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Biomedical subjects

R H Rubin

Publications and source records attributed to R H Rubin.

At least 73 records · Page 4Linked to original sources
PubMed1998

Pharmacokinetics of [18F]trovafloxacin in healthy human subjects studied with positron emission tomography.

Tissue pharmacokinetics of trovafloxacin, a new broad-spectrum fluoroquinolone antimicrobial agent, were measured by positron emission tomography (PET) with [18F]trovafloxacin in 16 healthy volunteers (12 men and 4 women). Each subject received a single oral dose of trovafloxacin (200 mg) daily beginning 5 to 8 days before the PET measurements. Approximately 2 h after the final oral dose, the subject was positioned in the gantry of the PET camera, and 1 h later 10 to 20 mCi of [18F]trovafloxacin was infused intravenously over 1 to 2 min. Serial PET images and blood samples were collected for 6 to 8 h, starting at the initiation of the infusion. Drug concentrations were expressed as the percentage of injected dose per gram, and absolute concentrations were estimated by assuming complete absorption of the final oral dose. In most tissues, there was rapid accumulation of the radiolabeled drug, with high levels achieved within 10 min after tracer infusion. Peak concentrations of more than five times the MIC at which 90% of the isolates are inhibited (MIC90) for most members of Enterobacteriaceae and anaerobes (>10-fold for most organisms) were achieved in virtually all tissues, and the concentrations remained above this level for more than 6 to 8 h. Particularly high peak concentrations (micrograms per gram; mean +/- standard error of the mean [SEM]) were achieved in the liver (35.06 +/- 5.89), pancreas (32.36 +/- 20. 18), kidney (27.20 +/- 10.68), lung (22.51 +/- 7.11), and spleen (21. 77 +/- 11.33). Plateau concentrations (measured at 2 to 8 h; micrograms per gram; mean +/- SEM) were 3.25 +/- 0.43 in the myocardium, 7.23 +/- 0.95 in the lung, 11.29 +/- 0.75 in the liver, 9.50 +/- 2.72 in the pancreas, 4.74 +/- 0.54 in the spleen, 1.32 +/- 0.09 in the bowel, 4.42 +/- 0.32 in the kidney, 1.51 +/- 0.15 in the bone, 2.46 +/- 0.17 in the muscle, 4.94 +/- 1.17 in the prostate, and 3.27 +/- 0.49 in the uterus. In the brain, the concentrations (peak, approximately 2.63 +/- 1.49 microg/g; plateau, approximately 0.91 +/- 0.15 microg/g) exceeded the MIC90s for such common causes of central nervous system infections as Streptococcus pneumoniae (MIC90, <0.2 microg/ml), Neisseria meningitidis (MIC90, <0.008 microg/ml), and Haemophilus influenzae (MIC90, <0.03 microg/ml). These PET results suggest that trovafloxacin will be useful in the treatment of a broad range of infections at diverse anatomic sites.

Adult↗
PubMed1998

Positron emission tomographic analysis of central dopamine D1 receptor binding in normal subjects treated with the atypical neuroleptic, SDZ MAR 327.

SDZ MAR 327 is a new neuroleptic agent with high in vitro affinity for dopamine D1 and D2 receptors. The goal of this study was to determine the effect of time after SDZ MAR 327 administration on central dopamine D1 receptor occupancy in healthy humans. Positron emission tomography (PET) with the dopamine D1 receptor ligand, [11C] SCH 23390, was performed in 6 male volunteers (age 22-34), in both the drug naive state and at 1, 2 and 4 h after a single oral dose of SDZ MAR 327 (9 mg). The pre and post drug treatment [11C] SCH 23390 dynamic data were analyzed using two different methods, each yielding a parameter proportional to the receptor density: i) a simple regional comparison approximating the specifically bound to free fraction, B/F; and ii) a two compartment, two parameter model yielding the apparent distribution volume DV". With both methods, a metabolite corrected arterial input function was used and the vascular fraction of tissue (Vb) was fixed at a previously determined value of 4%. Method I served as a qualitative comparison of the paired studies and demonstrated little difference between the pre and post drug conditions, method II also confirmed that there was no significant change in binding of [11C] SCH 23390 in the striatum. These data indicate that SDZ MAR 327 produces little if any effect on dopamine D1 receptor binding at the dose used.

Adult↗
PubMed1998

Robot-aided functional imaging: application to a motor learning study.

