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Biomedical subjects

S Kelley

Publications and source records attributed to S Kelley.

At least 19 recordsLinked to original sources
PubMed1995

Phase I clinical and pharmacological study of suppression of human antimouse antibody response to monoclonal antibody L6 by deoxyspergualin.

Development of human antimouse antibody (HAMA) is a major limiting factor in the application of murine mAb for clinical use. A novel immunomodulatory drug, deoxyspergualin (DSG), has shown potential to suppress antimouse antibody response in preclinical model systems. We conducted a Phase I trial to determine the effect of DSG on HAMA response to murine mAb L6 administered to patients with advanced cancers (in previous trials, this antibody elicited HAMA in two-thirds of the treated patients). L6 mAb was administered at a fixed dose of 200 mg/m2 on days 1-5. DSG was administered at doses of 50 mg/m2 [dose level (dl) 1] or 150 mg/m2 (dls II and III) on days 1-7. Treatment courses were repeated every 6 weeks (dls I and II) or every 3 weeks (dl III). HAMAs were quantitated by a commercially available ELISA assay (ImmuSTRIP; anti-isotypic antibodies) and a radiometric assay (antiisotypic and anti-idiotypic antibodies). Pharmacokinetics of L6 and DSG was also studied in all consenting patients. Among 24 evaluable patients, 2 patients developed detectable HAMAs using the ELISA (one each at dls I and II) after a median follow-up of 122 days (P = 0.0001 as compared to historical controls). Even in the two patients who developed HAMA, the HAMA levels were quite low (160 and 181 ng/ml; historical experience, 70-38,744 ng/ml). The radiometric assay detected anti-L6 antibodies in 13 patients (4, 6, and 3 at dls I-III, respectively) after a median of 82 days. The median highest anti-L6 antibody level was 129 ng/ml (range, 21-2150). The highest anti-L6 antibody level at dl III was only 44 ng/ml. The results suggest suppression of anti-idiotypic response also. No clinical antitumor activity was observed, and no significant changes in T4/T8 subsets or immunoglobulins occurred (suggesting a lack of generalized immunosuppression). We conclude that DSG can suppress HAMA response to L6. A starting dose of 150 mg/m2/day is recommended for Phase II trials to confirm this observation.

Adult↗
PubMed1995

Total vascular exclusion for major hepatectomy in patients with abnormal liver parenchyma.

BACKGROUND: Total vascular exclusion (TVE) of the liver has been used to increase the safety of hepatectomy and the feasibility of difficult resections. Until recently, however, concern about the detrimental effect of warm ischemia has limited the use of this technique to patients with normal liver parenchyma. OBJECTIVE: To compare surgical outcomes of 12 patients with abnormal livers (group 1) with outcomes of 48 patients with normal parenchyma (group 2), based on the hypothesis that uncontrolled bleeding may be more detrimental than planned hepatic ischemia. DESIGN AND SETTING: Retrospective analysis of 60 consecutive patients undergoing liver resection under TVE in a university medical center. PATIENTS: All 10 patients with cirrhosis had albumin levels of 30 g/L or higher and normal prothrombin times preoperatively; none had ascites. Two patients with cholestasis (one with cholangiocarcinoma and one with hepatocellular carcinoma) are included in group 1. INTERVENTION: All 12 group 1 patients and 44 of 48 group 2 patients underwent total or extended lobectomy, with TVE induced by clamping the hilum and the vena cava above and below the liver during parenchyma division. MAIN OUTCOME MEASURES: Hospital survival and selected surgical and laboratory parameters. RESULTS: Operative times, ischemic times, and blood loss (1975 +/- 1601 vs 1255 +/- 1291 mL) (P = .10) were comparable in both groups. Sixty-day operative mortality was zero in both groups. There was an increased rate of complications in group 1 (44% vs 17% [P = 0.06]). Transient abnormal liver function was observed in both groups. However, significant delay in restoration of normal function was observed in group 1 with respect to bilirubin levels and prothrombin time. CONCLUSIONS: Patients with cirrhosis can undergo successful resection using TVE. This conclusion must be limited to cirrhotic patients with good liver function. The trend toward increased blood loss may reflect greater difficulties in establishing hemostasis after reperfusion in group 1. While this group appears to have a higher risk for hepatic insufficiency, successful outcomes were achieved in all cases. Prospective study will be required to define the parameters for use of TVE in cirrhosis.

Aged↗
PubMed1995

Interaction between long-term potentiation and the action of a peptide transmitter.

