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Biomedical subjects

R V McCloskey

Publications and source records attributed to R V McCloskey.

At least 19 recordsLinked to original sources
PubMed1998

Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis.

OBJECTIVE: To investigate the regulation of expression of the angiogenic cytokine vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA), in order to determine whether new blood vessel formation could be a potential therapeutic target in RA. METHODS: Dissociated RA synovial membrane cells were cultured in the presence of cytokine inhibitors, or under hypoxic conditions. Serum VEGF levels were serially measured in RA patients enrolled in clinical trials of anti-tumor necrosis factor alpha (anti-TNFalpha) monoclonal antibody treatment. RESULTS: Combined neutralization of TNFalpha and interleukin-1 (IL-1) in RA synovial membrane cultures reduced VEGF release by 45% (P < 0.05 versus control), although blockade of either TNFalpha or IL-1 activities alone resulted in only small inhibitory effects. In addition, release of VEGF from RA synovial membrane cells was selectively up-regulated by hypoxia. Serum VEGF levels were significantly elevated in RA patients relative to control subjects, and correlated with disease activity. Treatment of RA patients with anti-TNFalpha significantly decreased serum VEGF, and this effect was enhanced by cotreatment with methotrexate. CONCLUSION: Inhibition of TNFalpha and IL-1 activity in vivo could reduce the drive to new blood vessel formation, and hence pannus mass, adding to other therapeutic effects of anti-TNFalpha therapy in RA.

Antibodies, Monoclonal↗
PubMed1997

Influence of alterations in foregoing life-sustaining treatment practices on a clinical sepsis trial. The HA-1A Sepsis Study Group.

OBJECTIVES: To evaluate the timing of foregoing life-sustaining treatments in patients enrolled in a sepsis trial and to determine their influence on patient outcome and trial results. DESIGN: Subset of patients in a prospective, randomized, double-blind, placebo-controlled study. SETTING: Twenty-three academic medical centers. PATIENTS: Enrolled patients who had life-sustaining therapies withheld or withdrawn. MEASUREMENTS AND MAIN RESULTS: The number of patients, types of disorders and interventions, reasons, and timing of withholding and withdrawing life-sustaining treatments and their effect on mortality and trial results were assessed. Foregoing of life-sustaining therapies took place in 117 (22%) of 543 patients and occurred within 72 hrs of study drug administration in 38 (32%) patients. Withholding treatment (60%) was more common than withdrawing treatment (40%), but withdrawing treatment was more frequent (51%) than withholding treatment (20%) in the first 72 hrs of the trial (p < .01). Sixty-one (52%) patients had severe underlying disorders with a poor prognosis. The hospital mortality rate was 94% (of the 117 patients). The mean time (SEM) from withholding or withdrawing of treatment until death was 2.83 +/- 0.57 and 0.32 +/- 0.13 days, respectively (p < .001). Patients who had therapies foregone in the first 24, 48, and 72 hrs after receiving the study drug had higher mortality rates in the first 72 hrs (p < .01). CONCLUSIONS: A substantial number of patients enrolled in a sepsis trial had severe underlying diseases and had foregoing of therapies early in the course of the trial, which led to a higher early mortality rate. Enrollment of patients in clinical trials with severe underlying disorders with a high likelihood of having therapies foregone may bias the potential for showing the efficacy of new therapeutic modalities.

Antibodies, Monoclonal↗
PubMed1996

Inhibition of immunoreactive tumor necrosis factor-alpha by a chimeric antibody in patients infected with human immunodeficiency virus type 1.

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine known to stimulate human immunodeficiency virus type 1 (HIV-1) replication, has been implicated in the pathogenesis of HIV-1 infection. Inhibition of TNF-alpha by a chimeric humanized monoclonal antibody, cA2, was investigated in 6 HIV-1-infected patients with CD4 cell counts < 200/mm3. Two consecutive infusions of 10 mg/kg 14 days apart were well tolerated, and a prolonged serum half-life for cA2 (mean, 257 +/- 70 h) was demonstrated. Serum immunoreactive TNF-alpha concentrations fell from a mean prestudy value of 6.4 pg/mL (range, 4.2-7.9) to 1.1 pg/mL (range, 0.5-2.2) 24 h after the first infusion and returned to baseline within 7-14 days. A similar response was seen after the second infusion. No consistent changes in CD4 cell counts or plasma HIV RNA levels were observed over 42 days. Future studies evaluating the therapeutic utility of long-term TNF-alpha suppression using anti-TNF-alpha antibodies are feasible and warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group.

