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Biomedical subjects

R H Rubin

Publications and source records attributed to R H Rubin.

At least 91 records · Page 5Linked to original sources

Opportunistic infections in the cardiac transplant patient.

The risk of opportunistic infection in the cardiac transplant patient is determined by the interaction between the epidemiologic exposures that the patient encounters and the patient's net state of immunosuppression. The epidemiologic exposures include those encountered in both the community and the hospital, with the latter being more important as they usually occur at a point in time when the patient's net state of immunosuppression is at its highest. The net state of immunosuppression is a complex function whose major determinants are the immunosuppressive program and the presence or absence of infection with a group of immunomodulating viruses, particularly cytomegalovirus. Strategies for preventing opportunistic infection in this patient population are based on the following factors: technically impeccable surgery, precisely managed immunosuppression, environmental protection (particularly in the hospital), and the use of preventative antimicrobial strategies. These last are of two types, prophylactic and preemptive. The key point in both these approaches is to link the preventative strategy to the intensity of the immunosuppressive program and to target the antimicrobial program to the time period and patient group at greatest risk. For most opportunistic infections this is the time period 1 to 6 months after transplantation (when viral infections are prevalent), and the small group of patients more than 6 months after transplantation who are chronically overimmunosuppressed because of rejection.

Anti-Infective Agents↗

Pharmacokinetics of [18F]fleroxacin in patients with acute exacerbations of chronic bronchitis and complicated urinary tract infection studied by positron emission tomography.

The pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, were measured by positron emission tomography (PET) with [18F]fleroxacin in five patients with acute bacterial exacerbations of chronic bronchitis and in five patients with symptomatic, complicated urinary tract infection. Two studies were performed with each patient, one within 24 h of the initiation and one within 24 h of the completion of a 7-day course of fleroxacin, 400 mg/day. For each study, the patient received an infusion of that day's therapeutic dose of fleroxacin (400 mg) supplemented with approximately 740 MBq of [18F]fleroxacin, and serial PET images and blood samples were collected for 6 to 8 h starting at the initiation of the infusion. Between studies, the drug was administered orally. In all infected tissues, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion. In kidneys, accumulation was greater in the presence of active infection (P < 0.01), while in lungs, accumulation was lower (P < 0.02). Infection of the lung or urinary tract had no effect on drug delivery to uninvolved tissues. Also, there was no difference between the results obtained at the beginning and the end of therapy. Overall, peak concentrations of drug many times the MIC at which 90% of the infecting organisms are inhibited (MIC90) were achieved in the kidneys (> 30 micrograms/g), prostate glands (> 11 micrograms/g), and lungs (> 14 micrograms/g). Plateau concentrations (2 to 8 h; given as mean micrograms per gram +/- standard error of the mean) of drug in kidneys (15.11 +/- 0.55), prostate glands (5.08 +/- 0.19), and lungs (5.75 +/- 0.22) were also well above the MIC90 for most relevant pathogens. All patients had a good therapeutic response to fleroxacin.

Acute Disease↗

An oral platelet-activating factor antagonist, Ro-24-4736, protects the rat kidney from ischemic injury.

The role of platelet-activating factor (PAF) in ischemic acute renal failure was evaluated by administering an oral PAF antagonist (Ro-24-4736) to rats prior to or after interruption of blood flow to both kidneys for 30 min. In animals treated with the PAF antagonist prior to ischemia, renal function was less impaired and histological abnormalities was less pronounced when compared with postischemic kidneys from vehicle-treated animals. Serum creatinine (mg/ dl) 24 h following renal ischemia was 1.58 +/- 0.17 in the PAF antagonist-treated rats compared with 2.19 +/- 0.15 in rats given placebo (P < 0.01). There was less necrosis in the outer medulla of kidneys of PAF antagonist-treated animals (P < 0.01). Tissue myeloperoxidase activity at 48 and 72 h postischemia was lower in kidneys of PAF antagonist-treated rats (P < 0.05). The PAF antagonist was also protective when administered 30 min but not 2 h following the ischemic insult. The coincident use of anti-intercellular adhesion molecule-1 monoclonal antibody did not confer additional protection over that observed with the oral PAF antagonist alone. These data suggest that PAF contributes to the pathophysiology of renal ischemic injury, perhaps by its effects on leukocyte-endothelial interactions. An orally active PAF antagonist can protect against the development of ischemic acute renal failure.

