bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug Therapy of Inflammatory Bowel Disease
Authors: Sack David M. , Peppercorn Mark A.
Published: December 2015

Although the etiology of inflammatory bowel disease is unknown and specific therapy is unavailable, enough information on existing empiric agents is availble to allow rational therapy. These agents include sulfasalazine, steroids, immunosuppressive drugs, metronidazole and cholestyramine.

Sulfasalazine is a two‐part molecule that depends on bacterial cleavage in the colon to deliver locally acting 5‐aminosalicylate, whose mechanism of action may relate to inhibition of prostaglandin synthesis. The other half of the molecule, sulfapyridine, is responsible for most of the side effects of the drug. While the efficacy of sulfasalazine in the treatment and prevention of attacks of ulcerative colitis is well established, its use in Crohn's disease appears to be limited to patients with active colitis and ileo‐colitis. Sulfasalazine is of major benefit in preventing relapses in patients with ulcerative colitis in remission. New formulations of 5‐aminosalicylate may allow delivery of the apparently active moiety to the small bowel and colon without concomitant sulfapyridine toxicity.

Corticosteroids are highly effective in acute attacks of ulcerative colitis and Crohn's ileitis and ileo‐colitis; the mechanism of antiinflammatory action remains speculative. However, maintenance therapy with steroids is ineffective in preventing relapses or recurrent attacks of either ulcerative colitis or Crohn's disease. Steroid enemas allow topical administration to patients with distal colitis and proctitis with few systemic side effects. In children with growth failure associated with active Crohn's disease, amelioration by steroid therapy may actually restore normal growth.

Immunosuppressive agents such as azathioprine and 6‐mercaptopurine are of little value in active Crohn's disease when administered alone; however, in combination with other agents they may help diminish steroid dose, close fistulae and prevent relapse. Their mode of action likely depends on long‐term cytostatic effects on immune effector cells. Concern for leukopenia and the development of late malignancy has limited their use to patients not responding to other therapies.

Metronidazole, an antimicrobial agent that is effective against anaerobes, has recently been shown useful in Crohn's disease involving the colon and perianal area. Its mechanism of action is uncertain, but may be related to its antibacterial actions on anaerobes.

Cholestyramine can be successfully used to control bile salt‐induced diarrhea in Crohn's patients with terminal ileal resections.

Effective drug therapy of inflammatory bowel disease is only part of a total program of management including reassurance, frequent explanations, well‐timed use of surgery, and an understanding physician.
Etomidate: A New Intravenous Anesthetic Induction Agent
Authors: Giese Jeffrey L. , Stanley Theodore H.
Published: December 2015

Currently available anesthetic induction agents provide adequate hypnosis but are not ideal, particularly in the high risk patient (ASA class III‐V), because most cause myocardial and/or respiratory depression and some have other important side effects. Etomidate was recently marketed as an intravenous anesthetic induction agent. It is a non‐barbiturate hypnotic without analgesic properties that has less cardiovascular and respiratory depressant actions than sodium thiopental, even in patients with minimal cardiovascular reserve. Laboratory studies indicate that etomidate is approximately 25 times more potent and has a therapeutic index six times greater than sodium thiopental. In contrast to most other induction agents, etomidate does not cause histamine release. Furthermore, tolerance does not occur with repeated administration. Etomidate's rapid distribution half life (t1/2α = 2.81 ± 1.64 min), short elimination half life 1/2β = 3.88 ± 1.11 hr) and rapid clearance (954 ± 178 ml/min) explain its rapid onset and short duration of action. The compound produces electroencephalographic changes and effects on cerebral blood flow, metabolism and intracranial pressure that are similar to sodium thiopental, suggesting that it may have a place in neurosurgery and as a “brain protective” agent in patients at risk of a brain hypoxic insult. Etomidate did not affect hepatorenal and hematologic function after repeated injections in animal toxicology studies, but few investigations addressing its effects on hepatic, renal, and neuromuscular function in man have been accomplished. The most noticeable side effects of etomidate include myoclonia, pain on injection and postoperative nausea and vomiting. Etomidate's most likely application will be as an anesthetic induction agent in patients with significant cardiovascular and/or respiratory disease or increased intracranial pressure, in patients with evidence of allergy to the barbiturates, and in combination with nitrous oxide in patients about to undergo short operations.
Mechanism of Action, Pharmacology, Clinical Efficacy and Side Effects of Auranofin: An Orally Administered Organic Gold Compound for the Treatment of Rheumatoid Arthritis
Authors: Furst Daniel E.
Published: December 2015

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.
Amoxicillin and Potassium Clavulanate: An Antibiotic Combination Mechanism of Action, Pharmacokinetics, Antimicrobial Spectrum, Clinical Efficacy and Adverse Effects
Authors: Weber David J. , Tolkoff‐Rubin Nina E. , Rubin Robert H.
Published: December 2015

