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Biomedical subjects

R Baughman

Publications and source records attributed to R Baughman.

At least 55 records · Page 3Linked to original sources
PubMed1998

Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group.

BACKGROUND: Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock. METHODS: In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days. FINDINGS: 382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, p=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, p<0.001; day 28, p=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group. INTERPRETATION: We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival.

Adult↗
PubMed1997

Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group.

OBJECTIVE: To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in the treatment of patients with severe sepsis. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis. SETTING: Ninety-one academic medical center intensive care units in North America and Europe. PATIENTS: Patients with severe sepsis or septic shock (n = 696) received standard supportive care and antimicrobial therapy for sepsis, in addition to rhIL-1ra or placebo. INTERVENTIONS: Patients were randomized to receive either rhIL-1ra (100 mg) or placebo (vehicle) by intravenous bolus, followed by a 72-hr continuous intravenous infusion of either rhIL-1ra (2.0 mg/kg/hr) or placebo. MEASUREMENTS AND MAIN RESULTS: The study was terminated after an interim analysis found that it was unlikely that the primary efficacy end points would be met. The 28-day, all-cause mortality rate was 33.1% (116/350) in the rhIL-1ra treatment group, while the mortality rate in the placebo group was 36.4% (126/346), yielding a 9% reduction in mortality rate (p = .36). The patients were well matched at the time of study entry; 52.9% of placebo-treated patients were in shock while 50.9% of rhIL-1ra-treated patients were in shock at the time of study entry (p = .30). The mortality rate did not significantly differ between treatment groups when analyzed on the basis of site of infection, infecting microorganism, presence of bacteremia, shock, organ dysfunction, or predicted risk of mortality at the time of study entry. No excess number of adverse reactions or microbial superinfections were attributable to rhIL-1ra treatment in this study. CONCLUSIONS: A 72-hr, continuous intravenous infusion of rhIL-1ra failed to demonstrate a statistically significant reduction in mortality when compared with standard therapy in this multicenter clinical trial. If rhIL-1ra treatment has any therapeutic activity in severe sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.

Adult↗
PubMed1995

Agent Orange and the Vietnamese: the persistence of elevated dioxin levels in human tissues.

OBJECTIVES: The largest known dioxin contamination occurred between 1962 and 1970, when 12 million gallons of Agent Orange, a defoliant mixture contaminated with a form of the most toxic dioxin, were sprayed over southern and central Vietnam. Studies were performed to determine if elevated dioxin levels persist in Vietnamese living in the south of Vietnam. METHODS: With gas chromatography and mass spectroscopy, human milk, adipose tissue, and blood from Vietnamese living in sprayed and unsprayed areas were analyzed, some individually and some pooled, for dioxins and the closely related dibenzofurans. RESULTS: One hundred sixty dioxin analyses of tissue from 3243 persons were performed. Elevated 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) levels as high as 1832 ppt were found in milk lipid collected from southern Vietnam in 1970, and levels up to 103 ppt were found in adipose tissue in the 1980s. Pooled blood collected from southern Vietnam in 1991/92 also showed elevated TCDD up to 33 ppt, whereas tissue from northern Vietnam (where Agent Orange was not used) revealed TCDD levels at or below 2.9 ppt. CONCLUSIONS: Although most Agent Orange studies have focused on American veterans, many Vietnamese had greater exposure. Because health consequences of dioxin contamination are more likely to be found in Vietnamese living in Vietnam than in any other populations, Vietnam provides a unique setting for dioxin studies.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1994

Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031.

Trimetrexate is a powerful inhibitor of the dihydrofolate reductase of Pneumocystis carinii. AIDS patients (n = 215) with moderate to severe P. carinii pneumonia were enrolled in a double-blind study of trimetrexate plus leucovorin versus trimethoprim-sulfamethoxazole (TMP-SMZ) for 21 days. By study day 10, study therapy failed because of lack of efficacy in 16% of patients assigned to TMP-SMZ and 27% assigned to trimetrexate (P = .064), and the PAO2-PaO2 improved significantly faster with TMP-SMZ. By study day 21, failure rates were 20% with TMP-SMZ and 38% with trimetrexate (P = .008), with respective mortality rates of 12% and 20% (P = .088). By study day 49, the difference in mortality (16% vs. 31%) was significant (P = .028). The cumulative incidence of serious and treatment-terminating adverse events including hematologic toxicities was less with trimetrexate (P < .001). Thus, trimetrexate plus leucovorin was effective, albeit inferior to TMP-SMZ, for moderately severe P. carinii pneumonia but was better tolerated than TMP-SMZ.

