Search PubMed⌕ Search

Biomedical subjects

R B Smith

Publications and source records attributed to R B Smith.

At least 199 records · Page 11Linked to original sources
PubMed1987

An evaluation of population pharmacokinetics in therapeutic trials. Part II. Detection of a drug-drug interaction.

The use of observational data, collected during the routine clinical care of patients, has been advocated as a means to obtain clinically relevant information regarding the pharmacokinetic parameters of drugs. However, the validity of this approach and its proper role in new drug development is unclear. This study was performed to evaluate the ability of three approaches to estimate population pharmacokinetic parameters: the traditional approach, mixed-effect modeling, and a simple pharmacokinetic screen. The evaluation was performed with data collected during a multicenter, open-label study evaluating the efficacy, safety, and pharmacokinetics of imipramine and alprazolam in combination. The traditional pharmacokinetic study demonstrated a 20% decrease in the clearance of imipramine in the presence of 4 mg/day alprazolam. Mixed-effect modeling extends these findings by suggesting that the interaction is dependent on the simultaneous concentration of alprazolam, a finding that was not possible under the study design typically used for traditional pharmacokinetic studies. Although the simple screen suggests the presence of the drug-drug interaction, limited information regarding pharmacokinetic parameters is available and those parameters that can be estimated are biased.

Adult↗
PubMed1987

Relationships between thromboxane production, platelet aggregability, and serum concentrations of ibuprofen or flurbiprofen.

Arachidonate-induced ex vivo platelet aggregations were performed before and after subjects received various doses of either ibuprofen or flurbiprofen. Both ibuprofen and flurbiprofen reduced the initial rate of thromboxane B2 (TxB2) production, but about 10% of control TxB2 production was refractory to either drug. Aggregation was observed after TxB2 concentrations exceeded a threshold of about 40 ng/ml. Once the threshold was achieved, aggregation and TxB2 production occurred independently of either drug. Ibuprofen and flurbiprofen concentrations of about 3 and 0.2 micrograms/ml, respectively, inhibited aggregation during the 5-minute testing period. A pharmacodynamic model was developed that predicts TxB2 production, aggregation lag times, and percent aggregation as a function of the time course of drug concentrations in serum.

Adult↗
PubMed1987

Intra-arterial thrombolysis for acute limb ischemia: a three-year experience.

Peripheral arterial thromboembolism and thrombosis of arterial grafts continue to threaten viability of extremities. Percutaneous intra-arterial thrombolysis (IAT) and angiodilatation have afforded limb salvage in some of these patients. Proper patient selection appears to be the hallmark of success with IAT. During a recent three-year period, we used IAT in 32 extremities in 28 patients who had acute arterial insufficiency. Before IAT, 16 extremities were painful at rest, and 16 had incapacitating claudication. The overall success rate was 38%, but some degree of thrombolysis occurred in 88%. Limb salvage was achieved in 27 of 32 extremities (84%). Only five of 17 limbs (29%) with arterial graft thrombosis required no operation or an operation of lesser magnitude than predicted before IAT. Of six extremities with native arterial embolism, four (67%) were completely cleared with IAT. Major complications occurred in eight cases (25%), with two IAT-related deaths (6%). This study suggests that IAT is best reserved for individuals with acute limb ischemia caused by arterial embolus, those whose degree of ischemia would tolerate a 24-hour trial of IAT, and those whose femoral or tibial runoff is not likely to require remedial operation.

Acute Disease↗
PubMed1987

Gas exchange in low-compression HFPPV is maintained at low distending pressures in the pig.

The fact that collateral ventilation normally occurs in the human lung has led to the suggestion that it might contribute to the successful clinical effects of low-compression high-frequency positive-pressure ventilation (HFPPV). As the pig has poor collateral ventilation, pulmonary vasoconstriction has to be part of the regulatory mechanisms matching ventilation-perfusion. A study was made on nine pigs anesthetized with ketamine hydrochloride intravenously to elucidate the maintenance of ventilation-perfusion balance during mechanical ventilation. Comparisons were made between the ventilatory patterns provided by a conventional ventilator (Servo-Ventilator 900C) and an improved prototype of a low-compression system for volume-controlled ventilation (system H). A ventilatory frequency of 20 breaths per min (bpm) with SV-900C (SV-20) and system H (H-20) and of 60 bpm with system H (H-60) was used. The experimental conditions were otherwise identical. Positive end-expiratory pressures (PEEP) were applied to maintain the same mean airway pressure with the three systems. The tidal volume required for normoventilation differed significantly between the three ventilatory patterns, but there were no differences in circulatory and oxygen-transport variables. By measurements of airway pressure and intrapleural liquid surface pressure, it was demonstrated that the distending pressure (at end-inspiration) was significantly lower with a low-compression system (H-20 versus SV-20), especially at a high ventilatory frequency (H-60 versus H-20). Consequently, although the mean airway pressure was set at the same level for the three different ventilatory modalities, the distending pressures required for the same alveolar ventilation and arterial oxygenation differed significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Femoral anastomotic aneurysms: a continuing challenge.

