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J B Lefkowith

Publications and source records attributed to J B Lefkowith.

62 records · Page 4Linked to original sources
PubMed1986

Essential fatty acid deficiency: a new look at an old problem.

Essential fatty acid (EFA) deficiency is a useful tool to study the role of arachidonate and its metabolites in various physiologic and pathologic states. Recent studies have clarified the effects of EFA deficiency on membrane arachidonate and its metabolites, and have demonstrated that 20:3(n-9) (which accumulates in EFA deficiency) can be metabolized to a variety of eicosanoids. EFA deficiency has been shown to exert an anti-inflammatory effect. The mechanism of this effect may in part be mediated through a decrease in leukocyte leukotriene formation. In contrast, studies using the novel fatty acid, columbinic acid, have shown that the epidermal dysfunction seen in EFA deficiency may be a function of linoleate and its lipoxygenase metabolites rather than of arachidonate and the prostaglandins. Finally, it has recently been shown that EFA deficiency potentiates the effects of volatile anesthetics. EFA deficiency may thus provide a useful tool to investigate the molecular mechanism of these drugs.

Anesthetics↗
PubMed1986

Manipulation of rat brain fatty acid composition alters volatile anesthetic potency.

The molecular mechanism of volatile anesthetic action remains unknown. Attempts to elucidate this mechanism have been complicated by the absence of models in which changes in neuronal cellular properties can be correlated with changes in whole animal anesthetic effect. In this study we describe a model where diet-induced alterations in rat brain fatty acid composition are correlated with alterations in volatile anesthetic potency. Rats maintained on a fat-free diet showed significant depletion of arachidonic acid (20:4 omega 6; 5,8,11,14-eicosatetraenoic acid) and docosahexaenoic acid (22:6 omega 3; 4,7,10,13,16,19,-docosahexaenoic acid) in brain, and a corresponding increase in Mead acid (20: 3 omega 9; 5,8,11-eicosatrienoic acid). These fat-deprived rats were significantly more sensitive to all volatile anesthetics tested than were age-controlled rats on a normal diet. Parenteral supplementation of the fat-deprived animals with linolenic acid (18: 3 omega 3, 9,12,15-octadecatrienoic acid) completely reconstituted the docosahexaenoic acid content of brain without affecting anesthetic sensitivity. In contrast, supplementation of the fat-deprived rats with linoleic acid (18: omega 6; 9,12-octadecadienoic acid) caused a dramatic decrease in anesthetic sensitivity, but only a small change in whole brain arachidonate content. Further analysis revealed that linoleate supplementation of fat-deprived animals resulted in a preferential normalization of the arachidonate content of brain phosphatidylinositol as compared with other brain phosphoglycerides. These results demonstrate for the first time a correlation between changes in membrane composition and anesthetic effect, and indicate that the precise fatty acid composition (perhaps in specific phospholipids) of brain is important in the mechanism of volatile anesthetic action.

Anesthetics↗
PubMed1985

Paradoxical conservation of cardiac and renal arachidonate content in essential fatty acid deficiency.