Acute Kidney Injury↗

Positron emission tomographic analysis of central 5-hydroxytryptamine2 receptor occupancy in healthy volunteers treated with the novel antipsychotic agent, ziprasidone.

Ziprasidone is a novel antipsychotic agent, with high affinity for dopamine D2 and serotonin (5-HT2) receptors in vitro and in animal models. The goal of this study was to determine the time course of 5-HT2 receptor occupancy (%RO) in healthy humans after a single p.o. dose. Positron emission tomography with the 5-HT2 ligand, [18F]setoperone, was performed in eight male volunteers, in the drug-naive, base-line (BL) state and 4 to 18 hr after ziprasidone (40 mg). Cerebral cortical binding potential [BP, maximum number of available receptors/KD or association rate for specific binding (k3)/dissociation rate for specific binding (k4)] was estimated using the cerebellum as reference. Transport rate from plasma to brain (K1), transport rate from brain to plasma (k2), association rate of nonspecific binding (k5) and dissociation rate of nonspecific binding (k6) were derived by fitting cerebellar time-activity curves to a three-compartment model. Fitting of cortical data to a 4-compartment model with K1/k2, k5 and k6, fixed at cerebellar values, was used to determine k3 and k4. %RO was calculated using the relation: %RO = [(BPBL-BPDRUG)/BPBL] x 100%. At BL, cortical parameter (mean +/- S.E.M) were: K1 = 0.121 +/- 0.0072 ml.min-1.g-1; k2 = 0.0581 +/- 0.004 min-1; k3 = 0.321 +/- 0.0026 min-1; k4 = 0.0957 +/- 0.0059 min-1; k5 = 0.0147 +/- 0.00066 min-1; and k6 = 0.0059 +/- 0.00042 min-1. Ziprasidone did not effect K1, k2, k5 or k6; however, k3 was reduced and k4 was elevated (P < .01). RO was nearly complete at 4 hr after dosing (98%) and remained elevated at 18 hr (46%). Plasma concentrations were well described by a biexponential function and decreased much more rapidly than RO. These results establish that ziprasidone has high potency for blocking 5-HT2 receptors in healthy humans; a potentially important characteristic of atypical antipsychotic agents.

Adult↗

Biodistribution and dosimetry of technetium-99m-hydrazino nicotinamide IgG: comparison with indium-111-DTPA-IgG.

UNLABELLED: The biological behavior of human polyclonal immunoglobulin G (IgG), radiolabeled with 99mTc via a nicotinyl hydrazine derivative (99mTc-HYNIC-IgG), was evaluated in normal human subjects. METHODS: Initial biodistribution and dosimetry studies were performed in six normal male volunteers. Additionally, 99mTc-IgG and 111In-DTPA-IgG were co-injected into six subjects and scintillation camera images were acquired at 6 and 18 hr later and serial blood and urine samples were collected. Biodistribution of both radiopharmaceuticals were measured by region of interest analysis. In the dual-injection group, images were crossover-corrected. RESULTS: All subjects tolerated injection of the radiolabeled IgG preparations without apparent ill effects. Biodistribution of the two antibody preparations were remarkably similar with an increase in liver and abdominal activity for the 111In preparation. Linear correlation of the tissue-to-blood ratios of 99mTc and 111In-labeled IgG was observed at both times (r2 > 0.98). The slopes of the regression line were 0.97 and 0.76 at 6 and 18 hr, respectively. The beta phase of the blood clearance of 99mTc-HYNIC-IgG was significantly delayed (p < 0.01) compared with 111In-IgG (t1/2: 51.9 +/- 6.5 versus 35.3 +/- 3.4 hr). In contrast, the volumes of redistribution and urinary excretions of the radiopharmaceuticals were not significantly different. CONCLUSION: These studies establish that the biodistribution of 99mTc-HYNIC-IgG in normal human subjects is nearly identical to 111In-DTPA-IgG.

Adult↗

Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial.