The combination of amoxicillin and potassium clavulanate will soon be marketed in 2:1 and 4:1 fixed ratio dosage forms. In vitro and in vivo evidence suggests that clavulanic acid, a potent inhibitor of many bacterial beta‐lactamase enzymes, will increase the spectrum of amoxicillin to include, at achievable serum concentrations, Haemophilus influenzae, H. ducreyi, Neisseria gonorrhoeae, Staphylococcus aureus and Branhamella catarralis and, at achievable urine levels, many beta‐lactamase‐producing strains of E. coli, Klebsiella, Proteus and Citrobacter. Both amoxicillin and clavulanic are well absorbed after oral administration, reach peak serum levels in 40–120 min and have similar half‐lives of 45 to 90 min. This combination will be suitable for the treatment of complicated urinary tract infections, otitis media, sinusitis and respiratory tract infections. However, precise recommendations for its use will need to await further clinical trials that compare amoxicillin/clavulanate to alternative therapies.
Ketoconazole: An Orally Effective Antifungal Agent Mechanism of Action, Pharmacology, Clinical Efficacy and Adverse Effects
Authors: Smith Edgar B. , Henry John C.
Published: December 2015

Ketoconazole is a new, orally effective, antifungal agent. It is an imidazole compound and like other antifungals of this group, has a wide spectrum of use. Effectiveness has been shown in a variety of deep fungal infections as well as in superficial infections such as candidiasis, dermatophytosis and tinea versicolor. Although it first appeared to be a remarkably safe agent associated with only minor side effects, with more use it has become apparent that symptomatic drug‐induced hepatitis occurs in approximately 1 in 12,000 patients. This idiosyncratic side effect and potential effects on testosterone and cortisol synthesis may limit the use of ketoconazole to deep fungal infections and severe recalcitrant superficial infections of the skin.
Selectivity of Bevantolol Hydrochloride, a β‐Adrenoceptor Antagonist, in Asthmatic Patients
Authors: Löfdahl Claes‐Göran , Svedmyr Karin , Svedmyr Nils
Published: December 2015

Bevantolol hydrochloride, a new β‐adrenoceptor antagonist, has been shown to be cardioselective in animals. To evaluate its selectivity in humans, a double‐blind, crossover study was conducted in 8 asthmatics. Following a single oral dose of placebo, bevantolol 75 or 150 mg or propranolol hydrochloride 40 mg, forced expiratory volume in 1 second (FEV1), heart rate, blood pressure and skeletal muscle tremor were measured before and after 4 increasing intravenous doses of terbutaline sulfate to establish terbutaline dose‐reponse curves. The FEV1 decreased after all active treatments. During terbutaline infusions there was an increase in FEV1 after both bevantolol doses and placebo. The terbutaline dose‐response curve after bevantolol shifted to the right, however. After propranolol, there was no increase in FEV1 during terbutaline stimulation. Heart rate and skeletal muscle tremor showed a similar pattern during the experiment. In dosages that have previously been shown to produce at least the same degree of blockade of exercise‐induced tachycardia, bevantolol has less influence on terbutaline‐induced bronchodilation, heart rate increase and skeletal muscle tremor than did propranolol. Thus bevantolol has relative β1‐adrenoceptor antagonist selectivity. Drawing upon the results of a previous study in the same patients, we believe bevantolol, atenolol and metoprolol have similar β1‐selectivity.
Surgical Antimicrobial Prophylaxis: Principles and Guidelines
Authors: Burnakis Thomas G.
Published: December 2015

Antimicrobial prophylaxis for surgical procedures is an area that is recognized as being subject to individual clinical variations. This review gives practitioners some basic principles of rational prophylaxis as defined by the medical literature. In addition, this literature is evaluated and condensed to provide clinicians with guidelines for particular procedures: obstetric, gynecologic, gastric, biliary, colonic, urologic, cardiac, thoracic, vascular, orthopedic and head and neck. Each section concludes with recommendations for the clinically most accepted prophylactic regimens. Antibiotics discussed include not only the older agents, but where good information exists, the newer cephalosporins. The suggested regimens consider efficacy, safety and cost as determinants in rational prescribing. Although research into even shorter, and perhaps more cost‐effective, regimens continues, this compilation lists state‐of‐the‐art recommendations.
Preclinical Pharmacology of Buspirone Hydrochloride
Authors: Skolnick Phil , Paul Steven M. , Weissman Ben Avi
Published: December 2015

Buspirone is an azaspirodecanedione that has anxiolytic actions in man and anticonflict actions in experimental animals. In contrast to many commonly used anxiolytic agents, buspirone does not appear to have significant sedative, muscle relaxant or anticonvulsant actions. Consequently, it has been termed an “anxioselective” agent. The effects of buspirone and related compounds have been examined in a number of neurotransmitter systems that have been linked to the actions of other anxiolytic agents. Buspirone has been shown to affect dopaminergic, serotonergic and noradrenergic pathways, as well as the GABA‐benzodiazepine receptor chloride ionophore complex. Nonetheless, the doses (in vivo) and/or concentrations (in vitro) of buspirone (and related compounds) needed to affect these systems are not consistent with a causal relationship between the anxiolytic actions of buspirone and any of these systems. The neurochemical mechanism by which buspirone and related compounds exert both anticonflict and anxiolytic actions remains unknown.
Glyburide: A Second‐generation Sulfonylurea Hypoglycemic Agent
Authors: Feldman Jerome M.
Published: December 2015

