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Biomedical subjects

D L Earnest

Publications and source records attributed to D L Earnest.

16 recordsLinked to original sources
PubMed1992

Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention.

Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) widely used for treatment of inflammatory arthritis. Recent experimental and clinical studies suggest that piroxicam, as well as other NSAIDs, may be useful for chemoprevention of colon cancer. While there is less information regarding NSAIDs for chemoprevention of urinary bladder malignancy, there are compelling data which suggest that this should be evaluated. A major effect of NSAIDs is inhibition of cyclooxygenase, the rate-limiting enzyme for conversion of arachidonic acid to important signal molecules, including prostaglandins, which profoundly affect cellular functions in many tissues. The initial enzyme reaction leading to formation of prostaglandin H can be accompanied by cooxidation of xenobiotics resulting in extrahepatic and local tissue production of reactive products which are carcinogenic. The end product prostaglandins, especially prostaglandin E2 (PGE2), are biological modifiers which can significantly affect cell proliferation and tumor growth. High levels of PGE2 stimulate growth of certain tumor cell lines while inhibition of prostaglandin synthesis with indomethacin or piroxicam can cause suppression. The mechanisms for this effect are unclear. Studies in cultured cells exposed to indomethacin show inhibition of G1-to-S phase progression of the cell cycle and a reduction in overall DNA synthesis. It is unclear whether this effect on cell growth results from some direct action of the NSAID or a reduction in prostaglandins or indirectly from modulation of important control signals, such as calcium flux. In addition to cyclooxygenase, NSAIDs can inhibit activity of other enzymes, including phosphodiesterases and cyclic GMP-AMP protein kinases, which may be central to cancer initiation and promotion. NSAIDs can also interfere with transmembrane ion fluxes and with cell-to-cell binding. Prostaglandins can modulate a variety of immunological responses and thereby play an important role in host antitumor immunity. For example, high levels of tissue PGE2 are frequently associated with suppression of immune surveillance and killing of malignant cells. Conversely, immune responses are generally enhanced by drugs that inhibit prostaglandin synthesis. PGE2 can act as a feedback inhibitor for cellular immune processes, such as T-cell proliferation, lymphokine production, and cytotoxicity. This effect is also seen for macrophage activity and natural killer cell toxicity. In general, either increased production of PGE2 or increased sensitivity to normal amounts of PGE2 results in depressed cellular immunity. Cyclooxygenase inhibitors (NSAIDs) such as piroxicam which decrease PGE2 production can stimulate cellular immune function both in vitro and in vivo. A variety of tumor cell lines and human malignancies produce large quantities of prostaglandins.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Reactive oxygen species in the progression of CCl4-induced liver injury.

Pretreatment of rats with large doses of vitamin A (retinol) dramatically increased the hepatotoxicity of carbon tetrachloride (CCl4). Experiments were performed to elucidate the mechanism of this potentiation. Hypervitaminosis A was produced by oral administration of retinol, 250,000 IU/kg for seven days. CCl4 was then administered at a dose of 0.15 ml/kg, ip. This large dose of vitamin A did not enhance the biotransformation of CCl4, but did produce a 4-fold increase in CCl4-induced lipid peroxidation, as assessed by ethane exhalation. Because vitamin A has been shown to activate macrophages, it was hypothesized that this increased lipid peroxidation and liver injury resulted from the release of reactive oxygen species from activated Kupffer cells. By using a chemiluminescence assay, an enhanced release of free radicals was detected in Kupffer cells isolated from vitamin A pretreated rats. In addition, Kupffer cells from vitamin A pretreated rats displayed enhanced phagocytic activity in vitro, towards sheep red blood cells. In vivo, vitamin A pretreated rats cleared carbon particles from the blood 2-3 times faster than non-pretreated rats. In vivo administration of superoxide dismutase (SOD) 2 hr after CCl4 exposure did not influence CCl4 toxicity in control rats but did block the enhanced ethane exhalation and also the potentiation of CCl4 liver injury in vitamin A treated rats. Administration of methyl palmitate, an inhibitor of Kupffer cell function, did not inhibit CCl4 toxicity in control rats, but did effectively block enhanced ethane exhalation and potentiation of CCl4 injury in vitamin A treated rats. We conclude that potentiation of CCl4 hepatotoxicity by hypervitaminosis A is mediated in part by reactive oxygen species released from activated Kupffer cells.

Animals↗
PubMed1991

Maintenance therapy in peptic ulcer disease.

