World of Drugs

World of Drugs - Volume 7, Issue 2 - June 1996


In This Issue ...
 Search Tip 
 Staff Profile 
 Current Clinical Issues -- Search Strategies 
 Outcomes -- A New Descriptor  
 FDA Drug Approvals 
 Exhibit Schedule 

SEARCH TIP: Searching for Pregnancy Articles Using the Disease Field

Most pregnancy articles are tagged with the disease term V22. PREGNANCY NEC, unless the pregnancy is specified as high-risk. In that case V23. PREGNANCY, HIGH-RISK NEC is used. This term includes pregnancies with a history of trophoblastic disease, a history of abortion or another unspecified risk. V23. is rarely indexed: only 77 entries in the entire database as opposed to 5,250 for V22.

If a specific condition is being treated in a pregnant woman, search V22. along with that specific disease term, found by checking the thesaurus. For instance, articles about the treatment of breast cancer in pregnancy will be retrieved by searching V22. and 174. NEOP, MGN-FEMALE BREAST.

However, if the condition is specified as complicating the pregnancy, arising because of the pregnancy, or aggravated by the pregnancy, do not use V22. but one of the following modified ICD-9 codes for pregnancy complication:

When indexing an article it is sometimes difficult to decide if the condition is complicating the pregnancy or not. Thus, to retrieve all articles for a certain condition in pregnancy, it is best to perform two separate searches:

1) V22. combined with the appropriate disease term found by checking the thesaurus, and
2) the specific pregnancy complication term by itself.

The above list contains only the modified ICD-9 codes used in the IDIS system. The IDIS system also uses several other disease terms related to ectopic pregnancy, abortion, delivery, and the puerperium. These will be the topic of a future article.

Lise Paulik, R.Ph.


Jamie Siegel

Jamie Siegel

IDIS STAFF PROFILE

The first contact an IDIS SYSTEM prospective or current subscriber has with IDIS is often through a telephone call. The friendly and efficient voice directing your call is most likely our departmental secretary, Jamie Siegel. Answering the phone and routing calls is just one of Jamie's many contributions to IDIS. She also performs extensive word processing, makes all travel and exhibit arrangements, and serves as the production/design coordinator for the World of Drugs.

Jamie has been with The University of Iowa for more than six years and has worked at IDIS for the last year and a half. Jamie and her boyfriend are planning to be married in September of 1997, and although their wedding is more than a year away, Jamie has been busy making arrangements for the big day!


CURRENT CLINICAL ISSUES -- SEARCH STRATEGIES

Tuberculosis, a Global Emergency

Tuberculosis, one of the oldest diseases known to humanity, is a leading infectious killer of adults around the world despite the introduction of chemotherapy in the mid 1940's. Difficulties in establishing effective national tuberculosis control programs, HIV epidemic, traveling and migration have had a deep impact on the resurgence of tuberculosis. The re-emergence of tuberculosis as a global health problem worldwide has prompted the World Health Organization (WHO) to declare tuberculosis a global emergency (April 1993). The objective of this article is to help you efficiently retrieve current tuberculosis information, a therapeutic challenge for any clinician.

The Disease
Tuberculosis is a chronic recurrent bacterial infection caused by the tubercle bacillus Mycobacterium tuberculosis and by Mycobacterium bovis.

Mycobacterium bovis infection caused by the consumption of contaminated milk is rare.

Mycobacterium tuberculosis infection is transmitted from person to person by inhalation of dry infectious airborne droplets. Inhaled mycobacteria are transported by lymphatic vessels to the regional lymph nodes in the lungs setting up granulomatous foci. These primary lesions may undergo a characteristic caseous necrosis, heal and calcify into nodules called Ghon's complex or primary tuberculous complex. This primary tuberculosis infection is usually silent and asymptomatic. In some populations, such as infants or immunocompromised individuals, it can evolve and progress to a clinical disease manifested in most cases as pulmonary involvement. The primary infection can be contained or spread through the blood stream. The bacilli can then be disseminated to different organs where they lie dormant and provide seedings for secondary or reactivation tuberculosis that can manifest clinically years after the primary infection.

Tuberculosis can affect every organ in the body from the meninges to the intestines, but pulmonary tuberculosis is by far the most common. IDIS offers a choice of 28 valid disease terms for primary and secondary tuberculosis. Their ICD-9 codes range from 010. to 018. Some examples of these valid disease terms and their modified ICD-9 codes are:

Tuberculosis, Primary Infect 010.
Tuberculosis, Resp Syst NEC* 011.
Tuberculosis, Pleurisy 012.0
Tuberculosis, Trachea/Bronch 012.2
Tuberculosis, Laryngitis 012.3
Tuberculosis, CNS NEC 013.
Tuberculosis, Meningitis 013.0
Tuberculosis, Intestinal 014.
Tuberculosis, Bone/Joint NEC 015.
Tuberculosis, Kidney 016.0
Tuberculosis, Bladder 016.1
Tuberculosis, Lymph Node 017.2
Tuberculosis, Thyroid 017.5
Tuberculosis, Organ NEC 017.
Tuberculosis, Miliary 018.