Glyburide, a second‐generation hypoglycemic sulfonylurea, is 200 times as potent as tolbutamide. This increase is due to greater intrinsic hypoglycemic potency of the molecule rather than to a prolonged biologic half‐life. Glyburide is inactivated by the liver to 4‐trans‐hydroxyglyburide and 3‐cis‐hydroxyglyburide; 50% of these compounds is excreted in the urine and 50% in the bile. Although the serum concentration of glyburide can be measured by radioimmunoassay and high‐performance liquid chromatography, the importance of its serum concentration in the reduction of hyperglycemia is not yet established. Glyburide has a therapeutic effectiveness comparable to that of the first‐generation sulfonylurea chlorpropamide; however, it has a lower frequency of adverse effects. To date it has a low frequency of clinically significant interactions with other drugs. Glyburide should not be prescribed for patients with liver disease or significant renal disease. Because glyburide is a potent hypoglycemic agent, it should be prescribed in small initial doses, particularly for elderly patients with diabetes. At the present time there is no definite evidence that it modifies the increased risk of cardiovascular disease of diabetic patients. Although glyburide is a potent stimulator of pancreatic insulin secretion after short‐term administration, an additional mechanism of action during long‐term administration is to decrease the resistance of muscle and liver to the action of insulin. It is a useful medication for patients with type II diabetes whose hyperglycemia is not adequately reduced by dietary management and exercise. It can be used as the initial drug in these patients or as the replacement drug for those with primary or secondary failure during therapy with first‐generation sulfonylureas.
Midazolam: The First Water‐soluble Benzodiazepine; Pharmacology, Pharmacokinetics and Efficacy in Insomnia and Anesthesia
Authors: Kanto Jussi H.
Published: December 2015

Midazolam is a 1,4‐benzodiazepine derivative with a unique chemical structure: depending on environmental pH, the drug can produce highly water‐soluble salts (pH < 4) or exist in lipophilic diazepine ring‐closed form (pH > 4). This characteristic contributes to rapid onset of action and to good local tolerance after parenteral administration. After both oral and parenteral administration, midazolam has a fast absorption rate and is rapidly excreted, with a half‐life of only about 2 hours. A reasonably good correlation has been found between plasma levels and clinical effects, indicating a fast but brief response. As a hypnotic, midazolam is mainly indicated in insomniac patients with difficulties in falling asleep or having a pathologic sleep pattern during the first half of the night. No marked hangover effects are present the next morning. In anesthesiology, midazolam appears to be a useful, short‐acting, sedative‐anxiolytic and amnesic premedicant after both oral and parenteral administration. In minor surgery, however, the slow, unpredictable onset and variable duration of action, as compared with thiopental, may inhibit its routine use as an induction agent, especially in young patients, without heavy premedication. In major surgery, midazolam is an alternative to thiopental for induction of anesthesia in spite of its slow, variable induction time. Its advantages include good cardiovascular stability, transient and mild respiratory depression, low frequency of venous irritation, production of anterograde amnesia and short duration of action in comparison with other benzodiazepines.
An Update on Sodium Valproate
Authors: Rimmer Elizabeth M. , Richens Alan
Published: December 2015

Sodium valproate has been in clinical use for the treatment of epilepsy in Great Britain since 1973 and in the United States since 1978. It is chemically quite different from the existing antiepileptic drugs. Although most authorities concentrate on its modification of GABAergic inhibitory transmission in the central nervous system, its mechanism of action remains obscure. It has been shown to be an effective antiepileptic drug in a wide variety of seizure types, but clinically, its major use to date has been in generalized seizures. It is particularly effective in photosensitive epilepsy and myoclonus. Most adverse reactions to sodium valproate are mild and reversible, but with increasing experience, the drug's rare, idiosyncratic, adverse effects are becoming apparent, particularly hepatotoxicity and teratogenicity. The role of therapeutic drug monitoring in the management of patients taking sodium valproate is controversial.
Initial Treatment of Adult Patients With Essential Hypertension
Authors: Moser Marvin
Published: December 2015

The stepped‐care approach to the treatment of hypertension suggests the use of a diuretic or, in some cases, a beta blocker as intitial monotherapy. If either of these agents proves to be ineffective, the other can be tried as monotherapy. Stepped‐care suggests the use of different classes of drugs that affect different mechanisms related to hypertension at various stages of treatment. Although empiric, the concept makes good physiologic sense. Results of its use in major clinical trials, as well as an extensive private practice experience, suggest that in a large majority of patients, hypertension can be controlled with relatively little expense, few titration problems and a high rate of adherence. Advocates of individualization of care, or sequential monotherapy, base their suggestion on theory, but widespread use of this approach would make management more complex and more expensive, and would probably decrease adherence to long‐term treatment. Stepped‐care treatment allows for adequate individualization and a wide choice of drugs, and should continue to be employed unless data are obtained that demonstrate a better outcome with sequential monotherapy or other more complex approaches.
II. Alternating Monotherapy is the Preferred Treatment
Authors: Kaplan Norman M.
Published: December 2015