OBJECTIVE: To determine whether preemptive ganciclovir therapy administered daily during antilymphocyte antibody therapy can prevent cytomegalovirus disease in renal transplant recipients who are positive for cytomegalovirus antibody. DESIGN: Randomized, controlled, multicenter trial. SETTING: 6 university-affiliated transplantation centers. PATIENTS: 113 renal transplant recipients who were positive for cytomegalovirus antibody. INTERVENTION: Patients were randomly assigned to receive either 1) ganciclovir, 2.5 mg/kg body weight administered intravenously on every day that antilymphocyte antibody therapy was administered or 2) no anticytomegalovirus therapy. MEASUREMENTS: Patients were observed for 6 months after completion of antilymphocyte antibody therapy for development of cytomegalovirus disease and cytomegalovirus viremia. RESULTS: Cytomegalovirus disease occurred in 14% of patients (9 of 64) who received preemptive ganciclovir therapy and in 33% of controls (16 of 49) (P = 0.018). Cytomegalovirus was isolated from buffy-coat specimens from 17% of patients (11 of 64) receiving preemptive ganciclovir and from 35% of controls (17 of 49) (P = 0.03). Controlling for the reason (induction or treatment of rejection) for using antilymphocyte antibodies in a Cox proportional hazards model, we found that preemptive ganciclovir still protected against cytomegalovirus disease (adjusted relative risk, 0.27; 95% CI, 0.12 to 0.64). No adverse events were attributed to preemptive ganciclovir therapy during or within 6 months of its administration. CONCLUSIONS: Preemptive ganciclovir therapy administered daily during courses of treatment with antilymphocyte antibodies reduced the excessive occurrence of cytomegalovirus disease in renal transplant recipients who were positive for cytomegalovirus antibody. This approach, which links the most potent immunosuppression to intensive antimicrobial therapy, allows preventive therapy to be given to those patients at greatest risk for developing infectious complications. These patients are likely to benefit most from the preventive strategy.

Adolescent↗

Synthesis of a 11C-labeled NK1 receptor ligand for PET studies.

Changes in substance P (SP) receptor concentration have been implicated in neuropsychiatric disorders, Parkinson's disease, arthritis, inflammatory bowel disease and asthma. Since, SP and peptide analogs are rapidly metabolized and do not penetrate into the CNS, they are not useful for PET. Recently, a non-peptide SP antagonist, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) was developed. As a prelude to PET studies, this compound was radiolabeled with 11C and biodistribution was determined in hamsters. CP-99,994 was radiolabeled by methylation of tert-Boc, desmethyl CP-99,994 with 11CH3I followed by deprotection and HPLC purification. The time required for the synthesis was 40 min from the end of bombardment. Radiochemical purity of the final product was > 95% and specific activity was routinely > 1000 mCi/mumol [EOS]. The biodistribution of 11C-CP-99,994 was determined in groups of six Syrian hamsters at 5 and 30 min after injection. The results of these studies demonstrated that significant concentrations (%ID/g +/- SEM) of CP-99,994 accumulate in most tissues of the hamster. The highest levels of drug were detected in the lung: 21.04 +/- 1.26 (5 min) and 13.49 +/- 1.71 (30 min). Brain accumulation was: 1.44 +/- 0.06 (5 min), 1.32 +/- 0.05 (30 min). These results indicate that 11C-CP-99,994 can be prepared in high purity and specific activity. This new radiopharmaceutical may be useful for studying both central and peripheral SP receptors by PET.

Animals↗

Detection of acute bacterial infection within soft tissue injuries using a 99mTc-labeled chemotactic peptide.

OBJECTIVE: Infection imaging with a 99mTc-labeled chemotactic peptide was evaluated in a rabbit model of Escherichia coli infections in burned tissue. MATERIALS AND METHODS: The peptide was radiolabeled with 99mTc via the hydrazino nicotinamide derivative. Three groups of six animals were studied: (group A) unilateral infected burns; (group B) bilateral burns with unilateral infection; and (group C) uninfected burns. Twenty-four hours after injury, groups A and B were infected, and 8 hours later, all animals were injected with approximately 0.50 mCi of 99mTc-peptide. MEASUREMENTS AND MAIN RESULTS: In groups A and B, excellent images of the infections were obtained at 3 to 4 and 16 to 18 hours after injection of the peptide. At 3 to 4 hours after injection, the target-to-background ratios (T/B) were 3.12 +/- 0.28 for group A and 4.33 +/- 0.61 for group B (p = n.s.). At 16 to 18 hours, the T/B ratios increased significantly (p < 0.01): group A = 8.10 +/- 1.03 and B = 7.70 +/- 1.25. The T/B ratio for group C was only slightly greater than unity. CONCLUSIONS: These results indicate that 99mTc-labeled chemotactic peptides are effective radiopharmaceuticals for the rapid detection of focal sites of infection within thermally injured tissues.