*NEC: Not Elsewhere Classified

Finding all tuberculosis articles
There are two main steps in searching IDIS:

1) identifying the valid search term, and
2) searching

1) Identifying the valid search term:

There are 177 entries for this look up. Each entry is preceded either by Dr (drug), Di (disease) or De (descriptor). To restrict to tuberculosis as a disease term, type Di Tuberculosis. All these disease entries have in common the term tuberculosis.

2) Search:

In the 1985- present file there are 1,164 articles and 2,113 in the 1966 - 1984 file for a total of over three thousand citations. Thus, limiting a tuberculosis search with population modifiers, individual drugs, age groups or tuberculosis at specific organ sites will be important. While tuberculosis can invade most any body site, the lung accounts for most cases. TUBERCULOSIS RESP SYST NEC is the most frequently used tuberculosis term in IDIS.

Finding primary tuberculosis articles
1) Thesaurus

There are eleven entries for this look up. All eleven entries are crossed to one single valid disease term TUBERCULOSIS, PRIMARY, INFECT 010.

2) Search

To avoid retyping, the cut and paste technique can be used: after identifying the valid disease term from the Thesaurus, Press Alt M, and move the cursor to the valid disease term or number by using the arrow keys, press Alt R (highlight the term), move the cursor to the last character of the valid term, press Alt R (delimit the term), F3 (select a search template), select Field Search, arrow down to disease, press Alt P (paste) then press F2 or enter to search (20 hits found). This cut and paste search technique is useful in preventing transcribing errors.

Finding site specific secondary tuberculosis articles
To find a listing of all possible search terms for tuberculosis, press F3, select search template Thesaurus from the pull down menu. Type Tuberculosis or use truncation. There are 177 entries. Each entry is preceded by either dr(drug), di (disease) or de (descriptor). To restrict to entries specific to disease, retype the term tuberculosis or truncated term followed or preceded by di. From the 172 disease terms found, select a specific term for example Tuberculous, Meningitis. Follow previous search steps. Forty articles related to tuberculous meningitis are found in the IDIS 1985 - present file.

Tuberculin Test
Several types of this immunologic product are available. Due to its sensitivity and specificity, the purified protein derivative (PPD) tuberculin is the most reliable. The application of the antigen to the outer layers of the skin of the volar or dorsal surface of the forearm can be done by different routes: intradermal injection (Mantoux test), six tine needle injection (Heaf test) or by scratch (cutireaction test). The Mantoux test is used in the United States. The standard dose for the Mantoux test is 0.1ml of PPD tuberculin containing 5 tuberculin units (TU). A lower dose (1 TU) is used in children and a much higher dose (250 TU)is used for retesting. The test is read after 48-72 hours. A softly palpable induration (wheal) of over 10 millimeters in diameter is indicative of current or prior mycobacterial infection, except in immunosuppressed patients or in patients with severe infections in whom skin reactivity is reduced and for whom an induration of over 5 millimeters is considered a positive reaction. Tuberculin skin test is a valuable tool but is non-specific to Mycobacterium tuberculosis so it cannot be used as a definitive diagnosis. The diagnosis of active cases of tuberculosis can only be confirmed by the identification of the acid-fast tubercle bacilli in body fluid or tissue smears. Chest X-Ray, and CT scans are other helpful diagnosis tools in cases of non conclusive smears and for the evaluation of the activity of the disease.

Finding articles comparing different types of tuberculin
Articles considering different formulations of the same drug are indexed under Formulation Efficacy, descriptor 22. After selecting the Field Search template, type Tuberculin in the drug field and Formulation Efficacy or 22 in the descriptor field. Press return or F2. There are 5 articles related to tuberculin formulation efficacy in IDIS from 1985 - present.

Findings articles related to tuberculin testing in AIDS patients
The interpretation of tuberculin test differs in immunosuppressed patients such as patients with aids or severe infections. The result of a search in the thesaurus for the terms Tuberculosis and Test shows that IDIS has a specific valid disease term for the diagnosis of tuberculosis Diag Test-Tuberculosis V74.1. A combination of either the disease term DIAG TEST-TUBERCULOSIS or the disease code V74.1 and the valid disease term for AIDS (Syn-Acq Immune Deficiency) or disease code 042. in the disease field of the Field Search template retrieves 10 articles related to tuberculosis testing in AIDS patients.