OBJECTIVE: To compare the effectiveness of 100 mg of HA-1A and placebo in reducing the 14-day all-cause mortality rate in patients with septic shock and gram-negative bacteremia in the Centocor: HA-1A Efficacy in Septic Shock (CHESS) trial, and to assess the safety of 100 mg of HA-1A given to patients with septic shock who did not have gram-negative bacteremia. DESIGN: Large, simple, group-sequential, randomized, double-blind, multicenter, placebo-controlled trial. SETTING: 603 investigators at 513 community and university-affiliated hospitals in the United States. PATIENTS: Within 6 hours before enrollment, the patients had been in shock with a systolic blood pressure of less than 90 mm Hg after adequate fluid challenge or had received vasopressors to maintain blood pressure. These episodes of shock began within 24 hours of enrollment. A presumptive clinical diagnosis of gram-negative infection as the cause of the shock episode and a commitment from the patients' physicians to provide full supportive care were required. MEASUREMENTS: Blood cultures were obtained within 48 hours of enrollment, and death at day 14 after treatment was recorded. Adverse events occurring within 14 days after enrollment were also tabulated. RESULTS: 2199 patients were enrolled; 621 (28.2%) met all enrollment criteria, received HA-1A or placebo, and had confirmed gram-negative bacteremia. Mortality rates in this group were as follows: placebo, 32% (95 and HA-1A, 33% (109 of 328) (P = 0.864, Fisher exact test, two-tailed; 95% CI for the difference, -6.2% to 8.6%). Mortality rates in the patients without gram-negative bacteremia were as follows: placebo, 37% (292 of 793) and HA-1A, 41% (318 of 785) (P = 0.073, Fisher exact test, one-tailed; CI, -0.8% to 8.8%). CONCLUSIONS: In this trial, HA-1A was not effective in reducing the 14-day mortality rate in patients with gram-negative bacteremia and septic shock. These data do not support using septic shock as an indication for HA-1A treatment. If HA-1A is effective in reducing the mortality rate in patients dying from endotoxemia, these patients must be identified using other treatment criteria.

Adult↗
PubMed1991

Oral ofloxacin for the treatment of acute bacterial pneumonia: use of a nontraditional protocol to compare experimental therapy with "usual care" in a multicenter clinical trial.

PURPOSE: This multicenter study was designed to compare an exclusively oral regimen with "usual care" in patients hospitalized with acute bacterial pneumonia. PATIENTS AND METHODS: One hundred forty-seven patients were enrolled. All patients presented with a clinical picture consistent with pneumonia: (1) clinical symptoms of a lower respiratory tract infection, such as chest pain, cough, and production of purulent sputum; (2) roentgenographic infiltrate compatible with acute infection; and (3) Gram's stain of purulent sputum or other appropriate bronchopulmonary specimen containing gram-negative organisms, staphylococci, or pneumococci. All patients required hospitalization. The design was a parallel-group, open-label study with randomization in blocks of four. Ofloxacin, a new fluoroquinolone antimicrobial agent, was administered orally or by nasogastric tube, 400 mg every 12 hours. This was compared with the individual investigator's best selection of therapy that was administered parenterally, at least initially. RESULTS: One hundred thirty-three patients were evaluable after exclusions for deviation from protocol, early death due to unrelated causes, incorrect diagnosis, or early adverse drug reactions. All 69 patients treated with ofloxacin and 61 of 64 control patients had favorable clinical and microbiologic responses. There were no statistically significant differences between the groups in terms of demographics, therapeutic outcome, and duration of therapy. There were few side effects overall and rates were similar for the two groups. CONCLUSIONS: An exclusively oral regimen, in this case ofloxacin, may be substituted for parenteral therapy in selected patients with pneumonia. This might significantly reduce costs and risks to the patient.

Administration, Oral↗
PubMed1989

Ehrlichiosis--"spotless spotted fever".

Ehrlichia Canis, a canine rickettsia, produces an acute infection in humans characterized by thrombocytopenia, leukopenia, and anemia. Patients should be closely questioned and examined for tick bites. Rash is not prominent, leading to the interesting if somewhat inaccurate label of "spotless spotted fever." The diagnosis is made by clinical presentation, absence of positive Lyme disease or Rocky Mounted Spotted Fever (RMSF) serology, and positive E. canis titers. Tetracyclines are preferred treatment. Ehrlichiosis should be considered in the differential diagnosis of fevers of unknown origin, Lyme disease, idiopathic thrombocytopenia, and hypoplastic anemia.

Animals↗
PubMed1988

Topical antimicrobial agents and antibiotics for the eye.

Antibiotics for eye infection can be given topically, by subconjunctival or intravitreous injection, or systemically. The bacteria responsible are reviewed and pharmacokinetics influencing topical concentration are discussed. An approach to treatment by the primary care specialist is suggested.

Anti-Bacterial Agents↗
PubMed1987

Leakage of beta-lactamase: a second mechanism for antibiotic potentiation by amdinocillin.