The interaction between long-term potentiation (LTP) and the action of a peptide transmitter was examined with evoked field potential recording in the CA1 region of the hippocampus in anesthetized male rats. The peptide transmitter transiently reversed and opposed the effects of LTP, and LTP reversed the action of the peptide transmitter. Because the peptide transmitter is released and has action particularly during sexual behaviors, the results are interpreted to mean that any memory trace encoded by potentiating mechanisms in the rat hippocampus is probably not accessible in the 20-30-min period of time surrounding reproductive activity in male rats.

Afferent Pathways↗
PubMed1992

Effects of therapy with didanosine on hematologic parameters in patients with advanced human immunodeficiency virus disease.

Myelosuppression is associated with human immunodeficiency virus (HIV) infection and may also be produced by agents used for the treatment of the disease or the treatment of its complications. Didanosine (ddl; 2',3'-dideoxyinosine) is a newer purine nucleoside that has recently become available for therapy for HIV infection. The effects of didanosine on peripheral blood counts have been retrospectively evaluated in the first 170 patients treated with this new agent in four phase I trials. Patients treated with didanosine showed statistically significant improvements in hemoglobin levels, white cell counts, and granulocyte and platelet numbers as compared with baseline values. These changes were seen with or without prior therapy with zidovudine, were somewhat more pronounced at higher doses of didanosine, and persisted for up to 1 year. Reported adverse events included peripheral neuropathy, diarrhea, and most notably, pancreatitis. It is concluded that, while some toxic side effects occur, didanosine therapy in HIV infection is associated with an amelioration of HIV-induced myelosuppression.

AIDS-Related Complex↗
PubMed1992

Rapid multivariate analysis and display of cross-reacting antibodies on human leukocytes.

We present an application which can rapidly determine the binding patterns of monoclonal antibodies on mixed populations of cells simultaneously in a single rapid analysis. It is an application of the tube identifier parameter (TIP) system which can provide fully correlated list-mode data of the entire patient phenotype in a single file. Using the phenogram analytical display, we are able to determine the cross-reacting antibodies for an entire antibody panel for each cell type. This information can be displayed in a single plot. Using light scatter gating to select different populations of lymphocytes, monocytes, and neutrophils, phenograms can be simultaneously generated. This provides a directly comparable means of displaying the positive and negative binding characteristics of each antibody on each cell population. Any marker combination that is abnormal will be identifiable in the phenogram. Additionally, by plotting the fluorescence distributions of each marker beside one another (termed overview), quantifiable differences in intensity can be determined. There are 3 major benefits of the proposed analysis. By using the TIP concept, several sets of antibodies can be compared simultaneously. Any light scatter gate can be used and this gate can be changed on one histogram or plot, yet apply to the total analysis. Data analysis is particularly rapid since the entire phenotype of a patient can be evaluated by performing a single rapid analysis.

Antibodies↗
PubMed1992

Integration of a barcode reader with a commercial flow cytometer.

This report describes the application and installation of a barcode reader on a standard EPICS Elite flow cytometer. The barcode reader system eliminates keyboard entry of sample information on the cytometer. The system automates the transfer of sample information already present in our laboratory database to the cytometer at run time. The system uses a standard "off-the-shelf" bar code wand with a personal computer keyboard interface and requires no additional software at run time. No typing of sample information is required by the operator at any stage of normal sample operation at the cytometer. All operations are automatically coded into the cytometry software using the macro functions of the software. Tubes are inserted into the tube reader and sample information is transferred automatically into the cytometer. We have found that the system allows rapid and continuous operation of routine clinical and research samples. This automated data entry also reduces the possibility of data input errors.

Electronic Data Processing↗
PubMed1992

Drug discovery and development in the pharmaceutical industry.

The discovery and development of new anticancer drugs is a complex and largely empirical process. New compounds can be discovered by screening, modification of existing compounds, rational drug design, and serendipitous basic research observations. Selection of compounds for clinical trials depends on assays of uncertain predictive value. In the pharmaceutical industry, priorities for development of potentially active entities are set and available resources allocated based on the availability and cost of supplies, patent status, potential spectrum of activity, ability to meet regulatory requirements, and market assessments. Competition for resources also occurs from noncancer drugs, eg, cardiovascular agents. Clinical development (testing and approval for commercial distribution) requires close attention to the requirements of national regulatory agencies such as the United States Food and Drug Administration. The arbitrary nature by which compounds with antitumor potential are chosen for development means that some that would be useful never reach clinical trial and others are never made generally available. This article reviews the decision making process in the pharmaceutical industry by which compounds are identified and selected for clinical trial, the regulations in the United States that govern such trials, and what is required to have the drug approved for commercial distribution.