Bacille Calmette Guerin Immunization
BCG vaccine, a live but attenuated strain of Mycobacterium bovis is used through the world for the prevention of serious forms of tuberculosis although it is not generally recommended in the United States. In areas of high tuberculosis risk, WHO recommends vaccination of children and infants including asymptomatic HIV infected children as early as possible in life if they have a negative tuberculin test. BCG benefits have not been seen in adults and BCG vaccination is contraindicated in persons with impaired immune response such as in leukemia patients, lymphoma patients, corticosteroid immunosuppressed patients. BCG immunization in adult HIV infected patients is also contraindicated. BCG vaccination can cause a positive reaction to tuberculin test thereby causing a misinterpretation of the skin test.

Identifying tuberculosis prevention -BCG vaccine articles
BCG vaccine is effective in active immunization programs against tuberculosis but is also used in the treatment of bladder or lung cancer. Active vaccination is cross-referenced to Inoculation and Vaccination (disease code 99.3) in IDIS. The combination of the terms BCG Vaccine in the drug field and Inoculation in the disease field on the Field Search template retrieves articles where BCG vaccine is used in an active tuberculosis prevention and exclude all citations where BCG is used as antineoplastic adjuvant.

Identifying BCG contraindications articles
The combination of the terms BCG Vaccine in the drug field and Contraindication or 52 in the descriptor field on the Field Search template retrieves all articles dealing with general BCG contraindications. Twenty-nine articles are found in 1985 - present and 20 in the 1966 - 1984 file.

Identifying interaction of BCG vaccine and tuberculin test articles
Drug-induced modification of laboratory test values causing a false result is indexed under Drug Modified Lab Value, descriptor 73. To locate articles related to BCG causing a misinterpretation of tuberculin skin test enter BCG Vaccine in the drug field and Drug Modified Lab Value or 73 in the descriptor field on the Field Search template. Nine articles are found in the 1985 - present and eight in the 1966 - 1984 file.

Preventive Therapy
In patients with a positive tuberculin skin test, a complete full course of isoniazid at a dose of 10mg/kg orally daily for children and adults, up to a maximum of 300mg a day for adults, for 6-12 months has been proven effective in preventing tuberculosis infection from progressing to an active stage. The length of the therapy varies depending on factors such as age or HIV status. Pediatric isoniazid preventive therapy should be at least nine months, whereas HIV infected patients should have a longer course up to one year. Non-compliance is always a problem for any prolonged therapy. A twice a week dose of 15mg/kg isoniazid, known as intermittent therapy, can increase compliance. Directly Observed Therapy (DOT) is highly recommended by WHO and Centers of Disease and Control and Prevention (CDC) as a mean to monitor therapeutic adherence. Isoniazid side effects include peripheral neuropathy such as hand or foot paresthesia, rash, mood change, drug fever and severe hepatitis. The incidence of hepatitis increases with age, older patients are at higher risk of severe hepatitis. Another acceptable preventive regimen is a four month combination therapy with isoniazid and rifampin when drug resistance is remote.

Identifying isoniazid in the prevention of tuberculosis articles
Select the Field Search template , enter Isoniazid in the drug field and the term Prophylaxis NEC or V07. together with the term Tuberculosis (or a truncation of the term) in the disease field. One hundred and thirty-six citations are found in the 1985 - present and 19 in the 1966 - 1984 file.

Identifying isoniazid compliance articles
Select the Field Search template, enter Isoniazid in the drug field and Patient Compliance or 103 in the descriptor field. This strategy retrieves 16 articles dealing with isoniazid compliance.

Identifying isoniazid age related hepatitis articles
Select the Field Search template, enter Isoniazid in the drug field, Modification Ef Age or 152 and Side Ef Digestive or 78 in the descriptor field. Six citations related to the influence of age in the occurrence of hepatitis caused by isoniazid. Note: Modification EF Age has only been available since August 1995.

Identifying isoniazid resistance articles
Since August 1995 bacteria, virus and fungi resistance are indexed under Drug Resistance (descriptor 148). It was previously indexed under Modification of Effect (Descriptor 42). To retrieve isoniazid resistance articles published since 1995 use the term Isoniazid in the drug field and the term Drug Resistance or code 148 in the descriptor field on the Field Search template. Forty citations, including in vitro studies, are found.

By using the term Modification of Effect instead of Drug Resistance, with isoniazid and limiting our range from 1985 - 1994, 242 articles are found. Modification of Effect was not a specific descriptor for antibiotic resistance. Concepts such as variation in response due to time or route of administration, environmental factors were indexed under this descriptor causing false hits.

Treatment
The recommended initial regimen for active tuberculosis consists of a combination of four drugs: isoniazid, rifampin, pyrazinamide and ethambutol or streptomycin for six to nine months. Drug susceptibility tests should be conducted for all patients and regimens modified accordingly. For some individuals, when there is little drug resistance (less than 4% isoniazid resistance), a regimen with isoniazid, rifampin and pyrazinamide seems to be adequate.