The methods used in management of 102 femoral anastomotic aneurysms (FAAs) were analyzed, and a case control study was performed in an effort to define potential etiologic factors. Most FAAs resulted from host vessel degeneration, although broken sutures, infection, and prosthetic graft dilatation contributed in some cases. Patients forming FAAs after aortofemoral bypass more often were hypertensive, had progression of distal disease, and showed diffuse atherosclerosis when compared with control patients. The use of braided synthetic sutures, woven Dacron grafts, and concomitant femoral endarterectomy correlated with FAA development, whereas diabetes mellitus, multiple femoral operations, local wound-healing problems, and occlusion of the superficial femoral artery did not correlate with the formation of FAAs. Ninety FAAs (88%) were treated surgically with an operative mortality rate of 3%. The most common surgical technique was aneurysmectomy with interposition prosthetic graft replacement. Durability of the repair was better if a simultaneous outflow procedure was performed and if the reconstruction was done before complications developed. Complicated FAAs are still responsible for significant morbidity and loss of life despite aggressive surgical management. Elective FAA repair is the preferred method of treatment.

Aneurysm↗
PubMed1987

The clinical pharmacist in drug research and development. An academic-industrial center.

The center for Pharmacodynamic Research represents a novel approach to academic-industrial research agreements that may be a useful model for others to pursue. It is designed to take advantage of the strengths of the company and the university in order to enhance the research conducted and to provide benefits to both. At the same time, it takes into account the responsibility of the university to provide graduate education and the need of industry for scientists in the future. The center was only recently established, however, and must be considered work in progress. Although it has been successful to this point, its value will only be established by longevity and productivity. We have every confidence that it will prove to be a valuable experiment.

Drug Industry↗
PubMed1986

LeVeen vs Denver peritoneovenous shunts for intractable ascites of cirrhosis. A randomized, prospective trial.

Peritoneovenous shunts (PVSs) have provided salutary effects on medically recalcitrant ascites, functional renal impairment, nutritional derangements, ventilatory embarrassment, and locomotion potential in patients with cirrhosis. While the LeVeen (LPVS) and Denver (DPVS) PVSs are most frequently implanted in such patients, postoperative complications of bleeding gastroesophageal varices, sepsis, and shunt occlusion occur with notable frequency. Addressing primarily the complication of PVS occlusion, a randomized prospective trial of LPVSs and DPVSs was conducted in cirrhotic patients with refractory ascites. From July 1, 1982 to July 1, 1984, 26 initial PVSs were implanted for hepatic-related intractable ascites. Twenty-two patients were eligible for randomization (cirrhosis, sterile ascites, initial PVS, total bilirubin level less than or equal to 6.0 mg/dL, prothrombin time less than or equal to 5-s prolongation, serum creatinine level less than or equal to 2.0 mg/dL [creatinine clearance rate greater than or equal to 20 mL/min], absence of recent [less than 30 days] bleeding gastroesophageal varices, or absent spontaneous encephalopathy). Twelve LPVSs and ten DPVSs were implanted; however, one patient with a DPVS was found to have hepatic polycystic disease and was excluded from analysis. All patients were followed up until death or Jan 1, 1985. The PVS patency determinations included contrast shuntography, technetium Tc 99m albumin scintigraphy, sequential manual compression (DPVS), and operative or autopsy observation. Using the Kaplan-Meier actuarial analysis, the LPVS patency proved to be highly superior to that of the DPVS, while survival was not significantly different. As LPVS and DPVS complications other than patency are comparable, the LPVS is preferred for its superior patency in cirrhotic patients with intractable ascites.

Actuarial Analysis↗
PubMed1986

Protein binding and pharmacokinetics of lincomycin following intravenous administration of high doses.

High-dose infusions of lincomycin 600, 1,200, and 2,400 mg were administered to 14 healthy, adult men. Using model-independent pharmacokinetics, it was found that the half-life, mean residence time, and steady-state volume of distribution of total drug increased with dose, whereas the same parameters remained unchanged for the unbound lincomycin. Although the mean clearance value for total drug increased, this change fell short of being significant at the 5% level and was associated with a decrease in unbound clearance following administration of the 2,400 mg dose. Protein binding studies using ultrafiltration gave direct evidence of saturable serum protein binding and indicated that binding involved at least two distinct classes of binding sites.

Absorption↗
PubMed1986

Temporal variation in triazolam pharmacokinetics and pharmacodynamics after oral administration.