The maxim "once an ulcer, always an ulcer" is still an appropriate description for the chronic nature of peptic ulcer disease. The goals for treating patients with ulcer disease are to relieve symptoms, heal the acute ulcer, reduce the risk of ulcer recurrence and complications, and decrease the economic impact of this chronic disease while maintaining the patient's quality of life. Patients with documented peptic ulcer disease should be carefully evaluated and a treatment plan devised that takes into account the possible need for maintenance therapy. Risk factors that seem to reflect a high likelihood of ulcer recurrence should be identified early in all ulcer patients and attempts made to minimize or correct them in the future. Assuming that a diagnosis of peptic ulcer disease has been firmly established and an adequate period of drug treatment makes complete ulcer healing likely, a reasonable way to proceed is outlined in Figure 4. If the patient is young and generally healthy, has an uncomplicated ulcer and few risk factors favoring ulcer relapse, either no treatment or symptomatic selfcare would be reasonable. If one chooses the latter course, the patient can be given a prescription for 3 to 6 months of medication and told to take full therapy for any recurrent symptoms, continuing the treatment until symptoms are relieved. The failure of such treatment to relieve symptoms after 2 to 3 weeks, the onset of alarming symptoms such as intense pain, vomiting, or melena, or possibly the exhaustion of the 6-month supply of medication with continued mild symptoms should lead to reevaluation. Alternatively, such a patient could be managed with no therapy and seen again if ulcer symptoms recur and reevaluated for further diagnosis and treatment. Obviously, patients who are candidates for these approaches to postulcer healing management are those with a low risk for ulcer recurrence and who are likely to be compliant with follow-up advice. Accordingly, careful patient selection seems most important in prescribing symptomatic self-care or intermittent full-dose maintenance treatment. On the other hand, if the patient has had a complicated course of ulcer disease, such as bleeding, or has a significant number of risk factors that would make early ulcer relapse highly likely, it would be prudent to institute continuous maintenance therapy while working to reduce or eliminate the adverse risk factors. Any relapse of symptomatic ulcer disease during noncontinuous maintenance therapy should indicate the need for return to a continuous dosing program.(ABSTRACT TRUNCATED AT 400 WORDS)

Histamine H2 Antagonists↗
PubMed1990

Controlling gastric pH: the impact of newer agents on the critically ill patient.

The critically ill patient is at increased risk for developing erosive injury of the stomach, duodenum, and esophagus. To date, the most effective way to prevent and treat this problem is by assuring excellent intensive care support and by reducing gastric acid secretion. The histamine H2-receptor antagonists (H2RAs) are effective in both prevention and treatment of such gastric mucosal injury. Newer agents are available that have potential for use in this setting, although none have been studied as extensively in critically ill patients as have the H2RAs. These new agents include proglumide, pirenzepine, misoprostol, omeprazole, and somatostatin. To date, only the latter has been extensively studied in critically ill patients. Omeprazole, which suppresses acid very effectively, may be problematic in the critically ill, limited by its oral dosage form, acid-labile properties, and potential drug interactions.

Alprostadil↗
PubMed1990

NSAID-induced gastric injury: its pathogenesis and management.

Injury to the gastric mucosa associated with the use of aspirin and other NSAIDs appears to be principally attributable to impairment of mucosal defense mechanisms against damage by acid and pepsin, that are mediated largely by prostaglandins. Modification of the drug dose or delivery system and substitution of a less gastrotoxic agent, such as a nonacetylated salicylate, are among the initial approaches that have been used to reduce the risk of NSAID-induced gastric injury. Other recommended measures include the avoidance of cigarettes, concentrated alcohol, and combination therapy with multiple NSAIDs. In high-risk patients, especially those with previous peptic ulcer disease, prophylactic therapy with a cytoprotective or acid-secretion-reducing drug is indicated. Drugs often used in the treatment of NSAID-associated mucosal damage include H2-receptor blockers, which inhibit gastric acid secretion, and agents such as synthetic prostaglandins and sucralfate, which improve mucosal defense. More potent inhibitors of gastric acid, such as drugs which block H+/K+ ATPase, may offer improved results for healing NSAID-induced gastric ulcers resistant to other therapy. Because NSAID-induced gastric lesions are not always accompanied by symptoms, patients receiving these drugs must be closely monitored for signs of gastric injury. Small ulcers can generally be healed with antiulcer medications. In patients with larger ulcers, withdrawal of NSAID therapy is usually required, at least until healing has occurred.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1978

Sex differences in hepatic sulfation of taurolithocholate in the rat.