It is estimated that on average up to 25% of patients are not compliant and do not adhere to their tuberculosis recommended regimen, thereby adding more risk to the emergence of drug resistance. Drug susceptibility testing (for example by minimum inhibitory concentration or disk diffusion) plays a major role in the choice of an antibiotic therapy especially with the emergence of mycobacterial strains that are resistant to more than one antitubercular.

Identifying minimum inhibitory concentration articles
To find articles related to the MIC of a specific antibiotic, type the drug term in the drug field and Antiinfective Conc or 94 in the descriptor field on the Field Search template and press return.

Identifying antitubercular articles
Each IDIS valid drug term is assigned a modified American Hospital Formulary Service (AHFS) number. These numbers are grouped by pharmacologic therapeutic class and within a class they are subgrouped into therapeutic category. A truncated drug code search will retrieve all citations related to a therapeutic category or class depending on the level of the truncation.

The Antiinfective class includes therapeutic categories such as antibiotics, anthelmintics, antivirals, antituberculars etc... Drugs used in the treatment of tuberculosis are grouped under the antitubercular subgroup.

8000000 Antiinfectives
8040000 Amebicides
8080000 Anthelmintics
8012000 Antibiotics
8160000 Antituberculars
8160001 Clofazimine
8160002 Aminosalicylate, Para-
8160003 Isoniazid
........ ........
8180000 Antivirals

To find articles related to drugs classified as antituberculars in IDIS, type the truncated drug number 8160* in the drug field on the Field Search template and press return.

The samples of the searches in this article can increase clinical knowledge about tuberculosis and bring relevant clinical answers to this national and international health problem. After several decades of progressive decrease in the number of reported cases, tuberculosis control is now more difficult than ever with the emergence of multi-drug resistant strains and the AIDS epidemic.

ThaiBinh TonThat, R.Ph., Pharm.D.

BIBLIOGRAPHY

Bass J, Farer R L, Hopewell P, Jacobs R, Et Al. Control of tuberculosis in the United States. AM REV RESPIR DIS 1992; 146:1623-1633. (IDIS Article Number 308127).

Bass JB, Farer LS, Hopewell PC, O'Brien R, Et Al. Treatment of tuberculosis and tuberculosis infection in adults and children. AM J RESP CRIT CARE MED 1994; 149:1359-1374. (IDIS Article Number 330253).

Bloch AB, Cauthen GM, Onorato IM, Dansbury KG, Et Al. Nationwide survey of drug-resistant tuberculosis in the United States. JAMA 1994; 271:665-671. (IDIS Article Number 325814).

Busillo CP, Lessnau KD, Sanjana V, Soumakis S, Et Al. Multidrug resistant mycobacterium tuberculosis in patients with human immunodefiency virus infection. CHEST 1992; 102:797-801. (IDIS Article Number 302750).

Carosi G, Matteelli A. Prophylaxis for tuberculosis in Europe--ongoing research. CLIN INFECT DIS 1996; 22:S55-S60. (IDIS Article Number 362404).

Colditz GA, Brewer TF, Berkey CS, Wilson ME, Et Al. Efficacy of BCG vaccine in the prevention of tuberculosis: meta-analysis of the published literature. JAMA 1994; 271:698-702. (IDIS Article Number 325816).

Fitzgerald JM, Gafni A. A cost-effectiveness analysis of the routine use of isoniazid prophylaxis in patients with a positive mantoux skin test. AM REV RESPIR DIS 1990; 142:848-853. (IDIS Article Number 273469).

Gilbert GL. Multidrug-resistant tuberculosis: prevention is better than cure. MED J AUST 1996; 164:121-124. (IDIS Article Number 361835).

Glassroth J. Tuberculosis treatment; risk, benefit and perspective. CHEST 1991; 99:266-267. (IDIS Article Number 283330).

Grabenstein JD. Tuberculosis and the pharmacist: rational use of tuberculins and BCG. HOSP PHARM 1990; 25:673-677. (IDIS Article Number 268488).

Huebner RE, Schein MF, Bass JB. The tuberculin skin test. CLIN INFECT DIS 1993; 17:968-975. (IDIS Article Number 323151).

Morse DI. Directly observed therapy for tuberculosis. Spend now or pay later. BMJ 1996; 312:719-720. (IDIS Article Number 363120).

Park MM, Davis AL, Schluger NW, Cohen H, Rom WN. Outcome of MDR-TB patients, 1983-1993: prolonged survival with appropriate therapy. AM J RESP CRIT CARE MED 1996; 153:317-324. (IDIS Article Number 359496).

Shafer RW, Edlin BR. Tuberculosis in patients infected with human immunodeficiency virus: perspective on the past decade. CLIN INFECT DIS 1996; 22:683-704. (IDIS Article Number 363644).

Sterling TR, Brehm WT, Frieden TR. Isoniazid preventive therapy in areas of high isoniazid resistance. ARCH INTERN MED 1995; 155:1622-1628. (IDIS Article Number 352478).

