World of Drugs

World of Drugs - Volume 7, Issue 4 - December 1996

In This Issue ...
 Database News 
 Renewal Notice 
 Search Tip 
 Exhibit Schedule 
 FDA Drug Approvals 
 Search Strategies--Current Clinical Issues 
 Staff Profile 

IDIS ARTICLES ON DISC

Have you had an opportunity to use the IDIS article test disc that was sent to you with the November Update? The technology necessary to put the IDIS articles on disc is now not only available but also priced in a range that makes it a reasonable option. While we are establishing quality standards and production mechanics for putting the articles on disc, we do need some guidance from our subscribers. Please complete the questionnaire that was enclosed with the article test disc. Your reaction is important and we appreciate your time and effort to return the survey to us.

Hazel Seaba, Director


RENEWAL NOTICE
Renewal materials for the 1997 IDIS database subscription were mailed in early September and November. We urge you to respond as soon as possible. Your current subscription will expire after the December 1996 update. We need to receive your renewal by January 10, 1997 to avoid interruption of service. Current microfilm subscribers should note a special offer included with their renewal materials. In the event you misplace or fail to receive a renewal form, please contact our office as soon as possible.

SEARCH TIP: Locating Transplantation Articles Using the Disease and Drug Fields

The field of organ transplantation is continually advancing with respect to the types of organs being transplanted, as well as the drug combinations being used to treat transplant patients. These patients provide challenging clinical situations for practitioners due to the complex drug regimens that are required to balance the need for immunosuppression with the desire to avoid infections and other complications related to impairment of the immune system. Bone marrow and stem cell transplantation share added concerns due to the use of antineoplastic and/or radiation therapy necessary for conditioning. The IDIS database is a ready means of locating current articles pertaining to the use of drugs in transplant patients. Several journals focusing on transplantation were added to IDIS in 1994. With an understanding of how these articles are indexed into the database, the practitioner may more easily retrieve citations pertinent to a specific situation.

Disease Field

The valid disease terms used to index articles related to solid organ transplant are:

Transplants involving blood components are identified by:

The underlying disease or condition necessitating transplantation is generally not indexed in cases of solid organ transplant. An exception would be an article that focuses on drug treatment options for the underlying disease, along with the option of transplantation. However, bone marrow and stem cell transplantation articles are indexed with the valid transplant term and the disease term for the condition being treated. For example: a study dealing with allogenic bone marrow transplant in breast cancer patients would be identified by the disease terms 41.0 TRANSPLANT, BONE MARROW and 174. NEOP, MGN-FEMALE BREAST. Using the disease term for the underlying condition in combination with the terms for bone marrow or stem cell transplant is a useful way to limit searches.

Other disease terms useful in locating transplant related articles:

When locating citations focusing on drug regimens for the prevention of organ rejection or graft versus host disease, searches may be limited by using V07. PROPHYLAXIS NEC in combination with 996.8 COMPLICATION, ORGAN TRANSPL. For articles dealing with treatment of organ rejection or graft versus host disease, 996.8 COMPLICATION, ORGAN TRANSPL may be used alone. 92.2 RADIATION THERAPY/NUCL MED is useful in locating studies comparing radiation to drug therapy in conditioning regimens prior to bone marrow or stem cell transplantation.

Drug Field

40120071 TRANSPLANT SOLUTIONS is a drug term added in 1994 to identify studies in which the type of organ preservation solution used was shown to influence the outcome of transplantation. As mentioned above, 16000020 STEM CELLS, HEMATOPOIETIC is used in combination with the disease term 99.0 TRANSFUSION BLOOD/COMPONENT to classify articles dealing with autologous stem cell transplantation.

No other drug terms are specific to transplantation in the IDIS database. Other drugs commonly indexed in transplantation articles are immunosuppressants and antineoplastics. These are often used in combination therapy, therefore descriptor 16 DRUG COMBINATION may be useful in limiting searches to specific immunosuppressant or conditioning regimens.

Citations including the immunosuppressant, 92000134 CYCLOSPORINE, are particularly abundant in transplant literature. A few tips on limiting cyclosporine searches include:

Organ transplantation is a source of many questions regarding drug combinations, drug interactions, adverse effects, pharmacokinetics and pharmacodynamics. The complex nature of the diseases, procedures and drug regimens involved, makes this area challenging for those providing drug information services. A knowledge of the transplant related disease terms and combinations of drug terms and descriptors commonly used in the IDIS database can facilitate efficient retrieval of the available information.

Lori Huynh, R.Ph., Pharm.D.


1997 IDIS EXHIBIT SCHEDULE

American Pharmaceutical Association (APhA)
Annual Meeting
Los Angeles, California
March 8-12, 1997

Academy of Managed Care Pharmacy (AMCP)
Annual Meeting
New Orleans, Louisiana
May 8-11, 1997

American Society of Hospital Pharmacists (ASHP)
Home Care '97
Reno, Nevada
August 16-18, 1997

Federation Internationale Pharmaceutique (FIP)
World Congress of Pharmacy and Pharmaceutical Sciences
Vancouver, Canada
August 31-September 5, 1997

American Society of Hospital Pharmacists (ASHP)
Midyear Clinical Meeting (MCM)
Atlanta, Georgia
December 7-11, 1997


