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Biomedical subjects

D E Furst

Publications and source records attributed to D E Furst.

At least 199 records · Page 11Linked to original sources
PubMed1979

Measurement of clinical change in progressive systemic sclerosis: a 1 year double-blind placebo-controlled trial of N-acetylcysteine.

N-acetylcysteine was employed as a therapeutic agent in a 1-year, parallel, double-blind, placebo-controlled, prospective study of 22 patients with progressive systemic sclerosis (PSS). Patients were closely followed-up and were extensively evaluated at baseline, 6 and 12 months. Most parameters remained unchanged during 1 year of study in both the NAC and placebo groups, which showed the need for prolonged studies of drugs in PSS if definitive results are to be obtained. Over the year of the study the diffusing capacity decreased in both groups, while several other parameters measured both increased and decreased. Several simple measures of function and skin distensibility were tested and two (oral aperature and handspread) were reproducible and sensitive enough to measure moderate changes of disease activity. They may be useful in future trials of drug effect in PSS.

Acetylcysteine↗
PubMed1978

Analysis for 1,3-bis(2-chloroethyl)-1-nitrosourea by chemical ionization mass spectrometry.

We used chemical ionization mass spectrometry to quantify the cancer chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea in biological fluids. A stable isotope-labeled internal standard was added to the fluid being analyzed. Protonated molecular ion intensity ratios were determined by selected ion monitoring of sample extracts inserted directly into the chemical ionization source. Peak ratios were calculated for chlorine isotope ratios in their natural abundance, to verify the integrity of the data acquired, and to compute the drug concentration. The assay was applied to measure the compound in rat blood and plasma and in human plasma, and to monitor in vitro metabolism in rat-liver microsomal preparations. For the analyses we used a quadrupole mass spectrometer interfaced to a commercial computer system. Data-system characteristics are described.

Animals↗
PubMed1977

Salicylate metabolism in twins. Evidence suggesting a genetic influence and induction of salicylurate formation.

To evaluate the contribution of genetic influences on the individual variation in plateau serum salicylate levels, salicylate metabolism was studied in seven pairs of identical and six pairs of fraternal twins.Under the conditions of this study, after a single i.v. dose (40 mg/kg) of sodium salicylate, the serum salicylate concentration versus time curve approximated a straight line on linear coordinates (appeared approximately zero order). The slopes of the decay curves ranged between 0.64 and 1.02. The intrapair variation for identical twin pairs was significantly less than for fraternal twin pairs (P = 0.044). Likewise pleateau serum salicylic acid concentrations (milligrams/deciliter) and total salicylic acid excretion rate after multiple doses demonstrated significantly less intrapair variation for identical twins than for fraternal twins (P = 0.043 and 0.006). Plateau salicylurate excretion (milligram/kilogram per hour) differences after multiple dosing had a P = 0.067. Michaelis-Menton constant for salicylurate formation and hours to 50% excretion after the i.v. dose were not different when comparing identical and nonidentical twins. Salicylurate formation rates were increased after 3 days of oral therapy, and this induction phenomenon may account for much of the apparent discrepancy between genetic influences on salicylurate formation rates observed after single and multiple dose salicylate administration. This study suggests that the plateau concentration of serum salicylate varies among individuals given the same weight-adjusted dose in part because of genetically determined variations in their metabolism of salicylate.

Adolescent↗
PubMed1977

Oral radiographic changes in patients with progressive systemic sclerosis (scleroderma).

Intraoral and panoramic radiographs were made of 35 patients with progressive systemic sclerosis. Of those patients, 13 (37%) were found to have abnormally thickened periodontal ligament spaces. Six of the 35 demonstrated mild to significant resorption of the posterior mandibular angle. Three patients, including two showing angle resorption also had some degree of coronoid process destruction. All patients with this disease should receive initial and follow-up panoramic radiographic examinations to determine any osseous changes.

Adult↗
PubMed1975

Lack of effect of rheumatoid arthritis on clonixin metabolism.