Animals↗
PubMed1992

Illness and efficiency of health services delivery in a district hospital.

Demographic data, medical problems and diagnosis, and efficiency of laboratory investigations and drug administration were evaluated in all patients admitted to an adult medical ward over a one month period at a district hospital in Kenya. The results show that the medical ward serves a poor, cosmopolitan population in the economically productive age range. Mental disorders (16%), symptoms and ill-defined conditions (16%), and infective and parasitic disease (15%) were the most common diagnoses. Out of 999 orders and/or results, 357 were delayed, interrupted, never done, or never received. Factors that affect medical education and efficiency of health services delivery at a district hospital are identified and discussed.

Adult↗
PubMed1991

An innovation in flow cytometry data collection and analysis producing a correlated multiple sample analysis in a single file.

The problems associated with rapid analysis and interpretation of data from multicolor immunofluorescence panels have been a formidable barrier to their routine use. Using present flow cytometry concepts, a panel of 11 tubes each containing multiple phenotypic markers or controls requires postdata acquisition manipulation of many multiparameter histogram and listmode files. We have developed a method that compresses all of the information from such a panel into a single listmode data file during run time. A single data file is used to record the entire phenotypic analysis for a particular patient or series within an experiment. This is accomplished by the incorporation of a tube identifier parameter (TIP) as well as the fluorescence and light scatter parameters normally collected. The TIP can then be used for gating discrimination of any tube or set of tubes within a panel. When the TIP is correlated with the PRISM parameter the entire patient phenotypic image can be represented within a single two-parameter histogram we have called a phenogram. This phenogram can be generated in real time, providing on-line preprocessing of a complex multicolor experiment. By examining the image created by the phenogram it is possible to rapidly flag abnormalities such as incorrect gating. This procedure was carried out on an EPICS Elite flow cytometer in its standard configuration with the addition of hardware to provide an input for the TIP.

Data Collection↗
PubMed1991

Time interval gating for analysis of cell function using flow cytometry.

We propose a method which significantly shortens the time required for both the collection and analysis of data derived from multiple sample, flow cytometric kinetic assays. We have defined the term Time Interval Gating (TIG) to describe this method. TIG effectively allows one flow cytometer to concurrently monitor several samples over the course of a kinetic assay. Data for all samples are stored in a single FCS 2.0 compatible listmode data file which we refer to as the TIG data file. TIG is adaptable to most commerical flow cytometers. Standard listmode analysis software can be used to analyze the TIG data files and correlate any combination of tubes and/or time intervals from the assay. Results for the entire assay can be displayed on a single two parameter plot. This paper describes how TIG is applied to neutrophil oxidative burst measurement using a standard EPICS Elite flow cytometer. In this assay, 11 samples were each monitored for 30 min to identify the extent to which volatile organic chemicals (VOCs) inhibited the oxidation of DCFH in stimulated neutrophils. TIG makes the oxidative burst assay practical for high volume screening by reducing the overall flow cytometer and analysis time required by a factor of ten. In addition, TIG provides an organized approach to managing data acquisition on instruments equipped with automated sampling systems.

Flow Cytometry↗
PubMed1991

Medication regimen complexity and adherence among older adults.

Two studies were conducted to examine the relationship between medication regimen complexity and adherence among older adults recently discharged from hospitals (N = 178) and those not recently hospitalized (N = 98). Medication regimen complexity was measured by the Medication Complexity Index (Kelley, 1988), which measures the number, frequency, and types of actions required to enact a medication regimen. Adherence to the regimen was measured by pill count and verbal self-report. The negative correlations between regimen complexity and adherence were in the predicted direction but did not achieve statistical significance. Medication regimen complexity may have a larger impact on aspects of medication management other than adherence to the prescriptive regimen.

Aged↗
PubMed1991

Cardiovascular actions of desflurane in normocarbic volunteers.