FDA DRUG APPROVALS

The FDA continues to approve new molecular entities at a steady pace. In August, bentoquatam, also known as quaternium-18 bentonite, became the first FDA approved topical barrier lotion for the prevention of poison ivy/oak/sumac to reach the market. It received approval as an over- the-counter (OTC) product. Labeling for the product states that the drug "helps to protect against poison ivy, oak, and sumac rash when applied BEFORE contact. It should be applied at least 15 minutes prior to exposure and every four hours thereafter for continued protection. The basis of approval included a 211 subject clinical study finding that 5% bentoquatam lotion prevented experimentally produced poison ivy and poison oak allergic contact dermatitis in 68% of the 144 subjects who were allergic to urushiol, the allergen in poison ivy, oak and sumac.1

1. Marks JG, Fowler JF, Sherertz EF et al. Prevention of poison ivy and poison oak allergic contact dermatitis by quaternium-18 bentonite. J Am Acad Dermatol 1995;33:212-6. (IDIS Article Number 350768)


Two more antihistamines have also received FDA approval. Fexofenadine, approved for treatment of seasonal allergic rhinitis appears to be a nonsedating antihistamine when used in recommended doses. In addition, fexofenadine does not possess cardiovascular toxicity that can occur rarely with terfenadine or astemizole, both nonsedating antihistamines.1 To date clinical studies of fexofenadine have been published only as abstracts.

1. Anon. Fexofenadine. Med Lett Drugs Ther 1996;38:95. (IDIS Article Number 374088)


Azelastine, an antihistamine to be available as a nasal spray, was also approved for the treatment of seasonal allergic rhinitis. Labeling includes a somnolence warning stating "the occurrence of somnolence has been reported in some patients using the nasal spray; due caution should be exercised when driving a car or operating potentially dangerous machinery. Concurrent use with alcohol or other CNS depressants should be avoided. The safety and efficacy of Azelastine nasal spray in the management of seasonal allergic rhinitis has been assessed in several randomized controlled trials. LaForce et al1 found that azelastine nasal spray used as two sprays per nostril twice daily demonstrated broad clinical antirhinitis activity in 264 subjects with seasonal allergic rhinitis. Common adverse drug effects noted were taste alteration, headache and somnolence. In a two day trial of 294 patients with seasonal allergic rhinitis, Meltzer it al2 found 73% of the patients treated with azelastine noted overall improvement upon global assessment of their symptoms. Improvement was observed by the second hour after drug administration and lasted up to 24 hours. Taste alteration and somnolence were frequent adverse drug effects.

1. LaForce C, Dockhorn RJ, Prenner BM et al. Safety and efficacy of azelastine nasal spray (Astelin NS) for seasonal allergic rhinitis: a 4-week comparative multicenter trial. Ann Allergy Asthma Immunol 1996;76:181-8. (IDIS Article Number 364165)

2. Meltzer EO, Weiler JM, Dockhorn RJ et al. Azelastine nasal spray in the management of seasonal allergic rhinitis. Ann Allergy 1994;72:354-9. (IDIS Article Number 328847)


In addition to the new therapies for seasonal allergic rhinitis, a new drug has been approved for prophylaxis and treatment of asthma. Zafirlukast (ICI 204,219) is the first leukotriene receptor antagonist to be cleared by the FDA for use in asthma management. In a six week study of 276 subjects with asthma, Spector et al1 found the drug improved both subjective and objective measures of asthma severity in moderately ill asthmatic subjects. Fifty-three percent of subjects reported adverse events. Headache was the most common event reported.

1. Spector SL, Smith LJ, Glass M et al. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Am J Respir Crit Care Med 1994;150:618-23. (IDIS Article Number 336168)


Over the past year, the FDA has approved four radiolabeled antibodies for diagnostic imaging. Arcitumomab was approved for use in conjunction with computerized tomography scans to detect colorectal cancer. (See World of Drugs 1996;7:10)


Imciromab pentetate (MyoScint) a murine monoclonal antibody Fab fragment linked to indium 111 binds with high affinity and specificity to human cardiac myosin, which is exposed following a loss to integrity of the myocyte cell membrane. The drug has received approval for use in cardiac imaging for detecting myocardial necrosis. In a study of 54 patients with acute myocardial infarction, Khaw et al1 found that indium-111 monoclonal antimyosin Fab scintigraphy detected myocardial necrosis in 96.3% of the patients. None of the patients showed positive weal and flare reactions following an intradermal test dose.

1. Khaw BA, Yasuda T, Gold HK et al. Acute myocardial infarct imaging with indium-111-labeled monoclonal antimyosin fab. J Nucl Med 1987;28:1671-8. (IDIS Article Number 242613)


Another monoclonal antibody Fab fragment, nofetumomab (NR-LU-10) linked to technetium 99m, has been approved for use in identifying advanced-stage disease in patients with small-cell lung cancer. (SCLC). In a multicenter, single-arm, open-label Phase III study of 89 evaluable SCLS patients, the antibody correctly staged 82% of the patients with extensive or limited stage disease, according to labeling. Labeling states a positive predictive value of 94% when the monoclonal antibody demonstrated extensive disease.


The monoclonal antibody capromomab pendetide (CYT-356) linked to indium 111 seeks out and attaches to prostate cancer and its metastases. It is not indicated as a screening tool for carcinoma of the prostate nor for assessment of response to treatment. In the pivotal trials false positive and negative image interpretations were high. In a study of 27 subjects who had undergone radical prostatectomy and whose only evidence of recurrent disease was an increasing serum prostate specific antigen, Kahn et al1 found that in 22 subjects with 1 or more lesions detected, 50% were confirmed by biopsy, computerized tomography or magnetic resonance imaging. Of 14 subjects with lesions detected in the prostatic fossa 13 had biopsies performed, eight (62%) were positive.