Animals↗

Quantification of inflammation in the wrist with gadolinium-enhanced MR imaging and PET with 2-[F-18]-fluoro-2-deoxy-D-glucose.

PURPOSE: To quantify the activity of joint inflammation with magnetic resonance (MR) imaging and positron emission tomography (PET). MATERIALS AND METHODS: Gadolinium-enhanced MR imaging and 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) PET of the wrist were performed prospectively in 12 patients receiving antiinflammatory therapy. Patients were studied three times: off medications for 2 weeks, after 2 weeks of treatment with prednisone or nonsteroid antiinflammatory drugs, and after 12 weeks of treatment with methotrexate. Volume of enhancing pannus (VEP) was determined from fat-suppressed MR images (12 patients). FDG uptake was calculated from PET images (11 patients). RESULTS: VEP and FDG uptake were closely correlated (r > .86, P < .0001), as were changes in VEP and standardized uptake volume (r > .91, P < .0002). VEP and FDG uptake were strongly associated with clinical findings in wrists (P < .002) but not with treatment outcomes (P > .05). CONCLUSION: Contrast material-enhanced MR imaging and PET allow quantification of volumetric and metabolic changes in joint inflammation and comparison of efficacies of antiinflammatory drugs.

Acetaminophen↗

Real-time monitoring of renal function during ischemic injury in the rhesus monkey.

The presence of delayed graft function (DGF) following cadaver donor renal transplantation is associated with inferior graft survival as well as decreased patient survival. Delay in onset of function eliminates a valuable indicator of allograft viability, which is not easily replaced by standard diagnostic procedures. The purpose of this study was to demonstrate that a new clearance technique could be used to measure renal function minute to minute and under conditions similar to those observed in humans in the immediate posttransplantation period. A monkey model was used to provide controlled conditions. Increasing levels of ischemic injury were produced in 12 Rhesus monkeys by renal hilum cross-clamping. Real-time measurements of glomerular filtration rate (GFR) were obtained from the rate of clearance of the extracellular fluid of the GFR agent 99mTc-DTPA, as measured with a specially designed external radioactivity counting device called the ambulatory renal monitor, or ARM. GRF was measured every 2-5 min as the slope (k) of the log of activity measured minute to minute versus time. GFR measurements were correlated with blood urea nitrogen (BUN), plasma creatinine (Cr), routine light microscopy, and measurement of proliferating cell nuclear antigen (PCNA), a marker of cell proliferation. Large changes in renal function due to ischemia or ureteral obstruction were observed within minutes. In addition, the rate constant on Day 1 was predictive of peak serum Cr(R =--0.86, R2=.74, p = .0001). Acute tubular necrosis (ATN) resolution was reflected more quickly when using the rate constant (Day 1) than when using either BUN or plasma Cr (Day 3-4). Because of renal functional reserve, BUN and plasma Cr were relatively insensitive indicators of mild to moderate reductions in GFR as compared with the rate constant. We conclude that ARM is a simple method which provide an accurate, near real-time GFR readout with potential applications not only for the clinical management of patients with DGF, but also as a research tool in acute renal failure (ARF).

Animals↗

The infectious disease problems of the diabetic renal transplant recipient.

Approximately 30% of patients with end stage renal disease who undergo transplantation develop renal failure as a result of their long-standing diabetes mellitus. Therefore, diabetics warrant special attention in considering the infectious disease problems associated with transplantation. The three categories that should be considered in infections affecting the diabetic renal transplant recipient are discussed in this article.

Diabetic Nephropathies↗

Infection in the organ transplant recipient. An overview.

Considerable progress has been made in elucidating the factors involved in the pathogenesis of infection in the organ transplant patient. One of the general principles that has emerged is that the risk of clinical infection, particularly opportunistic infection, is determined largely by the interaction between the patient's net state of immunosuppression and the epidemiologic exposures the patient encounters. The two major factors that determine the net state of immunosuppression are the nature of the exogenous immunosuppressive therapy that is administered and whether or not infection is present with one or more of the immunomodulating viruses (particularly cytomegalovirus, Epstein-Barr virus, and the hepatitis viruses). Finally, the therapeutic prescription for the transplant patient has two components--an immunosuppressive component to prevent and treat rejection and an antimicrobial component, which is linked to the intensity of the immunosuppressive therapy required, to make this safe. This reflects the recognition that the two major barriers to successful transplantation, rejection and infection, are closely tied together by the current requirement for lifelong immunosuppressive therapy. Progress in one area will have beneficial effects on the other.