The effect of rheumatoid arthritis on the metabolism of the analgesic, 2-(3-chloro-o-toluidino) nicotinic acid (clonixin), was evaluated in 12 patients with rheumatoid arthritis and in 12 matched healthy control subjects. Males, age-matched by decades, had no renal, gastrointestinal, or hepatic disease, and took no drugs during the study. Lower (p less than 0.02) serum albumins and higher globulins in the patients (albumin: 3.87 plus or minus 0.18; globulin: 3.14 plus or minus 0.28 gm/100 ml) than in the control subjects (albumin: 4.42 plus or minus 0.10; globulin: 2.36 plus or minus 0.08 gm/100 ml) were considered to be manifestations of rheumatoid arthritis. Fasting subjects were given single oral doses of 750 mg of clonixin. A spectrophotometric method was used to determine drug blood levels. Serum half-life was 1.45 plus or minus 0.12 hr in patients and 1.50 plus or minus 0.13 hr in control subjects (p greater than 0.5). Mean peak concentration developed at 1.7 hr and was 40.0 plus or minus 2.6 mug/ml for patients and 46.1 plus or minus 3.1 mug/ml for control subjects. Thus a single oral dose of clonixin results in comparable blood levels in male patients suffering from rheumatoid arthritis and in healthy control subjects.

Adult↗
PubMedDate not supplied

A double-blind trial of high versus conventional dosages of gold salts for rheumatoid arthritis.

In a double-blind study, patients were randomly selected for treatment using conventional doses (CD; 50 mg) or high doses (HD; 150 mg) of sodium aurothiomalate given weekly by injection. Twenty-three patients were assigned to the CD group and 24 to the HD group. Neither efficacy nor toxicity correlated with serum gold concentrations. Conventional doses were as efficacious as high doses with respect to both rapidity and degree of response. However, side effects were much more frequent and severe in the HD group. Thus there is no reason to recommend a 150 mg weekly dosage regimen.

Adult↗
PubMedDate not supplied

Muscle disease in progressive systemic sclerosis: diagnostic and therapeutic considerations.

Upon careful examination, 23 of 24 patients with progressive systemic sclerosis (PSS) were found to have abnormalities of muscle. Nineteen patients presented a homogenous pattern of muscle abnormalities, which untreated was associated with a stable course ("simple myopathy"). Three patients demonstrated inflammatory muscle disease indistinguishable from polymyositis while a fourth patient developed marked weakness associated with a generalized neuropathic process. Muscle enzymes, electromyogram, and muscle biopsy permitted distinction among the different muscle disorders, a distinction that could have prognostic and therapeutic importance.

Adult↗
PubMedDate not supplied

Biliary secretion of sulindac and metabolites in man.

The biliary secretion of sulindac and metabolites after a single 400 mg oral dose of the drug was studied in 3 elective gallbladder surgical patients following placement of an occludable T-tube in the common bile duct. Bile and systemic plasma were sampled at frequent intervals for up to 36 h postdose. The apparent biliary clearance (Vcl,bile) of the prodrug sulindac is about 25 times greater than that of the pharmacologically active sulfide metabolite. The total biliary flux of drug in normal man with an uninterrupted enterohepatic cycle, calculated from Vcl,bile and historic mean plasma drug AUCinfinity0 values, averages 144 and 12.2 per cent of the dose as sulindac and the sulfide metabolite, respectively. Thus, enterohepatic recycling of the drug in man is principally in the form of the prodrug which not only limits exposure of the intestine to the active moiety but also sustains systemic concentrations of active drug upon reabsorption of the prodrug.

Aged↗
PubMedDate not supplied

Changes in salicylate serum concentration and metabolism during chronic dosing in normal volunteers.

Steady-state serum salicylic acid (SA) concentrations and the formation rates of salicyluric acid (SU), salicylphenolic glucuronide (SPG), salicylacyl glucuronide (SAG), and gentistic acid (GA), and the excretion rate of unchanged SA were determined in three normal subjects following the administration of a single oral dose of acetylsalicylic acid (ASA) 37 mg kg-1 and during multiple dosing with ASA 56 mg kg-1 day-1. Steady-state SA concentrations fell 23 per cent during the 4-week study period (mean +/- SD: 239 +/- 35 to 183 +/- 23 micrograms ml-1; p less than 0.05). Absorption of drug did not decrease during this time. Significant increases in the Vmax for SU and SPG formation occurred between baseline and during multiple dosing. Mean Vmax SU increased from 0.93 to 1.68 mg kg-1 h-1 (p less than 0.05) and mean Vmax SPG increased from 0.09 to 0.19 mg kg-1 h-1 (p less than 0.05). First-order rate constants for the formation of SAG and GA and for the excretion of unchanged SA did not change significantly between baseline and multiple dosing. The mechanism for the decline in CpssSA with time during high-dose SA therapy is most likely due to the induction of the formation rates of the major metabolites of SA, namely SU and SPG.