Zhao FF, Murray C, Spinaci S, Styblo K, Et Al. Results of directly observed short-course chemotherapy in 112,842 Chinese patients with smear-positive tuberculosis. LANCET 1996; 347:358-362. (IDIS Article Number 360478).


Outcomes -- A New Descriptor

The word "Outcomes" started appearing in the medical literature several years ago. While still not completely defined, Outcomes Research is a recognized study type. The conclusions of these studies often have more far ranging implications than standard clinical setting studies. We have recently added a new descriptor to identify findings of outcomes research studies. The new descriptor is as follows:

154 OUTCOMES Findings of a comprehensive outcomes study that has systematically compared and/or evaluated relevant treatment strategies for a particular condition over a significant time period in a standard patient care setting (not a clinical research setting). Treatments are

evaluated by selected relevant outcomes with emphasis on establishing empirical therapy. Outcomes studies generally evaluate treatment effects on areas such as mortality, morbidity, complications, symptom reduction, functional status improvement, quality-of-life and financial concerns such as cost-benefit or cost-effectiveness.

Two prime examples of outcomes study articles in the IDIS database are from The New England Journal of Medicine. They are article number 335148 "The Efficacy and Cost Effectiveness of Vaccination Against Influenza Among elderly Persons Living in the Community" N ENGL J MED 1994, 331:778-784 and article number 356730 "Low -Molecular-Weight Heparin for the Treatment of Acute Ischemic Stroke" N ENGL J MED 1995, 333:1588-1593.

Brad Gilchrist, R.Ph.

FDA DRUG APPROVALS

Two more drugs have been approved by the FDA for treatment of HIV infection. Ritonavir and indinavir, both protease inhibitors, were approved in March. These drugs prevent cleavage of protein precursors essential for HIV infection of new cells and viral replication.

Indinavir was granted accelerated approval based onclinical data presented to the FDA (not published) indicating patients on indinavir alone or in combination therapy for 24 weeks experienced a marked increased in their CD4 levels and had a marked decrease in their viral load. For any drug granted accelerated approval, a true clinical benefit must be demonstrated within a reasonable period of time. Two trials are ongoing to evaluate the clinical benefits of indinavir. Recommended dosage is 800 mg every eight hours. Indinavir is generally well tolerated. Nephrolithiasis has been reported in about 4% of patients. This was not associated with renal dysfunction and resolved with hydration and temporary interruption of therapy. Elevated indirect bilirubin levels were observed in approximately 10% of patients; less then 1% were associated with elevations of the liver enzymes ALT or AST.

The FDA based its approval of ritonavir on data showing that the drug not only improves laboratory markers, such as viral load and CD4 counts, but reduces disease progression and mortality in people with advanced HIV disease. In short term randomized placebo-controlled trials, Danner et al1 and Markowitz et al2 found that ritonavir alone raised CD4 counts and lowered HIV RNA in HIV infected patients. Patients received daily doses ranging from 600 to 900 mg. Reported adverse reactions included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. In a placebo-controlled study of 1,090 patients with advanced HIV infection, ritonavir added to the therapeutic regimen decreased the incidence of disease progression or death after six months treatment. Twenty-six (5%) patients treated with ritonavir died compared to 46 (8%) given placebo.3

1. Danner SA, Carr A, Leonard JM et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. N Engl J Med 1995; 333:1528-33. (IDIS Article Number 357352)
2. Markowitz M, Saag M, Powderly WG et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med 1995; 333:1534-9. (IDIS Article Number 357353)
3. Anon. New drugs for HIV infection. Med Lett Drugs Ther 1996; 38:35-7. (IDIS Article Number 363399)

A new taxoid, docetaxel, has been approved by the FDA for breast cancer patients whose disease has progressed despite treatment with doxorubicin, the current standard first-line chemotherapy for breast cancer. Docetaxel is a semisynthetic taxane, prepared from a noncytotoxic precursor extracted from the needles of the European yew tree. The taxoids docetaxel and paclitaxel, both have a unique cellular mechanism of action; the promotion of tubulin polymerization into stable microtubules and the inhibition of tubulin depolymerization. In phase II trials, Ravdin et al1 and Valero et al2 found docetaxel to have a high level of antitumor activity in patients with anthracycline-resistant breast cancer and measurable recurrent disease. Both studies used the same rigorous definition of resistance and patients in both studies received the single-agent docetaxel 100 mg/m2 every three weeks. Ravdin et al1 observed three complete and 17 partial responses in 35 patients (57% response rate) while Valero et al2 observed 18 partial responses in 34 patients (53% response rate). No other single agent or combination has been reported to show this degree of activity in anthracycline-resistant breast cancer. The major dose-limiting effect for docetaxel is neutropenia. The majority of patients in these two trials experienced grade 4 neutropenia.1-2 The syndrome of cumulative fluid retention is unique to docetaxel and was first noted in phase I trials.3 It is manifested by gradual accumulation of peripheral edema and the appearance of nonmalignant effusions. This syndrome occurred in 25 of 42 patients in the Ravdin study1 and in 15 of 35 patients in the Valero study.2 The majority of patients experienced cutaneous side effects. Other clinically significant adverse reactions included stomatitis, neurosensory changes and asthenia. Mild diarrhea, nausea and vomiting also occurred.