The choice of initial therapy of hypertensive patients may be critical in the long‐term efforts to reduce premature cardiovascular morbidity and mortality. In the 1984 report of the third Joint National Committee (JNC), significant changes in the usual approach to initial therapy were suggested, including a more conservative approach toward the institution of drug therapy, more liberal use of nondrug therapies and broader choices for the initial drug. I support these changes and believe that even a greater number of choices for initial therapy should be considered. I am increasingly concerned about the hazards of diuretic therapy and believe that for most patients, an adrenergic inhibitor is preferable for first drug. Rather than limit the type of adrenergic inhibitor to a beta blocker as suggested in the JNC report, either an alpha blocker or a centrally acting drug may be preferable. In the near future, calcium antagonists will likely also become logical choices.
Anticonvulsant Therapy After Neonatal Seizures—How Long Should it Be Continued?
Authors: Gal Peter
Published: December 2015

The risk of epilepsy or afebrile seizures after convulsions in the neonatal period is compared with the benefits and risks of chronic use of anticonvulsants in infants. The best predictor of later seizures appears to be the presence of moderate to severe neurologic damage. In the absence of such deficits, the risk is below 10%, but increases to 50–70% when damage is severe. A comparison of reports indicates no difference in seizure recurrence rates when anticonvulsants are stopped early in the neonatal period or when treatment is longer, even in the high‐risk group. After phenobarbital is discontinued and the plasma concentration falls below the therapeutic range, seizures usually recur within a few days or not for several months. Only 50% of these seizure types are expected to be controlled with phenobarbital. Long‐term phenobarbital use is associated with impaired cognitive function in infants and toddlers, and retarded brain growth in rodent studies.
A Simplified Dosing Method for Initiating Vancomycin Therapy
Authors: Lake Kathleen D. , Peterson Charles D.
Published: December 2015

Vancomycin dosing regimens should be individualized for each patient. The routine use of standard doses 500 mg every 6 hours or 1.0 g every 12 hours regardless of patients' age, weight or kidney function is no longer appropriate. A simplified method for initiating vancomycin therapy was developed and evaluated prospectively in 30 patients. Average doses of 8.3 ± 0.6 mg/kg lean body weight (rounded to the nearest 50 mg) were administered to patients with varying degrees of renal function (estimated creatinine clearances 19–113 ml/min). The dosing interval was predicted by the patient's estimated creatinine clearance. Our simplified schedule resulted in desired serum levels and required no modification in 25 of 30 patients. Only slight dosage changes were needed in the remaining five patients. Mean peak and trough serum concentrations of vancomycin were 26.9 ± 5.8 μg/ml (range 18.8–39.7 μg/ml) and 7.7 ± 2.0 μg/ml (range 4.5–11.8 μg/ml) respectively. Our regimen is practical and simple and requires limited patient information.
The Effect of Ranitidine and Cimetidine on Single‐dose Diltiazem Pharmacokinetics
Authors: Winship Linda C. , McKenney James M. , Wright Jackson T. , Wood John H. , Goodman Robert P.
Published: December 2015

The effects of two histamine 2‐receptor antagonists, cimetidine and ranitidine, on the single‐dose pharmacokinetics of diltiazem were studied in 6 healthy subjects. A single 60‐mg oral dose of diltiazem was administered alone, after ranitidine 150 mg twice daily for 7 days, and after cimetidine 300 mg 4 times a day for 7 days. Plasma samples were obtained over a 10‐hour period and analyzed for the parent drug and one of its metabolites, deacetyldiltiazem (DAD). Concurrent cimetidine produced a significant (p < 0.05) increase in diltiazem levels at most time points, in peak concentration and area under the concentration‐time curve. These variables were also increased during concurrent ranitidine administration but did not reach statistical significance. The DAD plasma concentration was below measurable levels during the control phase but increased during concurrent cimetidine and ranitidine administration. Caution should be exercised when diltiazem is administered concurrently with cimetidine and possibly, ranitidine.
Nonsteroidal Antiinflammatory Drugs and Aspirin—Analyzing the Scores
Authors: Heller Caren A. , Ingelfinger Joseph A. , Goldman Peter
Published: December 2015

We reviewed 103 controlled clinical trials that compared the antiarthritic efficacy and tolerance of previously and currently marketed nonsteroidal antiinflammatory drugs (NSAIDs) and aspirin. Of 52 studies, 35 had data sufficient to calculate an NSAID efficacy index (the ratio of mean improvement in NSAID‐treated patients to that in aspirin‐treated patients) based on subjective and/or objective criteria. The mean indexes (obtained from all studies from which an index could be calculated) indicated no statistically significant difference in efficacy between aspirin and the NSAIDs as a group; the indexes tended to become less variable as the number of study subjects increased. Tolerance, assessed from the percentage of patients who discontinued the drug because of side effects, was significantly greater for NSAIDs than for aspirin. The NSAIDs had greater efficacy but not greater toxicity at increased doses. Efficacy differences described among NSAIDs in some studies were attributable either to comparisons at nonequivalent doses or to chance.
Acceptance of Transcutaneous Nitroglycerin Patches by Patients with Angina Pectoris
Authors: Schrader Bruce J. , Bauman Jerry L. , Zeller Frederick P. , Shanes Jeffrey G. , Rich Stuart
Published: December 2015