Discrepancies were observed between results of different beta-lactamase induction tests with amdinocillin, which appeared to be a strong inducer in whole-cell assays but a weak inducer in assays with cell-free sonic extracts. Results of a nitrocephin-disk test with constitutive beta-lactamase producers indicated that the positive results obtained in whole-cell assays were due to drug-produced leakage of enzyme from the cell and not to induction. Imipenem was also found to cause leakage of beta-lactamase from a similar number of constitutive enzyme producers, while cefoxitin was much less likely to cause leakage. A split-dose regimen was employed to treat mice infected with a strain of Enterobacter cloacae which appeared to leak enzyme on exposure to amdinocillin. Results indicated that prior treatment with amdinocillin significantly enhanced (P less than 0.025) the efficacy of azlocillin, an enzyme-labile drug, but did not affect the efficacy of cefotaxime, a relatively enzyme-stable drug. Conversely, prior treatment with amdinocillin did not potentiate the efficacy of either azlocillin or cefotaxime in the treatment of mice infected with an Escherichia coli strain that was highly susceptible to all three drugs. Thus, it appears that amdinocillin may potentiate the activity of other beta-lactam drugs not only by binding to a complementary penicillin-binding protein but also by causing leakage of beta-lactamase from the cell. This effect may be related to its ability to bind to penicillin-binding protein 2 and subsequently produce changes in outer membrane permeability.

Amdinocillin↗
PubMed1986

Comparative in vitro antimicrobial activity of carumonam, a new monocyclic beta-lactam.

The antimicrobial activity of carumonam (formerly RO-17-2301), a monocyclic beta-lactam antibiotic, was compared with those of aztreonam, cefotaxime, cefoperazone, ceftazidime, piperacillin, and gentamicin against 455 bacterial isolates. Carumonam did not possess activity against gram-positive cocci and was generally comparable to aztreonam and ceftazidime for most gram-negative bacilli. However, carumonam was the most active beta-lactam against gentamicin-resistant Pseudomonas aeruginosa strains (90% MIC, 8 micrograms/ml).

Anti-Bacterial Agents↗
PubMed1986

Clinical comparison of piperacillin and cefoxitin in patients with bacteriologically confirmed infections.

The objective of this double-blind study was to compare the efficacy and safety of piperacillin with that of cefoxitin in patients with bacterial infections. Seventy hospitalized patients were treated with intravenous piperacillin (18 g/day) or cefoxitin (12 g/day) for a mean period of 11.5 days. Multiple serious underlying conditions were present in 91% of the patients in both treatment groups. The infection sites were the respiratory, urinary, and gastrointestinal tracts, the skin and skin structures, and the bones. Among the patients with evaluated courses of therapy, 87% (20 of 23) of the patients in the piperacillin-treated group and 90% (19 of 21) of the cefoxitin-treated patients were cured or improved. Multiple sites of infection were present in 6 patients given piperacillin and in 11 patients given cefoxitin. Gram-negative aerobic bacteria were the most frequently isolated organisms (56% of isolates). In each treatment group, 91% of the pathogens were eradicated. Three piperacillin-treated patients (9%) and four cefoxitin-treated patients (11%) had adverse clinical effects related to therapy; most of the effects were moderate in intensity. In conclusion, both piperacillin and cefoxitin were clinically safe and effective antibiotics for the treatment of these patients, most of whom had severe underlying conditions.

Adult↗
PubMed1985

Treatment of skin and soft tissue infections with imipenem/cilastatin.

Ninety-eight adult patients with skin and soft tissue infections caused by a variety of bacterial pathogens were treated with imipenem/cilastatin (71), cefazolin (21), or moxalactam (six) at three medical centers. Favorable clinical responses were observed in 87 of the 90 evaluable cases (97 percent). Most etiologic pathogens were eradicated during treatment including five of seven which demonstrated in vitro resistance to the therapeutic agent. Strains that persisted during treatment were not associated with therapeutic failure except in one cefazolin-treated patient who was infected with Bacteroides fragilis. All three drugs were well tolerated and no specific patterns of adverse reactions were observed.

Adult↗
PubMed1984

Clinical and bacteriologic efficacy of ceftriaxone in the United States.

The clinical and bacteriologic efficacy of ceftriaxone given once or twice daily was evaluated in 153 studies. A total of 2,635 patients received ceftriaxone given intramuscularly or intravenously, 930 received comparative antibiotics, and 81 received placebo. For the 10 major categories of infections treated (central nervous system, upper and lower respiratory tract, intraabdominal, skin and skin structure, bone and joint, urinary tract, gynecologic, and bacterial sepsis), the clinical response rates were 89 percent or greater. Bacteriologic cure rates were 84 percent or greater overall and 90 percent or greater for seven of 10 categories. Ceftriaxone achieved a satisfactory clinical response (cure or improvement) for 89 (intraabdominal) to 99 percent (urinary tract) of the infections treated. Additionally, pediatric central nervous system infections responded to twice-daily ceftriaxone injection; ceftriaxone, in a single dose as low as 250 mg, cured gonorrhea, and a single dose of ceftriaxone was as effective as multiple doses of cefazolin in surgical prophylaxis.

