identified in 1,174 renal biopsies from nephritic patients. Patients were assigned to three groups on the basis of the immunofluorescent study of renal biopsy specimens and serologic findings. Group I included eight patients with antibodies to glomerular (anti-GBM) and tubular (anti-TBM) basement membranes; group II had eight patients with only anti-GBM antibodies; and group III had eleven patients with CSGN unassociated with antibodies to either GBM or TBM. Patients with anti-GBM/anti-TBM antibodies (group I) had severe tubulointerstitial (TI) nephritis, as characterized by the infiltration of polymorphonuclear leukocytes and macrophages along the TBM and peritubular vessels. In some patients, focal proliferation of epithelial cells of proximal convoluted tubules (PCT), gaps or extensive destruction of TBM, lesions in the walls of small peritubular vessels, and interstitial giant cells were also observed. Patients with anti-GBM antibodies (group II) had mild to moderate interstitial cellular infiltration and mild tubular changes. Five patients with CSGN not associated with antibodies to renal basement membranes (group III) had mild to moderate interstitial cellular infiltration and tubular changes. A sixth patient, with Wegener's disease had severe granulomatous TI lesions. The results of this study show that TI nephritis is most frequent and severe with anti-TBM antibodies are demonstrable and suggest that anti-TBM antibodies contribute to the development of TI lesions.

Adult↗