1. Kahn D, Williams RD, Seldin DW et al. Radioimmunoscintigraphy with 111indium labeled CYT-356 for the detection of occult prostate cancer recurrence. J Urol 1994;152:1490-95. (IDIS Article Number 337013)


Another biological, reteplase, was approved by the FDA the end of October for use in the management of acute myocardial infarction. Reteplase is a non-glycosylated deletion mutein of tissue plasminogen activator (tPA) containing the kringle 2 and the protease domains of human tPA. It contains 355 of the 527 amino acids of native tPA and is produced recombinantly in E. coli. The half-life of reteplase is 13-16 minutes and the drug is cleared primarily by the liver and kidney. The drug approval was based on three controlled trials. The 6,010 patient International Joint Efficacy Comparison of Thrombolytics (INJECT) study1 compared reteplase with a standard regimen of streptokinase for mortality and other outcomes. Reteplase showed no statistically significant difference in mortality compared to streptokinase, 8.9%versus 9.4% for 35 day mortality. However, there were significantly fewer cases of atrial fibrillation, asystole, cardiac shock, heart failure, and hypotension in the reteplase group. The RAPID 1 and 2 trials were arteriographic studies comparing reteplase to alteplase.2-3 Both trials found the reocclusion rates were similar for both reteplase and alteplase. The trials were not designed to compare the efficacy or safety of reteplase and alteplase with respect to the outcomes of mortality and stroke.

1. Hampton JR, Schroder R, Wilcox RG et al. Randomized, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet 1995;346:329-36. (IDIS Article Number 351255)

2. Smalling RW, Bode C, Kalbfleisch J et al. More rapid, complete, and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction. Circulation 1995;91:2725-32. (IDIS Article Number 348924)

3. Bode C, Smalling RW, Berg G et al. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. Circulation 1996;94:891-8. (IDIS Article Number 372165)


Other diagnostic agents have also been approved. Ferumoxides (AMI-25) has been approved for use as an adjunct to MRI for the detection and evaluation of lesions of the liver associated with an alteration in the reticuloendothelial system. It is the first organ-specific MRI contrast agent approved in the United States. In a pilot study of 15 patients, Stark et al1 found that ferrite-enhanced MR images of the liver obtained with standard pulse sequence techniques significantly increased the number of hepatic lesions detected and reduced the threshold size for detection to 3mm. Ferrite was administered at a dose of 20 micromol/kg as ferumoxides. In a phase II trial, Hahn et al2 studied 19 adults with histologically proved malignancy and with proved or suspected liver metastases. They found the use of both distribution phase and retention phase AMI-25 enhanced MR images offers improved diagnostic accuracy in the detection and characterization of focal liver lesions. Winter et al3 evaluated the efficacy of AMI-25 in the detection of focal hepatic lesions on MR images in a study of 21 patients with focal hepatic lesions and found that AMI-25 enhanced T2-weighted MR images were superior to unenhanced T2-weighted images and to contrast-enhanced CT scans. Hypotension was noted as an adverse drug effect.

1. Stark DD, Weissleder R, Elizondo G et al. Superparamagnetic iron oxide: clinical application as a contrast agent for MR imaging of the liver. Radiology 1988;168:297-301. (IDIS Article Number 316014)

2. Hahn PF, Stark DD, Weissleder R et al. Clinical application of superparamagnetic iron oxide to MR imaging of tissue perfusion in vascular liver tumors. Radiology 1990:174:361-6. (IDIS Article Number 301692)

3. Winter III TC, Freeny PC, Nghiem HV et al. MR imaging with IV superparamagnetic iron oxide: efficacy in the detection of focal hepatic lesions. AJR 1993:161:1191-8. (IDIS Article Number 322618)


Previously, the only way to accurately diagnose H. pylori infection was by endoscopy with stomach biopsy. With the FDA approval of UBT Breath test, the patients drink a non-radioactive diagnostic drug solution and then exhale into the collection kit. The procedure is performed in a doctor's office and takes about thirty minutes. The breath test kit uses carbon 13 enriched urea, a naturally occurring, non-radioactive compound to determine the presence or absence of an active H. pylori infection. Results indicate the breath test is able to detect the presence of H. pylori in 95% of the cases.1 These results were also confirmed in a study of 95 children conducted to assess the sensitivity and specificity of 13C-urea breath test to diagnose H. pylori infection in children.2

1. Klein PD, Malaty HM, Martin RF et al. Noninvasive detection of Helicobacter pylori infection in clinical practice: the 13C urea breath test. Am J Gastroenterol 1996;91:690-4. (IDIS Article Number 365388)

2. Vandenplas Y, Blecker U, Devreker T etal. Contribution of the 13C- urea breath test to the detection of Helicobacter pylori gastritis in children. Pediatrics 1992;90:608-11. (IDIS Article Number 303476)


The month of September saw an increase in the number of new drugs approved by the FDA.