Adult↗
PubMedDate not supplied

Effects of indomethacin and carprofen on renal homeostasis in rheumatoid arthritis patients and in healthy individuals.

The influence of carprofen and indomethacin on renal salt and water homeostasis was investigated. Carprofen is a new nonsteroidal antiinflammatory drug that is currently undergoing clinical trials in the United States. Both drugs were administered in usual clinical doses to steady state in six healthy individuals and in six individuals with rheumatoid arthritis. Blood pressure, weight, plasma renin activity, urine volume, creatinine clearance, fractional excretion of sodium and potassium, and free water reabsorption were determined. Both drugs were found to suppress plasma renin activity. Indomethacin suppressed plasma renin activity more than carprofen. Neither drug produced clinically significant changes in any of the other parameters. In healthy individuals and in patients with rheumatoid arthritis renal homeostatic mechanisms may compensate for the salt- and water-retaining effects of nonsteroidal antiinflammatory drugs.

Adult↗
PubMedDate not supplied

Comparison of tolmetin kinetics in rheumatoid arthritis and matched healthy controls.

We could find no significant differences in the kinetics of tolmetin when comparing five rheumatoid arthritis patients with moderate disease activity with a carefully matched group of normal healthy volunteers. Further, there were no discernible clinically significant differences in the kinetics of tolmetin when comparing a single dose to one week of therapy. These results, although limited by the small number of subjects involved and the large interpatient variability, suggest that it may be possible to extrapolate pharmacokinetic data from normals to patients with moderately active disease.

Adult↗
PubMedDate not supplied

Mechanism of action, pharmacology, clinical efficacy and side effects of auranofin. An orally administered organic gold compound for the treatment of rheumatoid arthritis.

The mechanism of action of auranofin, an oral organic gold compound used in the treatment of rheumatoid arthritis, is probably similar to the previously available parenteral gold compounds. Auranofin affects polymorphonuclear cells and monocytes at lower concentrations than gold sodium thiomalate and generally affects humoral and cell-mediated immunity in the same direction as the latter drug. The pharmacokinetics of auranofin are different from the intramuscular gold compounds. Auranofin is 20-25% orally absorbed and has less total body retention, greater fecal excretion, and less urinary excretion than gold sodium thiomalate. This may be due in part to its differing chemistry, including its lipophilicity and monomeric structure (at least in vitro). While many clinical studies are not yet complete, auranofin (6 mg/day) is clearly more effective than placebo for treating rheumatoid arthritis. Its efficacy relative to gold sodium thiomalate is not clear. Auranofin may be slightly less effective than gold sodium thiomalate, but because it is generally less toxic than intramuscular gold compounds, its therapeutic index may be more favorable.

Administration, Oral↗
PubMedDate not supplied

Clinical pharmacokinetics of oral and injectable gold compounds.