The acceptance, preference, and side effects of the 3 commercially available nitroglycerin patches were examined in 30 patients with chronic, stable angina pectoris. Patients were serially interviewed after each treatment period regarding patch comfort, aesthetics, discomfort upon removal, adhesiveness, efficacy, and side effects. They were also interviewed and examined for adverse skin reactions. There were significant differences among the 3 patches with respect to comfort, aesthetics, discomfort, and adhesiveness. Skin reactions (mostly mild) occurred in 83% of patients: patch A, 70%; patch B, 43%; and patch C, 57%. Intolerable reactions, which would have caused patch discontinuation, were noted in 40% of patients: patch A, 30%; patch B, 7%; and patch C, 10%. Most patients had an intolerable reaction to only 1 patch. Significant differences were present only between patches A and B with respect to total and intolerable skin reactions. Thus the systems differed in terms of patient preference and skin reactions. Skin reactions are probably more prevalent than previously reported but usually occur with just one of the patches. Physicians and hospitals should probably individualize nitrate patch therapy within formulary and budgetary constraints.
Analysis of the Analgesic Efficacy of Acetaminophen 1000 mg, Codeine Phosphate 60 mg, and the Combination of Acetaminophen 1000 mg and Codeine Phosphate 60 mg in the Relief of Postoperative Pain
Authors: Gertzbein Stanley D. , Tile Marvin , Robert Y , Kellam James F. , Hunter Gordon A. , Keith Roger G. , Harsanyi Zoltan , Luffman Joeann
Published: December 2015

Patients who experienced pain after surgery were administered a single dose of 1 of 3 treatments: acetaminophen 1000 mg, codeine phosphate 60 mg, or a combination of these. Patients rated their pain intensity on ordinal and visual analog scales just prior to medication and at intervals thereafter for up to 5 hours. They also rated pain relief, pain half gone, and any adverse effects. Sum of pain intensity difference and total pain relief scores were analyzed using Dunnett's procedure. The drug combination was statistically superior to codeine as measured by SPID, TOTPAR, pain half gone, and time to remedication. The combination achieved better mean scores than acetaminophen on all efficacy measures, but was (margnally) statistically superior only in pain half gone. No appreciable differences in adverse effects were noted among the treatments. The difficulty of showing the analgesic efficacy of codeine in a single dose trial is discussed.
Methotrexate in Rheumatoid Arthritis: An Update
Authors: Miller Donald R. , Letendre Peter W. , DeJong Douglas J. , Fiechtner Justus J.
Published: December 2015

Methotrexate, a folic acid antagonist, is being employed more frequently in an attempt to control rheumatoid arthritis that has not responded adequately to conventional therapies. Systemic administration of 7.5–15 mg weekly in a pulse fashion appears to be effective without precipitating serious adverse effects. Concern over potentially serious adverse effects and lack of well‐controlled clinical trials have limited its use to severe, refractory disease. Its use in the future is likely to increase in these patients because of its ease of administration and the high response rate noted in clinical studies.
Comparison of Etodolac, Aspirin and Placebo for Pain After Oral Surgery
Authors: Gaston Gerald W. , Mallow Richard D. , Frank Judith E.
Published: December 2015

Single oral doses of etodolac 50, 100 and 200 mg were compared with aspirin 650 mg and placebo in a double‐blind, parallel group study of 189 outpatients reporting moderate or severe pain after oral surgery. Overall efficacy of test drugs was evaluated by sum of pain intensity difference (SPID) scores and total pain relief (TOTPAR) scores over 0.5–3, 0.5–6, 0.5–8 and 0.5–12 hours. Etodolac 200 mg provided significantly greater analgesia than aspirin by these measurements over all SPID and all but one TOTPAR interval, and was significantly more effective than placebo over all intervals. Etodolac 100 mg was superior to aspirin for SPID 0.5–8 and 0.5–12 hours, and superior to placebo for both SPID and TOTPAR over all time intervals. Onset of analgesia for etodolac 100 mg, 200 mg and aspirin was 1 hour or less for the majority of patients in each group; 42% receiving etodolac 200 mg reported onset of analgesia within 0.5 hour. Duration of analgesia for etodolac 200 mg appeared twice that of aspirin. A significant positive dose‐response relationship was obtained for the three doses of etodolac. A low frequency of side effects was observed in all treatment groups.
Benefit‐risk Assessment of Investigational Drugs: Current Methodology, Limitations, and Alternative Approaches
Authors: Cocchetto David M. , Nardi Ronald V.
Published: December 2015