Nilutamide, approved for use in combination with surgical castration for the treatment of stage D2 metastatic prostate cancer was evaluated in a large multination double-blind randomized trial.1

Four hundred and fifty-seven patients with metastatic prostatic cancer without prior endocrine manipulation underwent orchiectomy and were then randomized to nilutamide or placebo. Progression-free survival was significantly longer in the nilutamide group. Common adverse drug effects included hot flushes, visual disturbances, nausea and dyspnea. In another multicenter study with a similar protocol, 203 patients were evaluated.2 Patients treated with nilutamide had a significantly greater number of positive objective responses than did the patients treated with castration alone (46% versus 20%). Similar adverse drug effects were seen.

1. Janknegt RA, Abbou CC, Bartoletti R et al. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J Urol 1993;149:77-83. (IDIS Article Number 307019)

2. Beland G, Elhilali M, Fradet Y et al. A controlled trial of castration with and without nilutamide in metastatic prostatic carcinoma. Cancer 1990;66:1074-9. (IDIS Article number 271667)


Penciclovir (BRL-39123) is an acyclic guanine analogue which has shown activity against herpes simplex virus (HSV) during in vitro and animal studies, and has been under investigation for the treatment of HSV, varicella zoster, and Epstein-barr virus infections. The FDA has approved its use in the treatment of herpes labialis. In vitro studies have shown that penciclovir is more effective in decreasing HSV yields than acyclovir.1 The tolerance and pharmacokinetics of penciclovir after intravenous administration were evaluated in a phase I trial of 15 healthy volunteers. 2 Penciclovir was distributed into tissues, with a mean volume of distribution of approximately 1.5 L/kg. It was rapidly eliminated and had a mean terminal half-life of two hours. Approximately 70% of the dose was excreted unchanged in the urine. The drug was well tolerated with no evidence of drug-related adverse effects.

1. Bacon TH, Howard BA, Spender LC et al. Activity of penciclovir in antiviral assays against herpes simplex virus J Antimicrob Chemother 1996;37:303-13. (IDIS Article Number 364505)

2. Fowles SE, Pierce DM, Prince WT et al. The tolerance to and pharmacokinetics of penciclovir (BRL 39123A), a novel antiherpes agent, administered by intravenous infusion to healthy subjects. Eur J Clin Pharmacol 1992;43:513-6. (IDIS Article Number 307389)


The serotonin-dopamine receptor antagonist, olanzapine, has been approved for the management of pyschotic disorders. Improvement in negative symptoms on the SANS total score were comparable with that of haloperidol.1 Clinical data also indicates that the drug has antipsychotic efficacy at doses that are well below extra-pyramidal symptoms thresholds for many patients.2

1. Anon. Choosing among old and new antipsychotics; new choices in antipsychotic therapy. J Clin Psychiatry 1996:57:427-8. (IDIS Article Number 373603)

2. Casey DE. Extrapyramidal syndromes and new antipsychotic drugs: findings in patients and non-human primate models (Review). Br J Psychiatry 1996;168(Suppl. 29):32-9. (IDIS Article Number 367408)


Brimonidine, a selective alpha2 adrenergic agonist, was approved for lowering intraocular pressure in patients with open angle glaucoma or ocular hypertension. Recommended dose is one drop in the affected eye 3 times daily. In a study of 21 subjects with ocular hypertension, brimonidine significantly reduced the intraocular pressure (IOP).1 Compared with baseline, aqueous flow was reduced by 20%, which may be partially responsible for the IOP reduction that was noted. Brimonidine has also been compared to timolol and betaxolol in a randomized, crossover study of 24 healthy young men.2 Study results showed that the ocular hypotensive effect of brimonidine was comparable to that of timolol and greater than that of betaxolol. The cardiopulmonary effects of brimonidine were limited to a slight reduction in systolic blood pressure during recovery from exercise and at 4 hours after instillation.

1. Toris CB, Gleason ML, Camras CB et al. Effects of brimonidine on aqueous humor dynamics in human eyes. Arch Ophthalmol 1995;113:1514-7. (IDIS Article Number 358199)

2. Nordlund JR, Pasquale LR, Robin AL et al. The cardiovascular, pulmonary, and ocular hypotensive effects of 0.2% brimonidine. Arch Ophthalmol 1995;113:77-83. (IDIS Article Number 341196)


Interstial cystitis is a relatively rare disease. Pentosan polysulfate sodium was approved in September for relief of bladder pain or discomfort associated with the disease. The drug is not a cure for interstitial cystitis but helps to relieve symptoms and restore quality of life in some patients. Results from clinical studies have been conflicting.1-3 Approximately 30% of patients who have taken the drug experience reduction or disappearance of symptoms. Side effects have been minor.

1. Parsons CL. Benson G, Childs SJ et al. A quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosanpolysulfate. J Urol 1993;150:845-8. (IDIS Article Number 319243)

2. Parsons CL and Mulholland SG. Successful therapy of interstitial cystitis with pentosanpolysulfate. J Urol 1987;138:513-6. (IDIS Article Number 234477)

3. Holm-Bentzen M, Jacobsen F, Nerstrom B et al. A prospective double-blind clinically controlled multicenter trial of sodium pentosanpolysulfate in the treatment of interstitial cystitis and related painful bladder disease. J Urol 1987;138:503-7. (IDIS Article Number 234475)


Ropivacine, approved for local or regional anesthesia and for postoperative pain management, is a long-acting anesthetic belonging to the same homologous series of compounds as bupivacaine and mepivacine. It is the first enantiomerically pure local anesthetic and exists as the S-enantiomer. Ropivacine pharmacodynamic and pharmacokinetic properties resemble bupivacine. Ropivacaine has been assessed in clinical studies for efficacy in anesthesia and relief of postoperative pain.1-3 Nausea, vomiting, and hypotension were the most common adverse effects reported.