The cardiovascular actions of three concentrations of desflurane (formerly I-653), a new inhalation anesthetic, were examined in 12 unmedicated normocapnic, normothermic male volunteers. We compared the effects of 0.83, 1.24, and 1.66 MAC desflurane with measurements obtained while the same men were conscious. Desflurane caused a dose-dependent increase in right-heart filling pressure and a decrease in systemic vascular resistance and mean systemic arterial blood pressure. As measured by echocardiography, left ventricular end-diastolic area did not change except for a small increase at 1.66 MAC desflurane, and systolic wall stress was less at all concentrations of desflurane than during the conscious state. Desflurane did not change cardiac index or left ventricular ejection fraction. Heart rate did not change at 0.83 MAC, but progressively increased with deeper desflurane anesthesia. Stroke volume index was less at all concentrations of desflurane than while the men were conscious, but desflurane did not alter the velocity of ventricular circumferential fiber shortening. Mixed venous blood PO2 and oxyhemoglobin saturation were higher during all concentrations of desflurane anesthesia than during the conscious state. No volunteer developed a metabolic acidosis. We conclude that desflurane with controlled ventilation and constant PaCO2 causes cardiovascular depression, as indicated by the increased cardiac filling pressure and decreased stroke volume index and by no change in the velocity of circumferential fiber shortening in the presence of decreased systolic wall stress. However, cardiac output is well maintained, and heart rate does not increase at light levels of anesthesia. The cardiovascular actions of 0.83 and 1.66 MAC desflurane were also reexamined in 6 of the 12 men during the seventh hour of anesthesia. Prolonged desflurane anesthesia resulted in lesser cardiovascular depression than was evidenced during the first 90 min. The measures of cardiac filling (central venous pressure and left ventricular end-diastolic cross-sectional area) did not differ between the early and late periods of anesthesia. Systemic vascular resistance decreased further during the late period, but systolic wall stress did not differ between the two time periods. During the seventh hour of desflurane anesthesia, heart rate and cardiac index were higher at both anesthetic concentrations than during the first 90 min of anesthesia. Left ventricular ejection fraction and velocity of fiber shortening did not change with duration of desflurane anesthesia. Oxygen consumption, oxygen transport, the ratio of the two, mixed venous PO2, and mixed venous oxyhemoglobin saturation (SO2) increased late in the anesthetic in comparison with the first 90 min.

Adult↗
PubMed1990

Psychotropic drugs and mental retardation: 1. Disabilities and the prescription of drugs for behaviour and for epilepsy in three residential settings.

The Birmingham Special Needs Register, a computerized database, was used to examine the disabilities of, and the use of psychoactive (psychotropic and antiepileptic) drugs among 1825 people over the age of 20 with mental retardation. People living in three different types of residential setting (hospitals, community residential facilities and family homes) were compared. The prevalence of physical disability, impaired communication and incontinence was highest among people resident in hospital, followed by those living with their families. People resident in community residential facilities were the least disabled group. Psychotropic drugs prescribed to alter behaviour were used most frequently in hospitals (prescribed for 40.2% of people), followed by community residential facilities (19.3%). Use was lowest in family homes (10.1%). Most hospital residents who received medication to alter behaviour did not have a diagnosed psychiatric disorder. The reported prevalence of behaviour disorders among the three populations was not significantly different. Drugs for epilepsy were prescribed for 26.2% of hospital residents, 9.3% of people in community residential facilities and 18.5% of people living with their families.

Activities of Daily Living↗
PubMed1990

Overview of hormonal therapy in advanced breast cancer.

Hormonal therapy of breast cancer is widely used and effective. Although never curative in advanced disease, significant palliation and durable remissions can be obtained with a wide variety of hormonal manipulations. Historically, surgical ablation was used to reduce endogenous hormone levels, but this invasive procedure has been largely supplanted by drugs that reduce hormone secretion or block steroid hormone activity. A number of such antagonists are available, with tamoxifen probably the most widely used. Response can also be achieved with hormone agonists. Estrogens and androgens or their congeners have about the same level of activity as surgical ablation or drug antagonists (20% to 30% overall response rate). The progestins, another class of agonists, are also effective in the palliation of advanced breast cancer. Megestrol acetate, in part because of its oral formulation, is probably the most commonly used progestational drug for the treatment of breast cancer. Reports of 16 trials involving 1,342 patients show a response rate of 26% in patients with advanced breast cancer treated with megestrol acetate. The drug has proved active in a small number of male patients and, in randomized trials, it has been shown to be comparable with tamoxifen in efficacy (30% response for megestrol acetate v 35% for tamoxifen). Studies are currently under way to evaluate the possibility that high doses of megestrol acetate may increase response rates, and to determine whether weight gain, a well-described effect of this drug, may prove beneficial in cancer treatment.

Breast Neoplasms↗