AIDS-Related Opportunistic Infections↗
PubMed1994

Piperacillin/tazobactam compared with ticarcillin/clavulanate in community-acquired bacterial lower respiratory tract infection.

The efficacy and safety of a new combination parenteral antibiotic, piperacillin/tazobactam, was compared with that of parenteral ticarcillin/clavulanate in the treatment of adult patients with community-acquired lower respiratory tract infections. A total of 299 patients were enrolled in this multicentre, double-blind, comparative study; 177 received piperacillin/tazobactam and 122 received ticarcillin/clavulanate. Of these, 119 met the evaluability criteria (69, piperacillin/tazobactam and 50, ticarcillin/clavulanate). The study drugs (piperacillin/tazobactam 3 g/375 mg or ticarcillin/clavulanate 3 g/100 mg) were given every 6 h by slow iv infusion for a minimum of 5 days. The favourable clinical response (cured and improved) rates of evaluable patients were 84% and 64% at endpoint (P < 0.01) for piperacillin/tazobactam and ticarcillin/clavulanate, respectively. The favourable bacteriological response at the early follow-up (eradicated and presumed eradicated) were 91% and 67% for piperacillin/tazobactam and ticarcillin/clavulanate, respectively (P < 0.01). At endpoint, 84% and 64%, respectively (P = 0.02) had a favourable response. The most common adverse experiences involved the gastrointestinal tract and occurred in 31.6% of the piperacillin/tazobactam group compared with 20.5% in the ticarcillin/clavulanate group (P = 0.02). These events were mild and generally did not affect therapy. Piperacillin/tazobactam appears to be more effective than ticarcillin/clavulanate in this patient population and is generally well tolerated.

Adolescent↗
PubMed1990

Prediction of cardiac and pulmonary complications related to elective abdominal and noncardiac thoracic surgery in geriatric patients.

PURPOSE: Major cardiac and pulmonary complications associated with abdominal and noncardiac thoracic surgery are a common cause of mortality and serious morbidity in elderly patients. We postulated that a simple, inexpensive bicycle exercise test could provide objective documentation of cardiopulmonary reserve and, therefore, predict perioperative pulmonary as well as cardiac complications. PATIENTS AND METHODS: Prior to elective surgery, 177 patients aged 65 years or older had assessment of the clinical history, results of physical examination, electrocardiogram, chest radiograph, blood chemistries, pulmonary function test findings, supine exercise test results, Dripps classification, and Goldman cardiac risk factors. Observations in patients with and without major perioperative cardiac and/or pulmonary complications were compared using univariate analysis followed by a multivariate logistic regression procedure. RESULTS: Major perioperative complications were pulmonary in 24 patients, cardiac in 25 patients, and either cardiac or pulmonary in 39 patients. By multivariate analysis, inability to perform two minutes of supine bicycle exercise raising the heart rate above 99 beats/minute was the best predictor of perioperative pulmonary, cardiac, and combined cardiopulmonary complication (p less than 0.0005). Among 108 patients who were able to achieve these exercise criteria, cardiac or pulmonary complications occurred in 10 patients (9.3%), with one death (0.9%). Among 69 patients unable to exercise satisfactorily, cardiac or pulmonary complications occurred in 29 patients (42%), with five total deaths (7.2%). CONCLUSION: Objective measurement of exercise capacity by supine bicycle ergometry appears to be of clinical value for preoperative risk stratification for both pulmonary and cardiac complications prior to major elective abdominal or noncardiac thoracic surgery in elderly patients.

Abdomen↗
PubMed1990

The effect of timing of intrathecal fibrinolytic therapy on cerebral vasospasm in a primate model of subarachnoid hemorrhage.