1. Finucane BT, Sandler AN, McKenna J et al. A double-blind comparison of ropivacine 0.5%, 0.75%, 1.0% and bupivacine 0.5% injected epidurally, in patients undergoing abdominal hysterectomy. Can J Anaesth 1996;43:442-9. (IDIS Article Number 366352)

2. Shug SA, Scott DA, Payne J et al. Postoperative analgesia by continuous extradural infusion of ropivacaine after upper abdominal surgery. Br J Anaesth 1996;76:487-91. (IDIS Article Number 363289)

3. Turner G, Blake D, Buckland M et al. Continuous extradural infusion of ropivacine for prevention of postoperative pain after major orthopaedic surgery. Br J Anaesth 1996;76:606-10. (IDIS Article Number 365360)


Betaine anhydrous for oral solution is the first drug to receive FDA approval for the treatment of homocystinuria, a rare genetic disorder caused by various inborn errors of methionine metabolism that effects about 1,000 patients in the United States. The majority of homocystinuria case studies treated with betaine have been pediatric patients. According to labeling, patients have been treated successfully without adverse effects within the first months or years of life with dosages of 6 grams per day or more with resultant biochemical and clinical improvement. Case reports in the literature discuss the use of this drug in young children.1-3

1. Ronge E and Kjellman B. Long term treatment with betaine in methylenetetrahydrofolate reductase deficiency. Arch Dis Child 1996;74:239-41. (IDIS Article Number 365485)

2. Pullon DHH, Aspects of treatment of homocystinuria: an illustrative case report. NZ Med J 1988;101:10-11. (IDIS Article Number 270263)

3. Holme E, Kjellman B, Ronge E. Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency. Arch Dis Child 1989;64:1061-4. (IDIS Article Number 264254)

Ruth Calloway, M.S., R.Ph.


Midodrine, a prodrug of a specific alpha-1 agonist, has been approved for the symptomatic treatment of orthostatic hypotension. It increases blood pressure by constricting arterioles and venous capacitance vessels. The drug is well absorbed after oral administration and has a longer half-life than other sympathomimetic agonists. It does not cross the blood brain barrier in significant amounts so it has no direct central nervous system effects. Midodrine is not associated with cardiac effects due to its alpha-1 receptor selectivity. Studies suggest that patients with orthostatic hypotension due to autonomic insufficiency may respond to this drug.

1. Jankovic J, Gilden JL, Hiner BC et al. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med 1993;95:38-48. (IDIS Article Number 317913)

2. Fouad-Tarazi FM, Okabe M, Goren H. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. Am J Med 1995;99:604-10. (IDIS Article Number 360182)

Angela Willsher, Pharm.D. Student


FDA DRUG/BIOLOGIC APPROVALS
Generic Name (FDA Therapeutic Classification)

Trade Name

Sponsor

(Approval Date)

Valid IDIS Drug Term

Drug Number

(IDIS Citations)*

Indication/Use

Valid IDIS Disease Term

Modified ICD-9-CM Number

Azelastine (1S)**

Astelin

Carter-Wallace

(Nov. 1)

AZELASTINE

4000027

(73 citations)

Treatment of symptoms of seasonal allergic rhinitis in adults and children 12 years and older. Allergic Rhinitis NEC

477.

Bentoquatam (1P)***

Ivy Block

EnviroDerm Pharmaceuticals

(Aug. 26)

BENTOQUATAM

84241203

(1 citation)

Protects against poison ivy, poison oak, and poison sumac rash when applied before contact. Dermatitis, Cont-Plant

692.6

Betaine, Anhydrous (1P)

Cystadane

Orphan Medical Inc.

(Oct. 25)

BETAINE

56160080

(23 citations)

Treatment of patients with homocystinuria. Disorder, Amino Acid Metab 270.

Brimonidine (1S)

Alphagan

Allergan

(Sept. 6)

BRIMONIDINE

24080028

(8 citations)

Effective for lowering intraocular pressure in patients with open angle glaucoma or ocular hypertension. Glaucoma, Open-Angle

365.1

Hypertension, Ocular

365.04

Capromab Pendetide

ProstaScint

Cytogen

(Oct. 28)

CAPROMAB

82000430

(10 citations)

Imaging biopsy-proven and suspected recurrent prostate cancer. Radioisotope Scan NEC

92.0

Neop, Mgn-Prostate

185.

Ferumoxides (1S)

Feridex

Advanced Magnetics

(Aug. 30)

FERUMOXIDES

36680041

(28 citations)

Adjunct to MRI (in adult patients) to enhance the T2 weighted images used in the detection and evaluation of lesions of the liver that are associated with an alteration in the reticuloendothelial system. Magnetic Resonance Imaging

88.9

Fexofenadine HCl (1S)

Allegra

(July 25)

FEXOFENADINE

4000016

(1 citation)

Treatment of symptoms associated with seasonal allergic rhinitis. Allergic Rhinitis NEC

477.