Metabolism of the bile salts by formation of sulfate esters is catalyzed by bile salt sulfotransferase, an enzyme isolated from rat liver and kidney. The activity of bile salt sulfotransferase was measured in liver and kidney of male and female rats and in oophorectomized rats with or without estrogen replacement. In vitro sulfotransferase activity was correlated with in vivo sulfation by measuring the percentage of an infused dose (0.03 micron per 100 g per min) of taurolithocholate, which was excreted in bile as the sulfate. The activity of sulfotransferase in liver was higher in females (26.3 +/- 3.0 pmoles per mg of protein per min) than in males (9.6 +/- 3.9) and was lower (12.1 +/- 3.8) after oophorectomy. The decrease in activity was prevented by replacement of estrogen. Renal sulfotransferase activity did not differ between the sexes and was unaffected by oophorectomy. Hepatic sulfotransferase activity measured in vitro correlated with in vivo sulfation of taurolithocholate. This study shows definite sex differences in hepatic bile salt sulfotransferase activity, which in females is affected by the presence of estrogen. The correlation between in vitro sulfotransferase activity and in vivo bile salt sulfation suggests that bile salt sulfotransferase is responsible for bile salt sulfation in vivo.

Animals↗
PubMed1977

Hyperoxaluria correlates with fat malabsorption in patients with sprue.

The effect of fat malabsorption on the absorption and renal excretion of dietary oxalate was studied in four patients with sprue and in two patients with dermatitis herpetiformis and sprue-like jejunal histology. Hyperoxaluria was present in all patients with sprue when fat malabsorption was severe. Urinary oxalate excretion decreased in two of the three patients with coeliac sprue when their fat malabsorption had improved after three months of dietary gluten restriction. Neither patient with dermatitis herpetiformis and sprue had steatorrhoea. In these patients, urinary oxalate excretion was always within normal limits. A significant positive linear relationship (y=28.25 +4-84x; r=0-82; P less than 0-01) was demonstrated between faecal fat and urinary oxalate excretion. The results of this study support the concept that severe malabsorption of dietary fat plays a primary causative role in enteric hyperoxaluria.

Calcium↗
PubMed1975

Sulfation and renal excretion of bile salts in patients with cirrhosis of the liver.

Renal excretion of bile salts was studied in 17 patients with cirrhosis of the liver. The average quantity of bile salts in urine was 10.2 plus or minus 8.3 mg per 24 hr, 56% of which were sulfated. Of the individual urinary bile salts, 24% oithocholate were sulfated. In contrast, neither sulfated nor nonsulfated bile salts could be detected in urine from 2 normal subjects. Kinetics of bile salt metabolism was measured in 2 of the cirrhotic patients after oral administration of [14C] cholate and [3H] chenodeoxycholate. Approximately 3 to 12% of bile salts synthesized in liver were excreted in urine. Most urinary bile salts (76 to 80%) were sulfated, whereas only 4 to 5% of serum bile salts and 7 to 10% of biliary bile salts were sulfated. Renal clearance of cholate was more than 3 times greater than the clearance of chenodeosycholate or deoxycholate. Renal clearance of sulfated bile salts was 20 to 200 times greaterthan the clearance of the corresponding nonsulfated bile salts.

Adult↗
PubMedDate not supplied

Ethanol and cytokine secretion.

Cytokines are regulatory polypeptides secreted during the generation of an immune or inflammatory response by lymphocytes, cells of the monocyte/macrophage series, and a variety of other cell types. Alterations in the production, site of action, or metabolism of cytokines by exogenous factors, such as ethanol (EtOH), may have deleterious effects on the immune system as a whole. EtOH has been implicated in the onset of a variety of immune defects in vivo including effects on the production of cytokines critically involved in inflammatory responses (tumor necrosis factor, interleukin 1 and interleukin 6). In this review, we examine current knowledge regarding the effects of EtOH on the release of cytokines in humans and in animal models, in vitro and in vivo, which may help to elucidate the adverse actions of EtOH on mammalian immune systems.

Animals↗
PubMedDate not supplied

Physiologic changes during colonoscopy.

We prospectively evaluated multiple physiologic parameters in 104 consecutive unselected patients undergoing elective colonoscopy. Changes observed during colonoscopy were then correlated with the type of anesthesia and level of sedation, position of the endoscope and presence of looping, existence of comorbid medical conditions, concomitant medication usage, and the occurrence of endoscopy induced pain. Clinically important changes in O2 saturation (54%) and in blood pressure (44%) were most frequently noted. Less frequent were changes in pulse (15%) or respiratory rate (4%). These clinically significant changes were associated with induction of anesthesia or endoscope looping and pain in 58 to 62% of the patients. In the remainder of patients, no obvious factor was associated with the observed alterations in physiologic parameters. There was no correlation with presence of comorbid medical conditions, use of concurrent medication, dose of anesthesia, level of sedation, and/or colon segment reached by the endoscope. Although there was no apparent morbidity associated with the induced changes in physiologic parameters, these data suggest that certain patients may be at increased risk of procedure-related morbidity and support the need for physiologic monitoring in high-risk patients.

Adult↗