The effects of essential fatty acid (EFA) deprivation on the arachidonate content and phospholipid composition of different tissues are quite diverse. When C57B1 mice were placed on a fat-free diet, hepatic liquids were readily depleted of arachidonate. In contrast, the renal cortex tenaciously retained arachidonate, whereas surprisingly the heart showed a doubling of its content of arachidonate. This increase in cardiac arachidonate was due to a four-fold increase in arachidonylphosphatidylethanolamine (PE). The renal cortex showed preservation of its arachidonate content in PE, phosphatidylserine, and phosphatidylcholine. Only phosphatidylinositol was depleted of arachidonate in heart or renal cortex. Using an in vivo labeling technique, it was shown that the liver incorporated most of the [1-14C]arachidonate initially following intraperitoneal injection. Over 11 days, as levels of labeled arachidonate fell in liver, the EFA-deficient heart accumulated arachidonate selectively in PE (8-fold greater than control), and the EFA-deficient renal cortex accumulated arachidonate in PE, phosphatidylserine, and phosphatidylcholine (2-3-fold greater than control). This uptake was shown to be specific for arachidonate over 20:3(n-9). Despite the conservation of cardiac and renal arachidonate seen with EFA deficiency, prostaglandin production by the isolated perfused EFA-deficient heart and kidney was markedly decreased relative to control in response to specific agonist stimulation with angiotensin II, although it was equivalent to control in response to nonspecific stimulation by ischemia. These data suggest that the liver serves to supply other tissues with arachidonate in EFA deficiency, and that the heart and renal cortex both contain mechanisms to accumulate arachidonate selectively in certain phospholipids. However, phosphatidylinositol, which is uniquely depleted of arachidonate in heart and renal cortex with EFA deficiency, appears to be the principal source of arachidonate in response to receptor-mediated agonists.

Animals↗
PubMed1985

Arachidonate metabolism in renal injury.

In conclusion, the evidence to date demonstrates that the enhanced arachidonate metabolism seen in hydronephrosis is responsible for the pathophysiological alterations observed in this model of renal injury. The balance between vasodilating prostaglandins and the vasoconstrictor thromboxane A2 may be critical in determining blood flow to the obstructed kidney. The alterations in arachidonate metabolism in this pathophysiologic state appear to result from the invasion of macrophages and the proliferation of fibroblasts in the cortical interstitium. Additionally, the macrophage appears to be necessary for the expression of the enhanced hormone-stimulated arachidonate metabolism. We envision the temporal sequence of events in this model to be as follows: ureter obstruction causes a mechanical disruption and/or immunologic stimulus in the cortex, which triggers a regional inflammatory response resulting in the proliferation of interstitial cells and the invasion of mononuclear cells. The macrophages, which are in direct contact with fibroblasts, are capable of releasing a factor that stimulates fibroblast proliferation, cortical microsomal cyclooxygenase activity, and prostaglandin E2 release (i.e., intrinsic arachidonate metabolism). The enhanced thromboxane synthetase levels and thromboxane A2 appear to come from the macrophage. The prostaglandin E2 and thromboxane A2 released modulate vascular tone. Prostaglandin E2 may also serve as an inhibitor of macrophage function. Two other models of renal damage also exhibit marked enhancement of renal prostaglandin synthesis and induction of thromboxane production: renal venous occlusion (32) and glycerol-induced acute renal failure (3). The finding that several models of renal damage have definite quantitative and qualitative alterations in the prostaglandin cascade reflects the importance of this pathway in renal pathophysiology.

Angiotensin II↗
PubMed1984

Macrophage-dependent arachidonate metabolism in hydronephrosis.

Unilateral ureteral obstruction in rabbits leads to an influx of macrophages into the kidney, a proliferation of interstitial cells, and an increase in arachidonic acid metabolism. The role of the macrophage in the metabolic changes of hydronephrosis was investigated by using endotoxin and nitrogen mustard. The in vivo administration of endotoxin, a macrophage agonist, 1 hour before perfusion of the hydronephrotic kidney markedly enhanced (fourfold to tenfold) the peptide-stimulated arachidonic acid metabolism of the perfused kidney. Nitrogen mustard made animals leukopenic and prevented the influx of macrophages into the hydronephrotic kidney. The peptide-stimulated arachidonic acid metabolism of these kidneys was suppressed, and no enhancement was seen with in vivo endotoxin administration. The macrophage thus appears to be an essential determinant of the enhanced arachidonic acid metabolism seen in experimental hydronephrosis. An inhibitory effect of prostaglandin E2 on macrophage function in this model of renal inflammation was also demonstrated. Hydronephrotic animals were given aspirin during the period of unilateral ureteral obstruction to prevent in vivo prostaglandin E2 production. In the perfused hydronephrotic kidney, the peptide-stimulated arachidonic acid metabolism, which appears to be a marker of macrophage function in this model, was enhanced by aspirin treatment.