Imciromab Pentetate

MyoScint

Centocor

(July 3)

IMCIROMAB PENTETATE

82000809

(63 citations)

Cardiac imaging agent for detecting myocardial necrosis. Radioisotope Scan, Cardiovas

92.05

Midodrine (1P)

ProAmatine

Roberts Pharmaceuticals

(Sept. 6)

MIDODRINE

12120034

(34 citations)

Treatment of symptomatic orthostatic hypotension. Hypotension, Orthostatic

458.0

Nilutamide (1S)

Nilandron

Hoechst Marion Roussel

(Sept. 19)

NILUTAMIDE

68080406

(41 citations)

For use in combination with surgical castration for the treatment of stage D2 metastatic prostate cancer. Neop, Mgn-Prostate

185.

Nofetumomab

Verluma

DuPont Merck

(Aug. 20)

NOFETUMOMAB

82000812

(1 citation)

Small-cell lung cancer imaging agent. Radioisotope Scan, Pulmonary

92.15

Olanzapine (1S)

Zyprexa

Eli Lilly

(Sept. 30)

OLANZAPINE

28160836

(11 citations)

Management of the manifestations of psychotic disorders (Serotonin-dopamine receptor antagonist). Psychosis, Nonorganic NEC

298.

Schizophrenia NEC

295.

Penciclovir (1S)

Denavir

SmithKline Beecham

(Sept. 24)

PENCICLOVIR

8180061

(8 citations)

Treatment of Herpes Labialis in adults. Herpes Simplex NEC

054.

Pentosan Polysulfate Sodium (1S)

Elmiron

Baker Norton

(Sept. 26)

PENTOSAN POLYSULFATE

20120406

(35 citations)

Relief of bladder pain or discomfort associated with interstitial cystitis. Cystitis, Chronic NEC

595.1

Reteplase

Retavase

Boehringer Mannheim

(Oct. 30)

RETEPLASE

20400012

(15 citations)

Improvement in ventricular function, reduction of incidence of CHF, and reduction of mortality in management of acute MI. Infarction, Myocard, Acute

410.

Ropivacine HCL (1S)

Naropin

Astra

(Sept. 24)

ROPIVACAINE

72000066

(47 citations)

Production of local or regional anesthesia for surgery, for postoperative pain management and for obstetrical procedures. Anesthesia/Paresthesia

782.0

Pain NEC

782.2

Aftercare NEC

V58.8

Urea, C-13 (1S)

UBT Breath Test

Meretek Diagnostics

(Sept. 17)

UREA

84160098

CARBON C-13

78000002

(15 citations)

Drug/diagnostic device for detection of H pylori associated urease. Diag Test-Digest/BMR

89.39

Zafirlukast (1S)

Accolate

Zeneca

(Sept. 26)

ZAFIRLUKAST

86000028

(26 citations)

Prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Asthma NEC

493.

Prophylaxis NEC

V07.

*Through November 1996 Update. Complete bibliographic citations will be provided upon request.
**(1S) New Molecular Entity given standard review by FDA.
***(1P) New Molecular Entity given a priority review.


CURRENT CLINICAL ISSUES -- SEARCH STRATEGIES

HYDROXYMETHYLGLUTARYL-COENZYME A REDUCTASE INHIBITORS (HMG-COA RIS): SIMVASTATIN, PRAVASTATIN, FLUVASTATIN, LOVASTATIN, ATORVASTATIN

In trials such as the Simvastatin Survival Study and the West of Scotland Coronary Prevention Study, the efficacy of the HMG-CoA RIs in preventing and treating primary and secondary coronary heart disease has been established.1,2 Clinical issues for drugs continue to arise in practice even after being shown safe and effective for marketing. In the case of the HMG-CoA RIs, one such issue is the treatment of hypercholesterolemia in transplant patients. Whether or not these drugs are effective and safe in this type of patient has been the subject of several studies. Economics is another area of interest. Therapies today must not only be safe and effective, they must also be economical. And finally, what new agents are being studied and how are they different/better than what is already available. The purpose of this article is to look at some of these issues surrounding the use of the HMG-CoA RIs and explain how to find this information in the IDIS database.

HMG-COA RIS IN TRANSPLANT PATIENTS

Search Strategy: Studies in transplant patients

The keywords are hypercholesterolemia, transplant, and the specific drug names. First, using the Thesaurus <F3>, it is apparent that 'hypercholesterol' is part of all the disease terms concerned with hypercholesterolemia. Hypercholesterol* could then be used in a global search to find this term in any index field. Press <F3> and select Global Search. Type hypercholesterol* in the first field. Tab over to the next field and enter transplant*. Leaving two fields blank, Tab or arrow down to the fields below the ======AND====== and enter each of the four drugs in their own field: pravastat*, fluvastat*, simvastat*, lovastat*. Press <Enter> to execute the search. Thirty records are found through November 1996 Update. To limit this search even further, enter study in one of the blank fields below hypercholesterol* and transplant*. Eleven records are identified.

Clinical Information: Overview of selected trials

Hypercholesterolemia is a problem in many kidney and heart transplant patients. Of the eleven records retrieved, six were studies looking at the cholesterol lowering effect in heart transplant patients and three were studies in kidney transplant patients. The two other studies involved persons receiving blood transfusions. Four of the nine studies in heart and kidney transplant patients were randomized controlled trials.