The effect of time of day of drug administration on triazolam pharmacokinetics was studied in ten healthy men. In a randomized, two-way, crossover investigation, each subject received one 0.5 mg triazolam tablet either in the morning (7 AM) or evening (10 PM). Blood samples were obtained immediately before dosing and at selected times up to 12 hours after dosing. Triazolam plasma concentrations were determined by gas chromatography with electron capture detection. Psychomotor performance tests, including digit symbol substitution, card sorting by suits, and card sorting by fours, were administered, and the subjects' sedation was rated before drug and at two, ten, and 12 hours after drug administration. In addition, anterograde amnesia was assessed by showing objects to subjects two hours after dosing and testing aided and unaided recall at ten hours following administration. Triazolam's apparent elimination half-life after evening administration was significantly longer than after daytime ingestion (3.77 hr vs. 2.94 hr, P less than .05). There was no difference between times of dosing in total oral clearance or apparent volume of distribution. The absorption of triazolam was slower after evening administration, with an absorption half-life of 21.9 vs 13.3 minutes after daytime dosing. Performance decrements were significantly greater two hours after dosing in evening than in the daytime, but anterograde amnesia was more pronounced after daytime dosing. There was no effect on psychomotor performance at ten or 12 hours after administration in daytime or evening. These results indicate temporal variation in triazolam absorption and elimination.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Pharmacokinetics and clinical effects of alprazolam following single and multiple oral doses in patients with panic disorder.

The anxiolytic triazolobenzodiazepine alprazolam was administered to six male patients, aged 26 to 46 years, with panic disorder or agoraphobia (with panic attacks) to assess clinical effects and steady-state pharmacokinetics following multiple dosing at three levels: 3.0 mg/d, 6.0 mg/d, and 9.0 mg/d. Multiple-dose kinetics of alprazolam were compared with alprazolam disposition after a 1.0-mg oral dose in the same patients. Kinetic variables after the single dose were very similar to those reported previously for healthy young male volunteers. Mean values were peak plasma concentration, 19 ng/mL; time of peak, 1.33 hours after dosage; elimination half-life, 10.0 hours; total oral clearance, 1.11 mL/min/kg. During multiple dosage, mean steady-state plasma concentrations (Css) was proportional to dosing rate, and steady-state clearance was independent of dosage. Clinical improvement was rapid, with the greatest decrement in symptoms at the 3-mg/d dosage, at a mean Css of 30 ng/mL. Further improvement was not seen at 6 mg/d (Css, 62 ng/mL), or at 9 mg/d (Css, 103 ng/mL). Side effects, however, were directly related to dosage and plasma level, and increased progressively in number at the 3-, 6-, and 9-mg/d dosage levels. Thus, the disposition of alprazolam in young male patients with panic disorder is essentially identical to that in healthy male volunteers of similar age. Alprazolam clearance is independent of dose and plasma concentration up to daily doses of at least 9 mg/d, with steady-state plasma level proportional to dosing rate.

Administration, Oral↗
PubMed1986

Pyelovesicostomy as a form of urinary reconstruction in renal transplantation.

The development of ureteral obstruction or ureteral fistula formation in the renal transplant recipient usually requires surgical repair. This involves reconnecting the donor ureter to either the recipient ureter (ureteroureterostomy) or bladder (ureteroneocystostomy), or creating an anastomosis between the renal pelvis and recipient native ureter (pyeloureterostomy). Occasionally, the donor or recipient ureter is absent, necrotic or diseased so that a ureteroureterostomy, ureteroneocystostomy or pyeloureteral anastomosis cannot be performed. In 8 such cases we have performed a direct anastomosis between the donor renal pelvis and recipient bladder (pyelovesicostomy) with a followup of between 2 months and 11 years. In all 8 patients there has been no deterioration in renal function attributed to obstruction at the anastomotic site or to the free reflux between the bladder and renal pelvis. Because of the excellent short-term and long-term results of pyelovesicostomy, this procedure should be considered as an excellent alternative to pyeloureterostomy, ureteroureterostomy and ureteroneocystostomy in the reconstruction of the upper urinary tract of the renal transplant patient.

Adult↗
PubMed1986

An evaluation of population pharmacokinetics in therapeutic trials. Part I. Comparison of methodologies.

NONMEM, a computer program that uses the method of extended least-squares analysis, has been advocated as a means of obtaining estimates of population pharmacokinetic parameters when only fragmentary information can be obtained from subjects. To assess the performance of this program, we compared NONMEM with traditional methods for the estimation of population pharmacokinetic parameters with data collected during a phase III clinical trial of alprazolam. NONMEM estimates of the population mean clearance and its coefficient of variation were identical to the estimates obtained with traditional pharmacokinetic techniques. Moreover, NONMEM estimates of these parameters remained stable even when a few as three data points were available per subject. NONMEM estimates of the mean volume of distribution and its coefficient of variation appear to be overestimated, apparently because of the sampling scheme used to generate data for the NONMEM analysis. Suggestions for the effective use of NONMEM in clinical trials, to maximize the benefits of this approach, are provided. Our results lend further support for the use of NONMEM to estimate population pharmacokinetic parameters of a drug from data generated during phase III clinical trials.