The purpose of this study was to examine the neural activity underlying an implicit motor learning task. In particular, our goals were to determine whether initial phases of procedural learning of a motor task involve areas of the brain distinct from those involved in later phases of learning the task, and what changes in neural activity coincide with performance improvement. We describe a novel integration of robotic technology with functional brain imaging and its use in this study of implicit motor learning. A portable robotic device was used to generate forces that disturbed the subjects' arm movements, thereby generating a "virtual mechanical environment" that the subjects learned to manipulate. Positron emission tomography (PET) was used to measure indices of neural activity underlying learning of the motor task. Eight health, right-handed male subjects participated in the study. Results support the hypothesis that different stages of implicit learning (early and late implicit learning) occur in an orderly fashion, and that distinct neural structures may be involved in these different stages. In particular, neuroimaging results indicate that the cortico-striatal loop may play a significant role during early learning, and that the cortico-cerebellar loop may play a significant role during late learning.

Adult↗
PubMed1997

The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG-Study Group. Cytogam, MedImmune, Inc. Gaithersburg, Maryland.

PURPOSE: To assess impact of cytomegalovirus (CMV) donor-recipient serostatus, infection, or disease on development of invasive fungal infection in orthotopic liver transplant recipients. PATIENTS AND METHODS: An analysis of prospectively collected data in 146 liver transplant recipients (intention to treat cohort) from 4 tertiary care, university-affiliated transplant centers in Boston (Boston Center for Liver Transplantation). Patients were observed for 1 year after transplantation for the development of CMV infection, CMV disease, CMV pneumonia, as well as for the development of opportunistic fungal infections, graft survival, and mortality. Weekly cultures were taken of urine and throat and every other week of buffy coat for CMV for 2 months, then monthly for 6 months, at 1 year, and at the time of any clinical illness. Pre- and posttransplant variables including CMV-serostatus of donor and recipient, fungal isolation from sterile body sites, fungemia, bacteremia, antibiotic use, immunosuppression, treatment for rejection, and volumes of blood products were measured. RESULTS: Survival analysis demonstrated that 36% of patients with CMV disease developed invasive fungal disease within the first year post-transplant compared with 8% of those without CMV disease (P < 0.0001). One-year mortality in patients with invasive fungal disease was 15 of 22 (68%) compared with 23 of 124 (19%) in those without invasive fungal disease (P < 0.001). A multivariable, time-dependent analysis demonstrated that being a CMV-seronegative recipient of a CMV-seropositive donor organ (P < 0.001), having bacteremia (P = 0.001), UNOS (United Network for Organ Sharing) status 4 (need for life support measures) at transplant (P = 0.002), and volume of platelets (P = 0.002) were independently associated with invasive fungal disease. Restriction of cases of invasive fungal disease to those that occurred more than 2 weeks after transplant demonstrated an association with CMV disease (P = 0.003), bacteremia (P = 0.003), need for life support (P = 0.03), and volume of blood products transfused (P = 0.02). CONCLUSION: CMV disease or being a CMV-seronegative recipient of a CMV-seropositive donor organ is an important predictor for invasive fungal disease following orthotopic liver transplantation.

Adolescent↗
PubMed1997

Urinary tract infection in the immunocompromised host. Lessons from kidney transplantation and the AIDS epidemic.

The occurrence of urinary tract infection and its clinical impact is determined, as with any infectious disease, by the interaction between the virulence of the infecting organism and the host defense mechanisms that can be mobilized. In the case of urinary tract infections, an anatomically and functionally intact kidney and urinary tract are the primary host defenses, with phagocytic function and immune mechanisms coming into play to limit the consequences of those infections. Of all the categories of immunocompromised hosts, the renal transplant patient is the one most susceptible to the direct and indirect consequences of urinary tract infections. In the first 3 months post transplant, the incidence of urinary tract infection is greater than 30%, and there is a relatively high rate of bacteremia and overt pyelonephritis of the allograft. After this time period, unless anatomic or functional derangement of the urinary tract is present, the direct clinical manifestations are far more benign. In addition to the direct effects of urinary tract infection on these patients, indirect effects are also important. These include the activation of CMV by TNF released as a consequence of a urinary tract infection and the initiation of allograft injury. Fortunately, low-dose trimethoprim-sulfamethoxazole or fluoroquinolones are safe and effective prophylactic strategies for preventing the direct and indirect consequences of urinary tract infections. Although the pathogenetic mechanisms are incompletely understood, data are emerging that AIDS patients have both an increased incidence and severity of urinary tract infection. The risk for urinary tract infections seem to be correlated with the degree of immune compromise and, perhaps, the amount of malnutrition and wasting that are present. The best strategies for preventing urosepsis in AIDS patients remain to be defined.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Cytomegalovirus infection in the liver transplant recipient. Epidemiology, pathogenesis, and clinical management.