Each of the nine studies found the HMG-CoA RIs to be effective in lowering total cholesterol. One study using simvastatin in heart transplant patients found 25% decrease in total cholesterol and 39% decrease in low density lipoprotein cholesterol after 12 months of therapy.3 Another study found a decrease in total cholesterol from 285 +/- 13 mg/dL to 233 +/- 10 mg/dL at sixteen weeks in kidney transplant recipients receiving lovastatin.4 Another simvastatin study in heart transplant patients found total cholesterol decreased by 12.5% and LDL decreased by 21.3% at four months.5

One of the concerns of using the HMG-CoA RIs in transplant patients is the potential interaction with cyclosporine. Rhabdomyolysis is thought to be induced by an interaction between cyclosporine and the HMG-CoA RIs. In the study by Kobashigawa, et.al.6 cardiac transplant patients received low dose lovastatin (10 to 20 mg) and cyclosporine. Rhabdomyolysis was reported in one patient when the lovastatin dose was raised to 40 mg. The authors believe that low dose lovastatin is safe and effective in these patients but there is a small therapeutic window.

COST-EFFECTIVENESS

Search Strategy: Cost-Effectiveness of any HMG-CoA RI

Pharmacoeconomics terms such as cost-effectiveness, cost-benefit, cost-minimization are sometimes used indiscriminantly when discussing the economics of drug therapies. There are, however, specific definitions for these terms. Select pharmacoeconomic terms have been defined and assigned a valid descriptor code in the IDIS database to aid in searching this topic area.

Search/Results: To find the definition and descriptor for a pharmacoeconomics term, first press <F3>, select Descriptor Definitions and enter ECON. This will pull all the valid pharmacoeconomics descriptors and their definitions. Scrolling through these, you will find that the descriptor for cost-effectiveness is 131 ECON COST EFFECTIVENESS. At the end of the definition, the year the descriptor was added to the database, 1993, is also listed. When searching you may notice that some of the records found using this descriptor appear before 1993. Articles already in the database were retrieved and updated with this descriptor when it was added.

To find articles regarding the cost-effectiveness of the HMG-CoA RIs enter 131 ECON COST EFFECT* (lowercase works too) in the first field of the Global Search template. Arrow down below the ====AND==== and enter simvastatin, pravastatin, fluvastatin, and lovastatin. Press <Enter>. Twenty-six records are found. When searching using the Global Search template do not use a descriptor code number e.g. 131, by itself. Searching globally with 131 will find not only descriptor 131 but also page, volume and issue numbers or where ever else the number 131 appears. It is best to combine the descriptor number with its code name (e.g. 131 ECON COST EFFECT*) for the most precise searching. Using the Field Search template it is, however, possible to use only the valid descriptor code number in the Descriptor field.

Clinical Information: Cost of Life Years Saved

In cost-effectiveness studies, the outcome is often reported in cost per life years saved. Several citations express the results in this manner. One study looking at the cost-effectiveness of pravastatin in secondary prevention of coronary artery disease (subjects already have coronary atherosclerosis) found that the cost of life years saved varied from $7,124 to $12, 665. A conclusion from this study was that compared to other treatment options e.g. percutaneous transluminal coronary angioplasty, coronary artery bypass, and hydrochlorothiazide in treatment of systemic hypertension, the cost of life years saved for pravastatin is lowest.7

Another study looked at the cost-effectiveness of pravastatin in the treatment of primary prevention of coronary artery disease (subjects have risk factors for coronary atherosclerosis) in middle age Swedish men. This study compared the cost-effectiveness of usual advice and intensive advice alone and in combination with pravastatin. The advice given in this study related to non-pharmacological treatments for lowering cholesterol. The cost per life year gained with usual advice and pravastatin is $61,000 assuming that the epidemiologically expected reduction in coronary heart disease is attained. The investigators of this study concluded that pravastatin was not cost-effective as a primary prevention in middle aged men with cholesterol levels of 6.50-7.8 mmol L-1 .8

An article appearing in JAMA9 found that the cost per year of live saved using lovastatin in the prevention of coronary heart disease varied by age and sex. Separated into categories by sex, age, low vs. high risk, and with or without non- coronary heart disease costs, the cost per year of life saved ranged from $22,642 to $151,132 (Canadian dollars). One of the main points drawn from this study was that due to longer life expectancy from lovastatin treatment, non- coronary heart disease costs may be significantly increased in the elderly.

These few studies also show that cost-effectiveness may be highly variable even for a single drug or drug class. What may be considered a cost-effective treatment in one scenario may not hold true for another set of circumstances. The studies also make clear that drug cost alone is not sufficient information to adequately compare therapeutic options.

ATORVASTATIN: A NEW HMG-COA RI

Search Strategy:Any published information

Using the Global Search template you may enter the drug term atorvastatin in any field without first checking the Thesaurus. If using the Field Search template, enter atorvastatin in the Drug field. If you are not sure if atorvastatin is a valid drug term, first check the Thesaurus by pressing F3, selecting Thesaurus and entering the term atorvastatin. The Thesaurus verifies that ATORVASTATIN is a valid drug term in the IDIS database. Searching the term atorvastatin using either the Global Search or Field Search retrieves nine articles.