Docetaxel has also been evaluated as first-line chemotherapy in metastatic breast cancer. Trudeau et al4 conducted a phase II study in fifty-one patients with measurable metastatic breast cancer. The planned dosage regimen was 100 mg/m2 intravenously every 3 weeks. Due to the high incidence rate of febrile neutropenia in the first 35 patients, the starting dose was reduced to 75 mg/m2 for the remaining patients. Sixty percent of the patients experienced hypersensitivity reactions. Edema developed in 63% of patients. The response rate for 32 assessable patients at 100 mg/m2 was 63% and 40% for 15 assessable patients registered at the 75 mg/m2.

1. Ravdin PM, Burris HA, Cook G et al. Phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. J Clin Oncol 1995; 13:2879-85. (IDIS Article Number 357157)
2. Valero V, Holmes FA, Walters RS et al. Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 1995; 13:2886-94. (IDIS Article Number 357158)
3. Tomiak E, Piccart MJ, Kerger J et al. Phase I study of docetaxel administered as a 1-hour intravenous infusion on a weekly basis. J Clin Oncol 1994; 12:1458-67. (IDIS Article Number 332411)
4. Trudeau ME, Eisenhauer EA, Higgins BP et al. Docetaxel in patients with metastatic breast cancer: a phase II study of the national cancer institute of Canada-clinical trials group. J Clin Oncol 1996; 14:422-8. (IDIS Article Number 362034)

Interferon beta-1a is the second interferon product to be approved by the FDA to treat relapsing multiple sclerosis and the first product shown to slow the disease process. The first interferon for the treatment of multiple sclerosis, interferon beta-1b, was licensed in July, 1993. In a randomized, double blinded, placebo-controlled, multicenter trial involving 301 patients with relapsing multiple sclerosis, patients receiving 6 million units interferon beta-1a by intramuscular injections once a week showed a significant delay in time to sustained disability progression compared to placebo. Interferon beta-1a treated patients also had significantly fewer exacerbations during the two-year study. Most common adverse reaction noted was flu-like symptoms.1

1. Jacobs LD, Cookfair DL, Rudick RA et al. Intramuscular interferon beta-1a fordisease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39:285-94. (IDIS Article Number 362581)

The non-ionic contrast agent iodixanol is indicated for intra-arterial use in visceral intra-arterial digital subtraction angiography and angiocardiography, and peripheral, visceral, and cerebral arteriography. It is also indicated for intravenous use in contrast enhancement computed tomography; head and body imaging, excretory urography and peripheral venography. Iodixanol has an osmolality that is less than half that of monomeric, nonionic agents. Sodium, calcium, and magnesium are added to iodixanol to make it isosmotic to blood.

In a randomized, double-blind study, Hill et al1 evaluated the hemodynamic and electrophysiologic effects of iodixanol and compared them with the standard nonionic contrast agent, iohexol, in 200 patients undergoing elective diagnostic cardiac angiography. No differences were noted between the two agents in the mean changes in systolic or diastolic blood pressure or heart rate during or immediately after any angiography. However, significantly more patients given iodixanol had a decrease in diastolic blood pressure of >20 mm Hg during left coronary angiography. Significant differences in electrophysiologic parameters noted were slightly more PR prolongation during left coronary angiography with iodixanol and more ST-segment depression with iohexol during coronary angiography. Neither was clinically significant. Injection-associated discomfort occurred with both agents. Angiographicquality was equal in all angiograms being assessed as good or excellent in both groups.

Gavant and Siegle2 evaluated the safety and radiographic efficacy of iodixanol in 40 patientsundergoing elective excretory urography. Two formulations of iodixanol were used in this study; iodixanol 270 and iodixanol 320. Bolus injection doses of iodixanol with either 27 or 32 g of iodine were used. No adverse event or idiosyncratic reaction occurred. Seven patients felt coolness at the injection site. Adequate diagnostic urographic examinations were obtained with both doses. Nossen et al3 studied the elimination of iodixanol and iohexol in 16 patients with severely reduced renal function, and investigated their use as markers of glomerular filtration rate in such patients. Patients were randomized to receive either iodixanol 320 mg I ml-1 or iohexol 350 mg I ml-1. Mean urine recovery was 76.1% for iodixanol and 74.8% for iohexol. Renal clearance of radiolabelled iothalamate, a marker of glomerular filtration rate (GFR), measured simultaneously, indicated that both contrast agents were eliminated by the kidneys by glomerular filtration only. Therefore, both media were found to be suitable GFR markers.