Development of investigational drugs is a process integrated traditionally into four overlapping phases. The goal is to introduce new therapies to clinical medicine by assessing benefits and risks associated with administering the new drug. Benefit assessment is performed with respect to the disease for which the drug may comprise an effective treatment. In contrast, safety assessment is relatively standardized across many pharmacologic classes of agents. For purposes of benefit‐risk assessment, investigational drugs are developed to provide benefit in three major disease categories: acute, episodic, and chronic. Benefit assessment is the major focus of conventional methodologies. Inherent limitations of risk assessment produced by conventional approaches are illustrated by the historical inability to detect toxicities of various drugs until large patient populations have been treated, typically after the drug is marketed. Alternative approaches to overcome these limitations include (1) assessment of safety in studies specifically designed to optimize such evaluation and (2) more extensive safety testing of investigational drugs in patient subgroups at higher risk. Such approaches serve the interest of patients, physicians, and developers by facilitating the development of new therapies by providing a more complete benefit‐risk assessment prior to initial marketing of the drug.
Pharmacology and Therapeutic Use of Low‐dose Dopamine
Authors: Dasta Joseph F. , Kirby M. Gray
Published: December 2015

The renal pharmacologic effects of intravenous dopamine in doses of 0.5–3.0 μg/kg/min include increases in renal blood flow, glomerular filtration rate, solute excretion, and urine flow. Clinical studies revealed that low‐dose dopamine can reverse oliguria, but these studies were poorly controlled, were confounded by the use of other diuretics, had small patient populations, and often did not evaluate mortality or long‐term renal function. When used in low doses, side effects are rarely seen. Because of dopamine's effect on hepatic and renal function, changes in drug clearance may occur. Low‐dose dopamine may be considered in the early course of oliguric patients; however, specific advantages over other diuretic therapy have not been established.
Combination Dihydroergotamine Mesylate and Heparin Sodium with Lidocaine HCI: Pharmacokinetics, Mechanism of Action, Clinical Efficacy, and Adverse Effects
Authors: Barone Joseph A. , Raia John J. , Levy David B.
Published: December 2015

Dihydroergotamine(DHE)‐heparin combination offers a unique treatment modality for the prevention of deep vein thrombosis. The combination appears to affect all 3 limbs of Virchow's triad: hypercoagulability, venous stasis, and endothelial damage. In most efficacy studies, data indicated that the combination of DHE 0.5 mg and heparin 5000 IU was superior to low‐dose heparin alone. Even when the efficacy of DHE‐heparin was the same as that of heparin alone, the use of the combination allowed for a decrease in the heparin dose required.
Fluoxetine: A Serotonin‐specific, Second‐generation Antidepressant
Authors: Sommi Roger W. , Crismon M. Lynn , Bowden Charles L.
Published: December 2015

Fluoxetine is a bicyclic antidepressant that is a specific and potent inhibitor of the presynaptic reuptake of serotonin. It has essentially no effect on the reuptake of norepinephrine or other neurotransmitters. Similarly, it has negligible binding affinity for neurotransmitter receptor sites. It is well absorbed after oral administration, with absolute bioavailability in dogs of approximately 72 ± 27.6%. The mean Tmax is between 4 and 8 hours, and it is approximately 94% protein bound. After a single dose, the elimination half‐life is 1–3 days. After long‐term administration, the elimination half‐life averages 4 days. Its pharmacokinetics appear nonlinear. It is metabolized to an active metabolite norfluoxetine, which is also specific for the inhibition of serotonin reuptake. Norfluoxetine's elimination half‐life averaged 7 days after long‐term administration. Little is known about potential drug interactions; however, fluoxetine appears to have minimal clinically relevant interactions. Fluoxetine is indicated in the treatment of major depression. Its efficacy is comparable to the tricyclics and it has a similar onset of action. Although doses as high as 80 mg/day have been used, the optimal dosage range appears to be 20–40 mg once daily. Fluoxetine has been used with success in obsessive‐compulsive disorder and intention myoclonus, however, its use in these disorders remains investigational. The frequency of side effects is low and dose related; the most common effects are nausea, anxiety, insomnia, anorexia, diarrhea, nervousness, and headache. Eight reports of intentional overdose with fluoxetine alone resulted in no deaths and mild adverse effects. It will be marketed as 20‐mg capsules under the brand name of Prozac. Although fluoxetine should be added to formularies, its use should be reserved for treatment of those who do not respond to or do not tolerate tricyclic agents.
Carprofen: A New Nonsteroidal Antiinflammatory Drug Pharmacology, Clinical Efficacy and Adverse Effects
Authors: O'Brien William M. , Bagby George F.
Published: December 2015

Carprofen (Rimadyl, Roche), a new nonsteroidal antiinflammatory drug (NSAID) will soon be commercially available. Not counting aspirin and other salicylates, there arenow at least a dozen NSAIDs commercially available in the United States.
Hemodynamic Responses to Indoramin at Rest and During Exercise in Congestive Heart Failure
Authors: Leier Carl V. , Majetich Nick , Binkley Philip F. , Unverferth Donald V.
Published: December 2015

Twenty patients with congestive heart failure underwent hemodynamic studies before and over 10 hours after the administration of 25, 50, and 75 mg of indoramin, an alpha1‐adrenergic antagonist. Hemodynamic studies were repeated during exercise after the administration of the optimal dose of indoramin. The drug reduced resting and exercise pulmonary capillary wedge pressure, right atrial pressure, systemic blood pressure and vascular resistance, and pulmonary artery pressure and vascular resistance. Resting and exercise stroke volume and cardiac output rose in response to the fall in vascular resistances. Heart rate was not altered at rest or during exercise. The first dose of the alpha1 blocker indoramin elicits a significant reduction in ventricular preload and afterload and augmentation of ventricular performance in patients with congestive heart failure.
Short‐Term Hemodynamic Effects of Intravenous Methyldopa in Patients with Congestive Heart Failure
Authors: Manolis Antonis S. , Varriale Philip , Nobile John
Published: December 2015