Clinical Information:Overview of studies found

Several of the articles found are studies focusing on the pharmacokineticsand pharmacodynamics of atorvastatin. One study10 compared morning and evening dosing and its influence on pharmacokinetics. Unlike other HMG-CoA RIs which have shown that evening doses reduce cholesterol more than morning doses, the elimination half life for atorvastatin indicates that it may not exhibit such a diurnal variation. Another study11 looked at gender and age influences. After a single oral dose, the Cmax was 42.5% higher in elderly subjects compared to younger subjects. The Cmax was 17.6% higher in women than in men. In a randomized controlled trial that appeared in JAMA12, the effectiveness and tolerability of atorvastatin was studied in patients with hypertriglyceridemia. In this study, participants were following the National Institutes of Health National Cholesterol Education Program Step I Diet and were assigned to either 5 mg, 20 mg, or 80 mg of atorvastatin or placebo. The authors concluded that at the 20 mg and 80 mg doses, total triglyceride levels were significantly reduced. They further asserted that triglycerides were actually reduced, not just redistributed.

IN CONCLUSION

This look at the HMG-CoA RIs is an example of the broad range of clinical information that can be pulled from the IDIS database. Whether it is an issue of efficacy, side effects, drug interactions or pharmacoeconomics, the IDIS database will help you answer the question.

Brad Gilchrist, R.Ph.


REFERENCES

1. Pedersen T R; Kjekshus J; Berg K; Haghfelt T; Et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The scandinavian simvastatin survival study (4s). LANCET 1994; 344:1383-1389 (IDIS Article Number 338582).

2. Shepherd J; Cobbe S M; Ford I; Isles C G; Et Al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N ENGL J MED 1995; 333:1301-1307 (IDIS Article Number 355664).

3. Pflugfelder P W; Huff M; Oskalns R; Rudas L; Kostuk W J. Cholesterol-lowering therapy after heart transplantation: a 12-month randomized trial. J HEART LUNG TRANSPLANT 1995; 14:613-622 (IDIS Article Number 352755).

4. Lal S M; Hewett J E; Petroski G F; Van Stone J C; Ross G. Effects of nicotinic acid and lovastatin in renal transplant patients: a prospective, randomized, open-labeled crossover trial. AM J KIDNEY DIS 1995; 25:616-622 (IDIS Article Number 345390).

5. Campana C; Iacona I; Regazzi M B; Gavazzi A; Et Al. Efficacy and pharmacokinetics of simvastatin in heart transplant recipients. ANN PHARMACOTHERAPY 1995; 29:235-239 (IDIS Article Number 344884).

6. Kobashigawa J A; Murphy F L; Stevenson L W; Moriguchi J D; Et Al. Low-dose lovastatin safely lowers cholesterol after cardiac transplantation (suppl). CIRCULATION 1990; 82:IV281-IV283 (IDIS Article Number 275227).

7. Ashraf T; Hay J W; Pitt B; Wittels E; Et Al. Cost-effectiveness of pravastatin in secondary prevention of coronary artery disease. AM J CARDIOL 1996; 78:409-414 (IDIS Article Number 372587).

8. Johannesson M; Borgquist L; Jonsson B; Lindholm L H; Et Al. The cost effectiveness of lipid lowering in swedish primary health care. J INT MED 1996; 240:23-29 (IDIS Article Number 371838).

9. Hamilton V H; Racicot F E; Zowall H; Coupal L; Grover S A. The cost-effectiveness of hmg-coa reductase inhibitors to prevent coronary heart disease: estimating the benefits of increasing hdl-c. JAMA 1995; 273:1032-1038 (IDIS Article Number 345001).

10. Cilla D D; Gibson D M; Whitfield L R; Sedman A J. Pharmacodynamic effects and pharmacokinetics of atorvastatin afteradministration to normocholesterolemic subjects in the morning and evening. J CLIN PHARMACOL 1996; 7: 604-609 (IDIS Article Number 370473).

11. Gibson D M; Bron N J; Richens A; Hounslow N J; Et Al. Effect of age and gender on pharmacokinetics of atorvastatin in humans. J CLIN PHARMACOL 1996; 36:242-246 (IDIS Article Number: 365677).

12. Bakker-arkema R G; Davidson M H; Goldstein R J; Davignon J; Et Al. Efficacy and safety of a new hmg-coa reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 1996; 275:128-133 (IDIS Article Number 357912).


IDIS STAFF PROFILE

Kevin G. Moores, Pharm. D., joined the Division of Drug Information Service as the Director of the Iowa Drug Information Network (IDIN), in December 1995. The Iowa Drug Information Network is an educational and service program designed to support the drug information role of the pharmacist in providing pharmaceutical care. Developed by the University of Iowa College of Pharmacy and supported by the Iowa Pharmacists Association, IDIN will be the center for the generation and communication of drug information to practitioners in order to optimize medication use and achieve specific health outcomes. IDIN provides personal support for the drug information needs of health care practitioners and an electronic network for access to resources and communications with other Network members. The educational programs of IDIN are designed to improve the drug informatics skills of practitioners, and to improve skills to define drug information needs, retrieve needed information and evidence, and analyze and interpret available evidence for use in health care decision making.

In addition to directing the IDIN, Dr. Moores participates in the teaching of the drug information components of the curriculum of the University of Iowa College of Pharmacy and precepts a drug information rotation for the Pharm. D. students.

Dr. Moores received his pharmacy degree from the University of Nebraska Medical Center, and completed a Hospital Pharmacy Residency program at the University of Iowa Hospitals and Clinics. Following the residency program, he joined the staff of the Drug Information Poison Control Center at the University of Iowa Hospitals and then served as the supervisor of the Center until August of 1992 when he became the Director of Drug Information for the University of Missouri at Kansas City.

Kevin Moores
Kevin Moores


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