World of Drug Information

World of Drug Information - Volume 9, Issue 3 - September 1998

In This Issue ...
 Current Clinical Issues 
 Year 2000 Compliance 
 Search Tips 
 1998 Exhibit Invitation 
 Perspective From an IDIS Subscriber
 FDA Approvals 
 Key References 
 Subscription Confirmation Reminder 
 Staff Profile 


NSAID-Induced GI Complications: What's New?

Identification and prevention of adverse drug reactions (ADRs) is a major focus in health care today. Based on the results of a recent meta-analysis (Lazarou, 1998), it was estimated that 2,216,000 hospitalized patients in the United States experienced a serious adverse drug reaction in 1994, and 106,000 had fatal ADRs. Based on this estimate, adverse drug reactions would be the fourth leading cause of death in the United States.

The single most frequent severe adverse drug reaction is gastrointestinal complications caused by nonsteroidal anti-inflammatory drugs (NSAIDs). The U. S. Food and Drug Administration has estimated that the incidence of symptomatic ulcers and potentially life-threatening ulcer complications in patients taking NSAIDs is 2-4% per year. More than 100 million prescriptions are filled for NSAIDs each year, and many more patients are taking nonprescription products, resulting in over 200,000 hospitalizations and 10,000 to 20,000 deaths due to NSAID-induced GI complications each year (Silverstein, 1998). Considering the frequent use of NSAIDs in arthritis, it is no wonder that NSAID gastropathy has been referred to as the second most deadly rheumatic disease.

Recent investigations into this problem include the Misoprostol Ulcer Complications Outcomes and Safety Assessment (MUCOSA) trial, evaluation of the use of high doses of famotidine or omeprazole for prophylaxis and evaluation of eradication of Helicobacter pylori in at-risk patients. Another promising development is COX-2 selective drugs that appear to have therapeutic efficacy in inflammatory conditions with possibly little or no risk for GI complications.

The MUCOSA trial (Silverstein, 1995) was the first randomized controlled study to determine the efficacy of misoprostol in reducing the incidence of serious GI complications (bleeding, perforation, obstruction) rather than just endoscopically identified ulcers. This is significant because there has been only a modest correlation between endoscopic findings and GI hospitalizations. Misoprostol has been shown to reduce endoscopic ulcers by almost 90% but the MUCOSA study showed a relative risk reduction in clinically significant complications of only 40%. Of the 4,406 patients randomized to receive misoprostol, 25 suffered a serious GI event in the six-month trial, compared to 42 events in the 4,433 patients in the placebo group. This difference represents an absolute risk reduction of 0.38% (p < .05), meaning that 263 patients would be treated for six months in order to prevent one serious gastrointestinal event. Misoprostol was not shown to reduce mortality in this study.

More informed decisions regarding the use of NSAIDs and prophylactic therapy with misoprostol require the identification of patients with additional risk factors such as age >75 years, previous peptic ulcer, previous GI bleeding, major comorbid conditions, high doses of NSAIDs, concomitant steroids or anticoagulation therapy. The Arthritis Rheumatism and Aging Medical Information System (ARAMIS) is currently developing a more precise calculator based on these factors to estimate the risk of GI events so that the benefits and risks of therapy can be more accurately evaluated (Singh, 1998).

Two recent studies have evaluated high-dose famotidine for the prevention of NSAID-induced ulcer (Hudson, 1997; Taha, 1996). Famotidine 40 mg bid significantly reduced the incidence of gastric and duodenal ulcers. However, these studies were criticized for three important reasons: 1) the definition of ulcer, a mucosal break of 3 mm or more in diameter, could represent clinically insignificant events, 2) the correlation with significant GI events is not certain and 3) the incidence of ulcers in the famotidine treated patients was higher than most studies with misoprostol. Numerous previous trials with histamine-2 receptor antagonists (H2RA) have shown benefit in reducing duodenal but not gastric ulcers in patients taking chronic NSAIDs, and an observational trial (Singh, 1996) has implicated H2RA as a risk factor for increased NSAID-induced GI complications. In spite of the recent study results, famotidine should not be considered effective prophylaxis for NSAID-induced GI events.