The acute hemodynamic effects of intravenous methyldopa were studied in six patients with chronic congestive heart failure (New York Heart Association class IV) at 4–6 hours after a 750‐mg bolus (period A) and 6–12 hours after a maintenance infusion of 1–2 mg/minute (period B). For period A, the most consistent and striking finding was a significant (48%) fall in pulmonary wedge pressure (33 ± 6 to 17 ± 2 mm Hg; p < 0.05). Stroke volume increased 39% (23 ± 3 to 32 ± 4 ml/m2; p < 0.05), while peripheral vascular resistance decreased 15% (3331 ± 363 to 2841 ± 241 dynes·s·cm−5; p < 0.05). Heart rate fell from 97 ± 7 to 76 ± 3 beats/minute (p < 0.05) with a nonsignificant decline in mean right atrial pressure (18 ± 4 to 9 ± 1 mm Hg). These hemodynamic changes were either sustained or enhanced during period B. Concomitant clinical improvement was also noted. As an agent with potent vasodilatory and antiadrenergic properties, methyldopa permitted a rise in stroke volume by virtue of unloading and possible inhibition of sympathetic activity that led to increased density of beta‐adrenergic receptors of the heart (up‐regulation). Significant reduction of ventricular filling pressure was attributed to venodilation and probable improved diastolic function. In selected patients with severe congestive heart failure, particularly underscored by excessive sympathetic tone, methyldopa may be considered as an alternative agent to improve cardiac performance and clinical symptomatology.
Recognizing, Setting Therapeutic Goals, and Selecting Therapy for the Prevention and Treatment of Stress‐Related Mucosal Damage
Authors: Peura David A.
Published: December 2015

Advances in the care of critically ill patients and in diagnostic techniques, such as fiberoptic endoscopy, have enabled greater recognition of stress‐related mucosal damage (SRMD). This condition is distinguished from chronic peptic ulcer disease by its greater number of lesions, proximal location in the acid‐producing portion of the stomach, and superficial bleeding. Endoscopy is considered the best method for detecting and monitoring mucosal damage. The onset of SRMD occurs early, within hours of the traumatic insult. Pharmacologic treatment has been oriented toward suppressing intraluminal acid and enhancing mucosal defense mechanisms. Antacid therapy is considered the best method for treatment of SRMD, although extensive experience has been gained with the H2‐receptor antagonists. The vast majority of experience with the H2‐receptor antagonists has been with cimetidine, which is as effective as antacids, as shown by endoscopy. Investigations of alternative forms of therapy (e.g., prostaglandins) are in progress.
Lipophilicity, Hydrophilicity, and the Central Nervous System Side Effects of Beta Blockers
Authors: Drayer Dennis E.
Published: December 2015

One of the attributes of beta‐adrenergic blocking agents that has distinguished these drugs from each other is degree of lipophilicity. While this feature may play a role in facilitating passage across the blood‐brain barrier, it is essential to realize that crossing the barrier is not necessarily synonymous with the ability to cause central nervous system (CNS) effects. Several studies have found some degree of CNS side effects, particularly tiredness and fatigue, with atenolol, a hydrophilic beta blocker. Pindolol, a moderately lipophilic beta blocker, has been reported to cause greater disturbances on electroencephalogram (EEG) than propranolol, the most highly lipophilic beta blocker. The investigational agent bevantolol exhibits a moderate degree of lipophilicity and a low frequency of CNS side effects. Drug‐induced increases in plasma catecholamine levels, the possible saturation of CNS receptor sites at relatively low drug levels, and the specific structural details of beta‐blocker molecules have been suggested as possible contributory factors in determining the degree of CNS effects.
Enalapril: A Long‐acting Angiotensin‐Converting Enzyme Inhibitor
Authors: Borek Mark , Charlap Shlomo , Frishman William
Published: December 2015

The development of angiotensin‐converting enzyme (ACE) inhibitors is of landmark importance in the understanding and treatment of cardiovascular disorders, particularly hypertension and congestive heart failure. Enalapril has recently joined captopril as an approved, orally active ACE inhibitor. Like captopril, it has been effective in the treatment of hypertension and congestive heart failure, with minimal adverse reactions noted. Differences in pharmacology exist between enalapril and captopril which may prove to be of clinical significance.
The Use of Intravenous Dipyridamole in Thallium 201 Myocardial Perfusion Imaging
Authors: Zeller Frederick P. , Blend Michael J.
Published: December 2015