Administration, Oral↗
PubMed1986

The natural history of carotid fibromuscular dysplasia.

Although graduated internal dilatation has proved to be an effective, safe, and durable operation for the treatment of symptomatic patients with fibromuscular dysplasia of the extracranial internal carotid artery, the role of surgical treatment in this entity remains unclear because the natural history is not well defined. Forty-nine patients, aged 29 to 82 years (mean, 58.5 years), with angiographically proven fibromuscular dysplasia of 88 internal carotid arteries have been evaluated since 1969. Twenty patients showed symptoms of focal cerebral or retinal ischemia, 10 patients had nonlateralizing neurologic symptoms, three patients sustained intracerebral hemorrhage, five patients complained of nonischemic symptoms, and 11 patients were asymptomatic. The three patients with intracranial hemorrhage and one person who suffered a massive stroke after angiography died within weeks of admission; no surgical therapy was performed. Initial management of the other patients included four internal carotid endarterectomies in four patients for associated atherosclerosis, one with simultaneous graduated internal dilatation; seven graduated internal dilatations in five patients; and one extracranial-to-intracranial bypass in a patient with occlusion occurring after graduated internal dilatation. Seventy-three nondilated arteries in 42 patients have been followed for up to 16 years (mean, 6.8 years). During this time only three patients have undergone surgical therapy; one carotid endarterectomy was done for an asymptomatic atherosclerotic lesion and two graduated internal dilatations in patients with nonfocal ischemia. Through follow-up of all 49 patients, none has had a new neurologic deficit. Fourteen patients who initially presented with focal ischemia were not treated surgically and all but one are now asymptomatic.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Continuous-flow apneic ventilation during thoracotomy.

Continuous-flow apneic ventilation (CFAV) by endobronchial insufflation of conditioned gas was evaluated in dogs during thoracotomy. In Group 1 (n = 6), dogs were anesthetized with pentobarbital (25 mg/kg). An endobronchial catheter (2.5 mm ID) was introduced into each mainstem bronchus using a fiberoptic bronchoscope and held in place by an endotracheal tube. Before the onset of CFAV (total flow 1.01 X kg-1 X min-1, the animals were paralyzed with pancuronium bromide and muscle relaxation was monitored with a peripheral nerve stimulator. The CFAV delivery system consisted of a flow meter, air/oxygen blender, oxygen analyzer, heated humidifier, and ultrasonic spirometer. Blood gas values were measured after 30 min of spontaneous ventilation, and CFAV with: 1) closed chest, fractional inspired O2 concentration (FIO2) 0.21; 2) open chest, FIO2 0.21; 3) open chest, FIO2 0.21, continuous positive airway pressure (CPAP) 5 mmHg; and 4) open chest FIO2 0.4, CPAP 5 mmHg. This last combination resulted in a mean PaO2 of 113.1 +/- 5.5 (SEM) mmHg and a PaCO2 of 35.0 +/- 2.1 (SEM) mmHg. In Group 2 (n = 6), animals with open chests were ventilated with CFAV (FIO2 0.4 and CPAP 5 mmHg) for 5 h. Adequate oxygenation and ventilation were achieved. PaCO2 after 5 h of CFAV was 41.8 +/- 1.9 (SEM) mmHg compared with 40.8 +/- 1.9 (SEM) mmHg during spontaneous breathing. PaO2 after 5 h of CFAV was 138.1 +/- 11.7 (SEM) mmHg. There were no significant changes observed in vascular pressures. Significant differences in other hemodynamic parameters were probably due to pentobarbital anesthesia. Adequate gas exchange can be achieved during CFAV in dogs with open chests for 5 h.

Animals↗
PubMed1986

Effect of nitrogen on carbon dioxide elimination during continuous flow apneic ventilation in dogs.

Continuous endobronchial insufflation of air in paralyzed animals (continuous flow apneic ventilation - CFAV) has been shown to maintain adequate oxygenation and carbon dioxide removal. CFAV in patients using oxygen resulted in adequate oxygenation but a mean rise in PaCO2 of 0.6 mmHg/min (0.08 kPa/min). This experiment compared carbon dioxide removal in dogs with air and oxygen. Ten dogs were anesthetized and paralyzed, and CFAV was used for 1 h with either air or oxygen in a randomized fashion. Adequate oxygenation was obtained with air and oxygen. Normal PaCO2 levels were obtained with air; however, in the animals where oxygen was used, PaCO2 levels rose to a mean of 6.45 +/- s.e. mean 0.4 kPa (48.5 +/- s.e.mean 3.2 mmHg).

Air↗