The effect of intrathecal tissue plasminogen activator administered at times from 0 to 72 hours after subarachnoid hemorrhage on the development of cerebral vasospasm in primates was examined. Thirty monkeys were randomly assigned into one of five equal groups: a control group that underwent subarachnoid hemorrhage alone, and 0-, 24-, 48-, and 72-hour treatment groups that received 0.75 mg of tissue plasminogen activator at those times after baseline cerebral angiography and subarachnoid hemorrhage on the right side. Seven days later angiography was repeated and the animals were killed. One animal in the 72-hour group developed a delayed ischemic deficit on Day 7 after subarachnoid hemorrhage. In the control and 72-hour groups significant vasospasm occurred in most of the major, right cerebral arteries (P less than 0.05), but no significant vasospasm developed in the 0-, 24-, and 48-hour groups. Although a large subarachnoid clot remained in the control animals, most clot had been dissolved in all treatment groups. Lysing of subarachnoid hematoma with intrathecal tissue plasminogen activator within 72 hours of subarachnoid hemorrhage is effective in preventing vasospasm in primates.

Animals↗
PubMed1990

Administration of recombinant enkephalinase (neutral endopeptidase) prevents capsaicin-induced miosis in the rabbit eye in vivo.

Substance P induced a dose-dependent contraction of iris sphincter muscles when applied in the presence of atropine to the isolated rabbit iris in vitro as evidenced by a decreased pupil diameter. Pretreatment of the iris with 20 micrograms of recombinant enkephalinase (neutral endopeptidase; EC 3.4.24.11) totally abolished the contractile response to substance P. Injection of 10 micrograms of capsaicin into the anterior chamber of atropine-treated rabbit eyes in vivo induced an immediate and intense miosis. Injection of 100 micrograms of recombinant enkephalinase, 1 or 5 min before capsaicin injection, significantly inhibited this miosis. This effect of enkephalinase was totally abolished by preincubating the enzyme with thiorphan, a high-affinity enkephalinase inhibitor. These results show that enkephalinase, which is known to hydrolyze substance P in vitro with high efficiency, also hydrolyzes endogenously released substance P in vivo. Furthermore, our results suggest that enkephalinase application may represent a novel therapeutic approach to treat substance P-mediated pathologies.

Animals↗
PubMed1989

Intrathecal fibrinolytic therapy after subarachnoid hemorrhage: dosage study in a primate model and review of the literature.

Because of the naturally low fibrinolytic activity of CSF many erythrocytes entrapped in subarachnoid blood clot undergo hemolysis in situ, releasing vasogenic oxyhemoglobin (OxyHb) in high concentrations around the basal cerebral arteries. In order to promote more rapid clearance of erythrocytes from the basal subarachnoid cisterns we are currently investigating intrathecal thrombolytic therapy with human, recombinant, tissue plasminogen activator (rt-PA) in a primate model of subarachnoid hemorrhage (SAH) and cerebral vasospasm (VSP). In the present study 16 monkeys were divided into 4 groups of 4, and each group received a different dose of sustained-release gel rt-PA at the time of experimental SAH. Cerebral angiography seven days later showed that whereas no VSP occurred in the groups receiving 0.5 or 0.75 mg of rt-PA, mild to moderate VSP occurred in the groups receiving 0.125 or 0.25 mg of rt-PA. Analysis of the combined 2 smaller dosage groups revealed significant (P less than 0.05) reduction of lumen caliber in the clot-side internal carotid (C3 and C4), proximal anterior cerebral (A1) and middle cerebral (MCA) arteries. Gross subarachnoid clot remained in all of the animals in the 0.125 and 0.25 mg dose groups, in 2 of the animals in the 0.5 mg dose group, and none of the animals in the 0.75 mg dose group. It was concluded that 0.75 mg of gel rt-PA is sufficient to completely lyse a 4.25 ml SAH and prevent VSP in our primate model. The literature on fibrinolysis and erythrocyte clearance in cerebrospinal fluid (CSF) is reviewed.

Animals↗
PubMed1989

Safety and efficacy of intrathecal thrombolytic therapy in a primate model of cerebral vasospasm.