Adolescent↗
PubMed1984

Cefmenoxime. Clinical, bacteriologic, and pharmacologic studies.

Cefmenoxime, a new semisynthetic third-generation cephalosporin, was evaluated in 105 patients (45 men and 60 women) with the following infections: skin or skin structure (33), pulmonary (22), urinary tract (30), and septicemia (20). Forty-two infections were hospital-acquired, 85 patients had underlying diseases, 29 patients required concomitant surgery, and 32 patients had positive results of blood culture. Cefmenoxime dosages ranged from 4 to 12 g per day intravenously for one and a half to 51 days. Cultures revealed 183 organisms in the 105 patients. Minimal inhibitory concentrations were obtained for cefmenoxime, cefoperazone, cefotaxime, cefamandole, cefoxitin, and moxalactam. Cefmenoxime and cefotaxime exhibited nearly equivalent activities against all organisms tested and were the most active agents tested against all aerobic and facultative organisms except Staphylococcus aureus. Mean serum peak and trough levels obtained after 2 g every six hours were 84.1 micrograms/ml (peak), 8.3 micrograms/ml (trough); and after 2 g every four hours, 106 micrograms/ml (peak) and 10.9 micrograms/ml (trough). Of 105 infections, 86 were clinically cured, three were not cured, and 16 were not evaluable. Safety studies revealed 24 transient reactions in 23 patients including eosinophilia, diarrhea, leukopenia, rash, elevated liver enzyme levels, Antabuse effect, and phlebitis. On the basis of these clinical and in vitro results, cefmenoxime is a safe drug for the treatment of infections caused by gram-negative and gram-positive aerobic organisms.

Adult↗
PubMed1983

Comparative clinical trial of imipenem-cilastatin (N-formimidoyl-thienamycin-dehydropeptidase inhibitor) and cefazolin.

One hundred and eighty-six patients were randomized to receive either imipenem-cilastatin (94 patients) or cefazolin (92 patients). Imipenem-cilastatin (250 mg 6 hourly iv) or cefazolin (1000 mg 6 hourly iv) were given for 5 to 14 days. An assessment of efficacy could be made in 141 patients, 72 of whom received imipenem-cilastatin and 69 of whom received cefazolin. Reasons for exclusion included failure to isolate a causative organism (20 patients), less than 5 days of treatment (16 patients), inadequate follow up or culture (5 patients), concomitant administration of another antibiotic (1 patient), and resistance to the study drug (3 patients, all of whom were in the cefazolin group). No isolates resistant to imipenem were found. Sites of infection included skin and soft tissue (91 patients), lower respiratory tract (21 patients), urinary tract (16 patients), bone and joint (8 patients), primary bacteraemia (4 patients) and miscellaneous other sites (1 patient). Bacteria isolated included Staphylococcus aureus (65 patients), group A streptococcus (42 patients), Escherichia coli (17 patients), other Gram-negative bacilli (37 patients), anaerobic bacteria (34 patients) and other bacteria. Imipenem was more active than cephalothin in vitro against pathogenic bacteria isolated from evaluable patients. Cure or improvement was seen in 68 of the 72 imipenem-cilastatin patients (94%) and in 68 of the 69 cefazolin patients (99%). Relatively few abnormal laboratory tests and adverse experiences were noted, and there were no differences in this between the two treatment groups. We concluded that imipenem-cilastatin is safe at the dose used. It is as effective as cefazolin in mild to moderate infections caused by common pathogens.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1983

Susceptibility of the Bacteroides fragilis group in the United States in 1981.

The minimal inhibitory concentrations of nine antimicrobial agents was determined for over 750 clinical isolates of the Bacteroides fragilis group of anaerobic bacteria collected from nine centers in the United States during 1981. High resistance rates were documented for cefoperazone, cefotaxime, and tetracycline. Cefoxitin had the best activity of the beta-lactam antibiotics, whereas moxalactam and piperacillin had good activities. The resistance rate for clindamycin was 6%. There were no metronidazole- or chloramphenicol-resistant isolates encountered. There were significant differences in susceptibility among the various species of the B. fragilis group, particularly with moxalactam, cefoxitin, and clindamycin. Clustering of clindamycin-, piperacillin-, and cefoxitin-resistant isolates was observed at different hospitals. The variability of resistance rates with the beta-lactam antibiotics and clindamycin indicates that susceptibility testing of significant clinical isolates should be performed to define local resistance patterns.

Anti-Bacterial Agents↗