1. Hill JA, Cohen MB, Kou WH et al. Iodixanol, a new isosmotic nonionic contrast agent compared with iohexol in cardiac angiography. Am J Cardiol 1994; 74:57-63. (IDIS Article Number 331626)
2. Gavant ML, Siegle RL. Iodixanol in excretory urography: initial clinical experience with a nonionic, dimeric (ratio 6:1) contrast medium. Radiology 1992; 183:515-18. (IDIS Article Number 295542)
3. Nossen JO, Jakobsen JA, Kjersgaard P et al. Elimination of the non-ionic x-ray contrast media iodixanol and iohexol in patients with severely impaired renal function. Scand J Clin Lab Invest 1995; 55:341-50. (IDIS Article Number 349278)

The orphan drug sodium phenylbutyrate has received FDA approval for treating urea cycle disorders. These disorders are genetic in nature and affect a patient's ability to remove nitrogen from the body. All have a specific liver enzyme deficiency that leads to an increased amount of ammonia in the blood, which may cause disturbed brain function and severe brain damage. The drug is indicated in all neonatal onset patients presenting in the first 28 days of life, and in patients with late-onset disease who have a history of hyperammonemic encephalopathy. Maestri et al1 monitored long-term survival and outcome of 24 infants born before 1990 with neonatal-onset argininosuccinate synthetase deficiency and treated with specific therapeutic protocols using sodium benzoate, sodium phenylacetate, and sodium phenylbutyrate. Cumulative survival rate was 87.5% at 5 years and 72% at 10 years of age. Fifteen of these survivors are currently treated with high doses of sodium phenylbutyrate. Among this group 11 are severely mentally retarded with the remaining four classified as borderline mentally retarded. All patients have had intercurrent hyperammonemic episodes, but their frequency has decreased with the use of sodium phenylbutyrate. In addition these patients are growth retarded.

1. Maestri NE, Clissold DB, Brusilow SW. Long-term survival of patients with argininosuccinate synthetase deficiency. J Pediatr 1995; 127:929-35. (IDIS Article Number 358531)

Trandolapril, a new nonsulfhydryl, long-acting, angiotensin-converting enzyme (ACE) inhibitor, approved by the FDA for the treatment of hypertension is efficacious in all types of hypertension, including blacks. In a double-blind, placebo-controlled dose ranging multicenter trial, De Bruijn et al1 studied 170 patients with mild-to-moderate hypertension randomized to receive either placebo or 0.5, 1 or 2 mg trandolapril once daily for 4 weeks. At the end of the study, the lowest dose to consistently produce a significant difference from placebo in reducing blood pressure was 1 mg. At the end of the study, both 1 and 2 mg doses were equally effective. The drug was well tolerated. Adverse reactions reported by 3% of the patients were headache, nausea, and insomnia. Two adverse reactions at the 0.5 mg dose were considered severe; headache and hypotension. To compare the efficacy and safety of trandolapril to a reference compound of the ACE inhibitors, Pauly and Safer2 compared trandolapril to captopril in a multicenter double-blind 16 week study. A total of 180 patients with mild-to-moderate hypertension were randomized to trandolapril 4 mg daily or captopril 50 mg twice daily. If blood pressure had not normalized at 8 weeks, hydrochlorothiazide 25 mg was added. At 8 weeks, the intention-to-treat analysis showed a significant difference for supine diastolic blood pressure between the two groups; trandolapril -13.5 +/- 0.9mm Hg, captopril -10.1 +/- 1.0mm Hg (mean +/- SEM). Blood pressure was normalized in 61% of patients receiving trandolapril compared to 44% for captopril. At 8 weeks, 26% of the trandolapril group received hydrochlorothiazide compared to 38% on captopril. The addition of hydrochlorothiazide further increased the antihypertensive effect. At the end of the study, 77% of the trandolapril group had normalized blood pressure compared to 58% in the captopril group. Overall incidence of adverse reactions was higher in the captopril group. In the trandolapril group none of the adverse reactions were considered by the investigators to be treatment related. To evaluate the effects of trandolapril on 24 hour blood pressure, Mancia et al3 conducted a multicenter, randomized double-blind , placebo-controlled study in patients with mild-to-moderate essential hypertension.. Following a washout period of 4 weeks, 42 patients were randomized to receive trandolapril 2 mg daily and 20 patients to receive placebo for six weeks. The investigators found that blood pressure was reduced at this dose level and this antihypertensive effect was manifested throughout the 24 hours. Trandolapril has also been evaluated on a long term basis. Backhouse et al4 evaluated the efficacy of trandolapril as the treatment of first choice and long-term tolerance in a large population, used alone and in combination with other antihypertensive agents, in the stepped-care regimen. An international study was conducted in which 1,049 patients with mild-to-moderate hypertension were recruited. Patients were treated unblinded for 1 year; therapy being started at 2 mg once daily. If blood pressure was not normalized after 1 month, the dose was increased to 4 mg daily, and then combined with diuretics and/or calcium antagonists in increasing doses if necessary. At the end point, blood pressure was normalized in 60% of the patients with monotherapy. The drug was well tolerated. Only 3.9% patients reported dry cough.