The effects of cytomegalovirus (CMV) on the liver transplant patient can be divided into two general categories: the direct infectious disease effects (e.g. CMV mononucleosis, hepatitis, pneumonitis, GI infection) and the indirect effects that are mediated by cytokines elaborated as a consequence of the infection. These indirect effects include an immunosuppressive effect that contributes to the development of superinfection with fungi, bacteria, and Pneumocystis carinii; a role in the pathogenesis of allograft injury; and a role in the development of post-transplant lymphoproliferative disease. The two key steps in the pathogenesis of CMV infection-reactivation of the virus from latency and systemic spread-are modulated by the immunosuppressive therapy administered. New antiviral programs, primarily those involving ganciclovir, have resulted in considerable progress in the prevention and treatment of CMV disease among liver transplant recipients.

Cytomegalovirus↗
PubMed1997

International Conference for the Development of a Consensus on the Management and Prevention of Severe Candidal Infections.

Because of the rapidly increasing incidence of serious candidal infections, a consensus conference of 22 investigators from the United States, Europe, and Japan was held to discuss strategies for the prevention and treatment of deep-organ infections caused by Candida species. Commonly asked questions concerning the management of candidal infections were selected for discussion by the participating investigators. Possible answers to the questions were developed by the investigators, who then voted anonymously for their preferences. In certain instances, unanimity or a strong consensus was the result. In all cases, the full spectrum of responses was recorded and is presented in this report. The forms of candidal infection addressed included candidemia, candiduria, hepatosplenic candidiasis (chronic systemic candidiasis), candidal endophthalmitis, and candidal peritonitis. Prevention and treatment strategies were considered for patients who have undergone surgery, for neutropenic and nonneutropenic patients, and for patients who have undergone bone marrow and solid organ transplantation. The therapeutic roles of amphotericin B (standard and lipid formulations) and the azoles were considered.

Animals↗
PubMed1997

The role of positron emission tomography in pharmacokinetic analysis.

The physiological and biochemical measurements that can be performed noninvasively in humans with modern imaging techniques offer great promise for defining the precise state of a patient's disease and its response to therapy. In general, there are two critical points in drug development when PET measurements are likely to be particularly useful: (1) In preclinical studies, a new drug can be precisely compared to standard therapies or a series of analogs can be screened for further development on the basis of performance in appropriate animal models. (2) In phase I-II human studies, classic pharmacokinetic measurements can be coupled with imaging measurements (a) to define optimal dosing schedule; (b) to define the potential utility of interventions in particular clinical situations; and (c) to formulate the design of phase III studies that are crucial for drug licensure. In general, the types of measurements that are possible can be grouped into the following categories: 1. In those situations in which the drug can be radiolabeled, the time course of tissue delivery can be determined noninvasively in vivo in health and disease. Such information should be useful for determining dosing schedules, establishing efficacy, and predicting possible toxicity. 2. Ligand-receptor binding can be assessed in vivo in two ways. The ability of the drug to displace standard radiolabeled ligands from their receptors can be determined; alternatively, labeled drug can be used to more directly assess the distribution and time course of binding. These measurements are particularly useful for studying drugs that are active in the central nervous and cardiovascular systems. 3. Measurements of tissue metabolism will be useful in determining the effects of therapies aimed at particular metabolic abnormalities. In addition, these measurements may be useful in defining viability and function of tissues in such widely disparate clinical situations as cancer chemotherapy and cardiology. For example, effects of CNS or cardiovascular drugs can be monitored by observing 18FDG metabolism in brain and heart. We suggest that the joining of classic clinical pharmacology to exquisite imaging measurements will help form the basis for 21st-century clinical drug development.

Animals↗
PubMed1997

Positron emission tomography in drug development.

There are four kinds of measurements that can be carried out with positron emission tomography (PET) that can contribute significantly to the process of drug development: pharmacodynamic measurements of tissue metabolism influenced by a given drug; precise measurements of tissue blood flow; tissue pharmacokinetics of a given drug following administration of a particular dose; and the temporal course of ligand-receptor interaction. One or more of these measurements can greatly improve the decision making involved in determining the appropriate dose of a drug, the clinical situations in which a drug might be useful, and the linkage of pharmacokinetics with pharmacodynamics, which is at the heart of effective drug development. The greater the potential of a particular compound as a therapeutic agent, the greater the potential for PET to contribute to the drug development process.