Graft Rejection↗

Cytokines as potential vaccine adjuvants.

There is a compelling clinical need for adjuvants suitable for human use to enhance the efficacy of vaccines in the prevention of life-threatening infection. Candidate populations for such vaccine-adjuvant strategies include normal individuals at the two extremes of life, as well as the ever increasing population of immunocompromised individuals. In addition, adjuvants that would increase the efficiency of vaccination with such vaccines as those directed against hepatitis B and Streptococcus pneumoniae would have an even greater general use. Cytokines, as natural peptides intimately involved in the normal immune response, have great appeal as potential adjuvants. An increasing body of work utilizing recombinant versions of interleukin-1, -2, -3, -6, -12, gamma-interferon, tumor necrosis factor, and granulocyte-monocyte-colony stimulating factor has shown that cytokines do have vaccine adjuvant activity. However, in order to optimize adjuvant effect and minimize systemic toxicity, strategies in which the cytokine is fused to the antigen, or the cytokine is presented within liposomes or microspheres appear to be necessary to make this a practical approach suitable for human use. There is much promise in this approach, but there is much work to be accomplished in order to optimize the pharmacokinetics of cytokine administration as well as its side effect profile.

Adjuvants, Immunologic↗

Imaging of focal sites of inflammation in rhesus monkeys with 99mTc-labeled human polyclonal IgG.

The biological behavior of human polyclonal immunoglobulin G (IgG) radiolabeled with 99mTc via a nicotinyl hydrazine derivative, was evaluated in Rhesus monkeys. 99mTc-IgG and 111In-MACROSCINT DTPA-IgG were co-administered to Rhesus monkeys with focal sites of sterile inflammation and scintillation camera images were acquired at 6 and 19 h after injection. The biodistribution of the two antibody preparations were similar, however, small differences were detected: 99mTc-IgG > 111In-IgG in spleen and lung; 99mTc-IgG in bone and skeletal muscle. A linear correlation of the tissue-to-blood ratios of 99mTc- and 111In-labeled IgG was observed at both times (r2 > 0.98). The slopes of the regression lines were not significantly different from unity: 6 h-0.982 +/- 0.018; 19 h 1.0334 +/- 0.0226. Also, at both 6 and 19 h after injection, the target-to-background ratios (T/B) for the sites of inflammation were remarkably similar for 111In and 99mTc. These studies establish that human polyclonal IgG labeled with 99mTc via a nicotinyl hydrazine modified intermediate is equivalent to 111In-MACROSCINT DTPA-IgG for imaging focal sites of inflammation in monkeys.

Animals↗

Infection imaging with technetium-99m-labeled chemotactic peptide analogs.

The localization of occult sites of infection is frequently essential to the therapeutic management of critically ill patients. Current imaging procedures, including computed tomography, ultrasound, magnetic resonance imaging, and conventional radiography, rely primarily on focal changes in tissue density or composition to define the lesion. Typically, these are relatively late changes in the inflammatory process. Radionuclide procedures which have been used to localize early inflammatory processes, require a minimum of 12 hours, and usually 24 to 48 hours, from the time of injection to imaging. Clearly, a method of rapidly localizing sites of acute inflammation would be helpful for patient management. Recently, we developed methods for preparing analogs of the leukocyte chemoattractant peptide, N-formyl-methionyl-leucyl-phenylalanine (ForMLF), that can be radiolabeled for external imaging. In vitro, these compounds have bioactivity and neutrophil ForMLF receptor binding comparable with that of the native peptide. Studies in animals demonstrate that these agents bind to leucocytes in vivo, clear from the circulation rapidly, and localize at sites of Escherichia coli infection to an extent sufficient to yield external images early after injection. However, even at relatively low doses, the peptides elicit a profound but transient reduction in peripheral leukocyte levels. Despite this, if the peptides could be radiolabeled at very high specific activity, imaging might be possible with doses of peptide that do not reduce peripheral leukocyte levels. Recently, hydrazino nicotinamide--derivatized peptides were prepared and radiolabeled with technetium-99m at extremely high specific activity (> 20,000 mCi/mumole). In a rabbit model of E coli infection, these peptides yielded excellent images of sites of infection at injected doses that are approximately 1,000-fold below the level that produces a significant reduction in peripheral leukocytes. In addition, studies of thermally injured infected animals indicate that peptide localization may be infection selective, with very low levels of accumulation at sites of sterile inflammation.

Animals↗