Dosage of trandolapril in the elderly does not appear to need modification. Arner et al5 found no difference in maximal plasma ACE inhibition for a 2 mg dose of trandolapril administered for 10 days in 10 young and 14 elderly patients with mild-to-moderate hypertension. Absorption was rapid in both groups and elimination half-life was the same. At steady state, the Cmax and AUC 0-24 h for trandolaprilat, the active metabolite, were similar in the two groups. Maximal reductions in systolic/diastolic blood pressures were -14.1%/-16.1% in young patients and -14.6%/-17.5% for the elderly. Tolerance was good with no adverse reactions reported.

1. De Bruijn JHB, Orofiamma BA, Pauly NC. Efficacy and tolerance of trandolapril (0.5-2 mg) administered for 4 weeks in patients with mild-to-moderate hypertension. J Cardiovasc Pharmacol 1994; 23 (Suppl 4):S60-4. (IDIS Article Number 335159)
2. Pauly NC, Safer ME. Comparison of the efficacy and safety of trandolapril and captopril for 16 weeks in mild-to-moderate essential hypertension. J Cardiovasc Pharmacol 1994; 23 (Suppl 4):S73-6. (IDIS Article Number 335161)
3. Mancia G, De Cesaris R, Fogari R et al. Evaluation of the antihypertensive effect of once-a-day trandolapril by 24-hour ambulatory blood pressure monitoring. Am J Cardiol 1992; 70:60D-6D. (IDIS Article Number 304781)
4. Backhouse CI, Orofiamma B, Pauly NC. Long-term therapy with trandolapril, a new nonsulfhydryl ACE inhibitor, in hypertension: a multicenter international trial. J Cardiovasc Pharmacol 1994; 23 (Suppl 4):S86-S90. (IDIS Article Number 335164)
5. Arner P, Wade A, Engfeldt P et al. Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to young and elderly patients with mild-to-moderate hypertension. J Cardiovasc Pharmacol 1994; 23 (Suppl 4):S44-9. (IDIS Article Number 335157)

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

1996 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

Docetaxel (1P)**

Taxotere

Rhone-Poulenc Rorer, Inc.

(May 15)

DOCETAXEL

10120115

( 43 citations)

Treatment for breast cancer NEOP, MGN-FEMALE BREAST
174.

Indinavir (1P)

Crixivan

Merck & Co.

(Mar. 13)

INDINAVIR

8180069

(16 citations)

Treatment of HIV infection in adults when antiretroviral therapy is warranted SYN-ACQ IMMUNE DEFICIENCY
042.

INFECTION, HIV, ASYMPTOMATIC
V08.

Interferon Beta-1a

Avonex

Biogen

(May 17)

INTERFERON BETA-1A

14000205

(8 citations)

Treatment of multiple sclerosis SCLEROSIS, MULTIPLE
340.
Iodixanol (1S)***

Visipaque

Nycomed

(Mar. 22)

IODIXANOL

36680051

(7 citations)

New, nonionic, radiographic contrast media DIAG X-RAY-NEC
88.3
Ritonavir (1P)

Norvir

Abbott

(Mar. 1)

RITONAVIR

8180092

(14 citations)

In combination with nucleoside analogues/as monotherapy for the treatment of HIV infection when therapy is warranted SYN-ACQ IMMUNE DEFICIENCY
042.

INFECTION, HIV, ASYMPTOMATIC
V08.

Sodium Phenylbutyrate (1P)

Buphenyl

Ucyclyd Pharma

(Apr. 30)

SODIUM PHENYLBUTYRATE

40100007

(7 citations)

As adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of carbamyl phosphate synthetase ornithine transcarbamylase, or argininosuccinic acid synthetase DISORDER, AMINO ACID METAB
270.
Trandolapril (1S)

Mavik

Knoll

(Apr. 26)

TRANDOLAPRIL

24080223

(44 citations)

Treatment of hypertension

HYPERTENSION
401.

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


1996 IDIS EXHIBIT SCHEDULE

American Society of Health-System Pharmacists (ASHP)
Home Care '96
Orlando, Florida
July 27-29

American College Clinical Pharmacy (ACCP)
Annual Meeting
Nashville, Tennessee
August 4-7

American Society of Health-System Pharmacists (ASHP)
Midyear Clinical Meeting (MCM)
New Orleans, Louisiana
December 8-12


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