To test the safety of a large intrathecal dose of human recombinant tissue plasminogen activator (rt-PA), 6 cynomolgous monkeys were given 10 mg of rt-PA (mean, 2.7 mg/kg) through an Ommaya reservoir after craniectomy and dissection of the basal cisterns. Bleeding occurred briefly at the incision in 2 animals; otherwise the clinical condition of all 6 remained normal throughout the postoperative period. Systemic fibrinolysis did not occur, and gross and microscopic examination of the brain and meninges revealed no abnormality. Next, we evaluated the efficacy of unilateral administration of rt-PA suspension (0.5 mg) plus slow-release gel rt-PA (1.25 mg) in lysing a bilateral subarachnoid clot and preventing vasospasm in a randomized, placebo-controlled trial. Sixteen monkeys were divided randomly into 2 equal groups, each of which underwent baseline cerebral angiography, followed by frontotemporal craniectomy and induction of subarachnoid hemorrhage on the left side and then on the right. Before closure on the right side either rt-PA or an equal volume of placebo was injected into the subarachnoid space. On day 7 angiography was repeated, and the animals were killed under anesthesia for necropsy. One of the animals in the placebo group developed a cerebral infarction on day 5. In the placebo group significant vasospasm occurred in all major right and left-sided anterior cerebral vessels (P less than 0.01). No vasospasm occurred in the rt-PA-treated animals. Whereas gross subarachnoid clot was found in all animals in the placebo group (mean clot weight 1.13 g), only a small fragment of clot was found in a single rt-PA-treated animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Healing following meniscoplasty, eminectomy, and high condylectomy in the monkey temporomandibular joint.

The healing of meniscoplasty, eminectomy, and high condylectomy was studied in five Macaca fascicularis monkeys. After five months of healing, no discontinuity defects were found in any of the plicated menisci, and all recontoured bone surfaces had new soft tissue linings. Fibrous adhesions to the adjacent plicated meniscus developed in 62.5% of the recontoured bony surfaces.

Animals↗
PubMed1986

Variation of differential cell counts of bronchoalveolar lavage fluid.

Bronchoalveolar lavage (BAL) is a common research and clinical tool to retrieve cells from the lower respiratory tract. Differential cell counts of the nucleated cells retrieved by BAL provide important diagnostic and prognostic information. There is much variation between laboratories in the reported normal percentages of lymphocytes and macrophages of cells retrieved by BAL. We compared three methods of identifying cells in the BAL fluid: a modified Wright-Giemsa (WG) stain, a nonspecific esterase stain, and a monoclonal marker for T lymphocytes. There was good agreement between the percentage of macrophages identified by WG and nonspecific esterase and the percentage of lymphocytes determined by WG stain and monoclonal marker. Intrasubject and intersubject agreement of the differential cell counts determined by the WG stain was good. We concluded that cells from BAL fluid can be analyzed using the WG stain alone.

Adolescent↗
PubMed1981

Dopamine metabolism following irreversible inactivation of aromatic amino acid decarboxylase in retina.

The effects of an intravitreal injection of alpha-fluoromethyldopa, an irreversible mechanism-based inactivator of aromatic-L-amino acid decarboxylase, on the retinal dopamine content of light-adapted chicks and rabbits have been examined. A single administration of 10 nmol of alpha-fluoromethyldopa totally inactivates aromatic L-amino acid decarboxylase within 2 hr in vivo in rabbits. By 4 to 6 hr, the level of dihydroxyphenylalanine increased 7-fold and the levels of dopamine and dihydroxyphenylacetic acid fell by 90%. With an injection of 50 nmol, similar results were observed in chicks. The levels of dihyroxyphenylacetic acid began to fall soon after injection when significant (30 to 40%) amounts of dopamine were still present. These results are discussed in relation to the use of tissue dihydroxyphenylacetic acid levels to indicate the level of dopaminergic neuronal activity or dopamine synthesis. Recovery by the retinae of both species was shown by the return of aromatic L-amino acid decarboxylase activity and the resynthesis of dopamine.

3,4-Dihydroxyphenylacetic Acid↗