Thallium 201 myocardial perfusion imaging is a standard method of evaluating regional myocardial blood flow. Myocardial perfusion is best evaluated at rest and during exercise, however, alternative methods have been sought to increase coronary blood flow in patients incapable of performing adequate exercise. A promising new method is the use of intravenous dipyridamole for pharmacologic stress imaging. It has distinct advantages over traditional treadmill exercise testing. The primary advantage of combining intravenous dipyridamole and thallium 201 is for testing patients in whom exercise is impractical or contraindicated. Examples include patients taking beta blockers and those who have had myocardial infarction or have severe peripheral vascular disease. To date, this agent has been available only to clinical investigators in approved protocols. With continued success, it should be approved for general use in the near future.
Spiramycin in the Treatment of Cryptosporidiosis
Authors: Pilla Alison M. , Rybak Michael J. , Chandrasekar P. H.
Published: December 2015

Spiramycin, a macrolide antibiotic, has been advocated for the treatment of cryptosporidiosis. The disease most commonly occurs in patients with AIDS and can be debilitating, as diarrhea and malnutrition may be contributing factors in the death of these patients. Until recently, treatment for cryptosporidiosis has been largely symptomatic. Response rates with drug therapy such as metronidazole, quinidine‐clindamycin, and pentamidine have been extremely poor. Although response to spiramycin has appeared promising, there have been several reported cases of treatment failure. Further investigation with the agent is advocated to determine its role in the treatment of cryptosporidiosis.
Ciprofloxacin: Chemistry, Mechanism of Action, Resistance, Antimicrobial Spectrum, Pharmacokinetics, Clinical Trials, and Adverse Reactions
Authors: LeBel Marc
Published: December 2015

Ciprofloxacin, considered a benchmark when comparing new fluoroquinolones, shares with these agents a common mechanism of action: inhibition of DNA gyrase. While ciprofloxacin demonstrated a fairly good activity against gram‐positive bacteria, it is against gram‐negative organisms that it proved to be more potent than other fluoroquinolones. It is the most active quinolone against Pseudomonas aeruginosa, with MIC90s on the order of 0.5 μg/ml. When given orally, ciprofloxacin exhibited 70% bioavailability and attained peak serum levels ranging between 1.5 and 2.9 μg/ml after a single 500‐mg dose. Nineteen percent of an oral dose was excreted as metabolites in both urine and feces. In most cases, body fluids and tissue concentrations equaled or exceeded those in concurrent serum samples. In clinical trials, oral and intravenous ciprofloxacin yielded similar clinical and bacteriologic results compared to standard therapy in a wide array of systemic infections, including lower and upper urinary tract infections; gonococcal urethritis; skin, skin structure, and bone infections; and respiratory tract and gastrointestinal tract infections. Major benefits with the oral form of this quinolone are expected in chronic pyelonephritis and bone infections, and in pulmonary exacerbations in patients with cystic fibrosis. Emergence of ciprofloxacin‐resistant microorganisms has been noted in clinical practice, primarily Pseudomonas aeruginosa and Staphylococcus aureus. The most frequent side effects are related to the gastrointestinal tract; but attention should be given to adverse central nervous system effects.
Human Infection with Herpes Zoster: Etiology, Pathophysiology, Diagnosis, Clinical Course, and Treatment
Authors: Strommen Gordon L. , Pucino Frank , Tight Robert R. , Beck Carol L.
Published: December 2015

Herpes zoster is a cutaneous vesicular eruption resulting from recrudescence of the chickenpox virus. It is mainly a disease of adults, with a predisposition for the elderly or immunocompromised. Although usually localized, the disease can disseminate to visceral organs. Diagnosis is often made based on the characteristic pattern of the lesion and clinical features. Tzanck smear, viral isolation, seroconversion, antibody titers, and monoclonal antibodies may further aid or confirm the diagnosis. Clinical features of herpes zoster may follow a progression through 3 stages, prodromal, acute, and chronic. The prodromal and acute phases seldom require more than symptomatic management. The chronic pain syndrome, postherpetic neuralgia (PHN), demands a more aggressive approach. Pharmacologic intervention, neuroaugmentation, and/or surgery may prevent or alleviate PHN, but universal response to any of these therapeutic approaches is unlikely. Tricyclic antidepressants remain the first choice in treating this pain syndrome. A trial of antiviral therapy may be warranted in patients with disseminated disease or in immunocompromised patients with localized disease. Of the antiviral agents, acyclovir is considered the drug of choice by most clinicians.
The Use of Benzodiazepine Hypnotics in the Elderly
Authors: Baker Myrna I. , Oleen MerriKay A.
Published: December 2015

An epidemiologic study was conducted to observe patient‐reported use and effects of triazolam, flurazepam, and oxazepam taken at bedtime among 2260 outpatients age 65 years or older in Canada. The study used pharmacy‐based enrollment, with participant follow‐up through a 3–day diary and a telephone interview. The study also evaluated how the three benzodiazepine hypnotics were prescribed. Prescription information showed that 66% of the flurazepaam prescriptions were for the highest strength, compared to 39% and 35% for triazolam and oxazepam, respectively. As patient age increased, the highest strength of each agent was prescribed less frequently. For all drugs, 53% of prescriptions were written for use as necessary (prn), and the proportion who received such prescriptions increased with age. Patient reports, however, revealed that 57% were using a hypnotic every day, and this regular use increased with advancing age. Regular daily use was more common among those who used triazolam and oxazepam (62%) than those who took flurazepam (42%).