Animals↗
PubMedDate not supplied

Economic and gastrointestinal safety comparisons of etodolac, nabumetone, and oxaprozin from insurance claims data from patients with arthritis.

This study was conducted to compare the effect of etodolac, nabumetone, and oxaprozin use on gastrointestinal (GI) safety and associated costs based on insurance claims information from practice settings. Data were obtained from a national claims database (MarketScan) for the years 1992 to 1994. The claims data of interest were for patients with arthritis who had used etodolac, nabumetone, or oxaprozin exclusively during a 9-month follow-up period (ONLY groups), or these drugs plus (PLUS groups) the other nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen, diclofenac, sulindac, piroxicam, ketoprofen, or indomethacin. For each group, we obtained information on the use of inpatient and outpatient services for GI-related events and the associated costs. All GI admissions were classified as NSAID-induced or possibly NSAID-induced events based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9 CM) codes. All outpatient upper GI ulcers or bleeding episodes were also identified by specific ICD-9 CM code. There were no significant between-group demographic differences. The proportions of patients with NSAID-induced and possibly NSAID-induced GI admissions were 0.1% and 0.4% for the etodolac-ONLY, 0.3% and 1.0% for the nabumetone-ONLY, and 0.1% and 0.5% for the oxaprozin-ONLY groups, respectively (P > 0.05), and a similar pattern was observed among the PLUS groups. In outpatient settings, 3.9%, 4.2%, and 4.9% of the etodolac-, nabumetone-, and oxaprozin-ONLY patients, respectively (P > 0.05), and 6.0%, 5.3%, and 4.7% of the etodolac-, nabumetone-, and oxaprozin-PLUS patients, respectively, had at least one upper GI ulcer/bleeding claim (P > 0.05). The total health care costs for 9 months were approximately $3000 each for the etodolac-, nabumetone-, and oxaprozin-ONLY groups. Oxaprozin, nabumetone, and etodolac had similar GI-safety and associated-costs profiles based on information from practice settings. Also, in patients who used multiple NSAIDs, the groups did not differ in their GI-safety and cost profiles.

Adult↗
PubMedDate not supplied

Comparative efficacy and safety of celecoxib and naproxen in the treatment of osteoarthritis of the hip.

Osteoarthritis (OA) is responsible for more disability of the lower extremities in the elderly than any other disease in the US. The pain associated with OA is the primary symptom leading to disability in these patients. Current ACR guidelines recommend consideration of acetaminophen for mild-to-moderate pain and conventional non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 specific inhibitors for moderate-to-severe OA symptoms. The aim of this study was to compare the efficacy and safety of the COX-1 sparing, COX-2 specific inhibitor, celecoxib, with the conventional NSAID naproxen, and placebo, in the treatment of OA of the hip. In this multicenter, randomized, placebo-controlled trial, 1061 patients with symptomatic OA of the hip were randomized to receive celecoxib at doses of 100 mg, 200 mg, or 400 mg/day; naproxen 1000 mg/day; or placebo, for 12 weeks. Patients were evaluated using standard measures of efficacy at baseline, 2-4 days after discontinuing previous NSAID or analgesic therapy, and after 2, 6, and 12 weeks of treatment. All doses of celecoxib and naproxen significantly improved the symptoms of OA, at all time points compared with placebo. This sustained treatment effect of celecoxib was dose dependent. In terms of pain relief and improvement in functional capacity, celecoxib 200 mg/day and 400 mg/day were similarly efficacious and were comparable to naproxen. Both drugs were generally well tolerated. Celecoxib at a dose of 200 mg/day is as effective as a standard therapeutic dose of the conventional NSAID, naproxen, in reducing the pain associated with OA of the hip.

Adult↗