Animals↗
PubMed1996

Hepatitis C virus and organ transplantation.

Hepatitis C virus (HCV) is both the leading cause of cirrhosis and hepatic failure leading to liver transplantation and a cause of chronic hepatitis in approximately 10% of all transplant recipients. Beginning 5-10 years or more posttransplant, HCV causes progressive liver disease in a significant fraction of infected individuals and contributes to an increased incidence of opportunistic infection and hepatocellular carcinoma. The existence of multiple genotypes of HCV with differing biologic behaviors and the generation of antigenic diversity of the virus (quasispecies) during the course of infection, limit the capacity of the immune system to generate protective immunity. Antiviral therapy with interferon-alpha is effective in only a minority of transplant patients, and since allografts from HCV infected donors are quite efficient in transmitting the virus, great attention is paid to the appropriate use of organs from HCV-positive donors. At present, these organs should be particularly targeted for patients in emergent need of lifesaving heart, liver, or lung transplants. Issues requiring further investigation include the impact of viral superinfection on HCV-infected recipients of organs from HCV-infected donors and the use of such organs in seronegative patients who are older, diabetic, or highly sensitized, for whom quality of life issues may outweigh the long-term impact of HCV infection.

Hepacivirus↗
PubMed1996

In vivo tissue distribution of CD4 lymphocytes in mice determined by radioimmunoscintigraphy with an 111In-labeled anti-CD4 monoclonal antibody.

The tissue distribution of CD4 lymphocytes in normal C57/BL mice and CD4 knockout mice was determined by biodistribution measurements and gamma camera imaging with an 111In-labeled rat IgG2b monoclonal antibody directed against the murine CD-4 antigen. In normal mice high concentrations of antibody accumulated in the spleen and lymph nodes. At 45 hr after injection, the concentration of radiolabel in the spleen and lymph nodes of normal mice were 10- to 20-fold greater than in the corresponding tissue of the CD4 knockout mice and nonlymphoid tissues of both types of mice. At 24 and 45 hr, gamma camera images showed high concentrations of radiolabeled antibody in lymph node and spleen of normal but not knockout mice. These results indicate that radioimmunoscintigraphy with 111In-anti-CD4 is an excellent method for studying tissue distribution of CD lymphocytes in mice. Using an equivalent anti-human CD antibody, this method might be useful for studying the pathophysiology of conditions in which these cells play a critical role and for monitoring therapies for these disorders.

Animals↗
PubMed1996

18F-labeling and biodistribution of the novel fluoro-quinolone antimicrobial agent, trovafloxacin (CP 99,219).

[18F]CP 99,219 [(1 alpha, 5 alpha, 6 alpha)-7-(6-amino-3-azabicyclo [3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid] was prepared by 18F for 19F exchange followed by reverse-phase HPLC purification. Studies of the effects of reaction time and temperature on 18F incorporation demonstrated that heating 1.0 mg of CP 99,219 in 0.5 cc of DMSO with 4.5 mg of K2CO3 and 24 mg of Kryptofix for 15 min at 160 degrees C results in the optimal compromise between radiochemical yield and purity. This method routinely provides radiochemical yields of 15-30% [EOS] with radiochemical purities of > 97%. Varying the concentration of CP 99,219 in the reaction mixture had no effect on yield. Biodistribution studies in rats demonstrated that significant concentrations of drug accumulate in most tissues. The tissues with the highest concentrations of drug were intestine, liver, kidney, and stomach.

Animals↗
PubMed1996

Radionuclide imaging of infection in the immunocompromised host.

Early diagnosis of infection in the immunocompromised patient is often difficult because of an impaired inflammatory response to microbial invasion. Radioscintigraphy has certain advantages in approaching this problem: because it is based upon either delivery of leukocytes to the site of infection or the leakiness of capillaries to radiolabeled proteins, earlier diagnosis is possible, even in patients with surgically altered anatomy; whole-body imaging allows the detection of focal sites of infection that are unsuspected clinically; and the semiquantitative nature of the information obtained allows for serial studies to assess the response to therapy. Three reagents are either currently available (gallium-67 citrate and radiolabeled leukocytes) or soon to be available (indium-111-labeled nonspecific polyclonal IgG) for this purpose. A major disadvantage of all three techniques is that a delay of 18-24 hours between injection and imaging is required. Experimental reagents such as technetium-99m-labeled chemotactic peptides appear to require < 3 hours between injection and imaging.

Abdomen↗