The pharmacokinetics of oral gold (auranofin) in some respects resemble, and in other respects differ from, those of existing parenteral gold compounds such as gold sodium thiomalate (GST). This may in part relate to physicochemical differences as GST is a water-soluble polymeric compound in vitro whereas auranofin is lipid-soluble and characteristically monomeric. Furthermore, intramuscularly administered gold is greater than 95% bioavailable, whereas only 20 to 30% of an orally administered dose of auranofin is absorbed. Following a standard 50mg intramuscular injection of GST, serum gold concentrations rise sharply, peaking between 4 and 8 mg/L in approximately 2 hours and declining to an average of 3 mg/L by 7 days. With repeated injections of GST stable serum concentrations of gold (3 to 5 mg/L) are eventually achieved (usually within 5 to 8 weeks) although absolute concentrations may vary widely between patients. On the other hand, long term treatment with auranofin is associated with lower and more stable serum concentrations of gold (0.5 to 0.7 mg/L), on the standard dosing regimen of 6 mg daily. Both compounds are retained within the body for prolonged periods. However, the amount of gold retained with auranofin is significantly less compared with GST (less than 5% of a tracer dose of auranofin--about 20% of the absorbed dose--is retained by 100 days whereas the retention for a single labelled dose of GST over a similar interval is greater than 50%). Excretory patterns of GST and auranofin also differ. Most of an absorbed dose of GST (greater than 70%) is excreted by the kidneys whereas only 50% of an absorbed (15% of an administered) dose of auranofin is excreted in the urine. Both compounds are avidly bound by plasma proteins and auranofin shows a particularly strong association with circulating cellular elements. In human subjects, parenterally administered gold is widely distributed among bodily tissues, showing a predilection for tissues of the reticuloendothelial system as well as the kidney and adrenal cortex. Comparable studies in humans are not available for auranofin but animal studies have shown comparatively less affinity for the liver, kidney and spleen. Valuable insight has been gained in analysing the comparative pharmacokinetics of oral and injectable gold compounds. Unfortunately, attempts to correlate pharmacokinetic findings with clinical response or pharmacodynamic changes, as a whole, remain largely unsuccessful with these agents.

Administration, Oral↗
PubMedDate not supplied

Pharmacotherapeutic strategies for disease-modifying antirheumatic drug (DMARD) combinations to treat rheumatoid arthritis (RA).

OBJECTIVE: To provide a rational model for the use of disease-modifying antirheumatic drug (DMARD) combinations in the treatment of rheumatoid arthritis. METHODS: The DMARDs used today were examined for their mechanisms of action, kinetics, and toxicity, and collected into tabular formats for easier comparison. From these tables, matrices of potential positive or negative interfaces among combinations were constructed. Finally, these matrices were used to examine the usefulness of DMARD combinations by comparing them with published data. RESULTS: When clearly overlapping cells were found with respect to mechanisms of action, kinetics, or toxicity (e.g., methotrexate [MTX] plus azathioprine or MTX plus auranofin) predictions were good. When knowledge in these areas of kinetics and/or mechanisms of action were inadequate, predictions and results were not always consonant (e.g. MTX plus sulfasalazine; D-penicillamine plus hydroxychloroquine). CONCLUSIONS: The approach demonstrated in this paper toward rational combination therapy is logical and can be successful, although its success is circumscribed by our knowledge about the drugs we use. The rational approach to combination therapy demonstrated in this article can: 1) help prevent the use of combinations unlikely to be effective; 2) can point toward directions for useful research; and 3) can even be used when physicians are faced with patients whose needs have exceeded our present scientific knowledge.

Antirheumatic Agents↗
PubMedDate not supplied

Future directions in pain management.

Relevant aspects of pain physiology and anatomy are reviewed, including hyperalgesia (an exaggerated response to normally mild stimuli) and allodynia (pain in response to normally non-noxious stimuli). Although the principal animal models do an excellent job at separating thermal, mechanoreceptor, and visceral aspects of pain, they are not very good predictive models because human pain is more complex. Human pain includes overlapping aspects of specific pain types, such as spontaneous and induced pain, and is modified by gender, stress, states of vigilance, and depression. Nonsteroidal anti-inflammatory drugs (NSAIDs) have both peripheral and central analgesic effects. While prostaglandin-mediated effects are clearly operative, there are also other potential mechanisms involved in many cases and these may be quite important in certain patients. Effects mediated by cyclooxygenase-1, leukotriene B4, and intracellular transcription elements such as peroxisomal proliferator-activated receptors gamma (PPARgamma) may account for part of the spectrum of NSAID actions. Future directions for analgesic research are many, but include the use of nitric oxide (NO) NSAIDs; the possibility of decreasing NO in the central nervous system; inhibiting the vanilloid receptor-1; inhibiting adenosine kinase; activating PPARgamma; and mimicking superoxide dismutase, as well as combinations of complementary-acting analgesics.

Analgesia↗