Omeprazole has been compared to misoprostol (Hawkey, 1998) and to ranitidine (Yeomans, 1998) for treatment and prevention of NSAID-induced ulcers. Omeprazole was as effective as misoprostol in ulcer healing (71% to 76%) at eight weeks, and was more effective at maintaining remission during six months of continued NSAID therapy after ulcer healing, 61% vs 48% (p = 0.001). Compared to ranitidine, omeprazole was more effective in ulcer healing at eight weeks (80% vs 63%, p < .001) and more effective at maintaining remission during six months of continued NSAID therapy (72% vs 59%). The primary criticism of these studies is that they were not designed to show that omeprazole is effective in reducing serious NSAID-associated GI complications or hospitalizations. Much larger studies would be needed to show this difference.

There have been conflicting results regarding the benefits of eradication of H. pylori in reducing the incidence of NSAID-induced peptic ulcers. One randomized trial (Chan, 1997) of eradication of H. pylori prior to initiation of eight weeks of naproxen therapy demonstrated a reduction in the incidence of ulcer: 26% in H. pylori-infected patients vs 3% with successful eradication (p = 0.002). Cross-sectional studies on the risk of H. pylori and NSAID-induced ulcers have shown conflicting results (Wilcox, 1997), and previous prospective trials have not shown an effect of H. pylori on the incidence of NSAID-induced ulcers (Bianchi Porro, 1996). In addition, examination of the results from two trials (Yeomans, 1998; Hawkey, 1998) designed to evaluate the effects of acid inhibition or misoprostol on NSAID-induced ulcers, suggested that H. pylori may offer protection from ulcer in this setting. The physiologic argument for this result is that H. pylori infection increases prostaglandin production. It is possible that there are multiple interactions of various risk factors of age, previous ulcer, use of prophylactic therapy, etc., that will eventually be identified as important for decision making for treatment of patients. Certainly the issue of H. pylori infection and the risk for developing NSAID-induced ulcer is not resolved; however, it is difficult to justify not treating H. pylori infection in a patient who has developed an ulcer.

In spite of many years of research into the incidence, risk factors, mechanisms of injury, pathophysiology and other issues, many unanswered questions remain regarding the most effective and cost-effective clinical management strategies for prevention of NSAID-induced GI complications.

For patients at low risk of NSAID-induced ulcers, no prophylaxis would be indicated considering the low level of potential benefits and the significant associated adverse reactions and costs. Patients infected with H. pylori may benefit from eradication therapy. Patients at high risk of serious gastrointestinal complications from NSAIDs should avoid use of these drugs if at all possible. If NSAIDs must be used, the lowest effective dose, for the shortest duration, and in combination with misoprostol should be considered. For at-risk patients unable to tolerate at least 200 mcg bid of misoprostol, a proton pump inhibitor may be considered for prophylaxis.

We need new studies to assess the relationship of NSAID-induced ulcer complications and the H. pylori status of the patient (infected, uninfected, cured). The relative and absolute benefits and risk of preventive and curative therapies may be significantly different based on this status, and current evidence does not allow this difference to be analyzed. Standard doses of H2RA, sucralfate and antacids are not effective in reducing the incidence of NSAID-associated gastric ulcers and should not be used as prophylaxis for GI events. Further data are needed to confirm the clinical safety and efficacy of the COX-2 selective drugs.

Search Strategies

The IDIS database offers several options for locating key studies related to the prevention or treatment of NSAID-induced peptic ulcers. The search strategies for this information may also be applied in a similar manner for retrieving information about side effects associated with other drugs.

One simple strategy for retrieving articles related to side effects of drugs is to use the specific descriptor term for the side effect of interest, in this case 78 Side EF Digestive. Combine the Side EF descriptor with a drug term (e.g., ibuprofen) or a drug class term (e.g., NSAID 28080400). Another useful strategy to search a category of drugs is to take advantage of the hierarchical structure of the drug coding system in the IDIS database. Use the leading digits of the drug code number reflecting the drug's pharmacologic class, followed by the truncation symbol *. To do this you can look up one representative drug (e.g., ibuprofen) in the Drug Hierarchy to obtain the code number (which is 28080509), then scroll upward to obtain the drug's pharmacologic-therapeutic class number or numbers. In this example, NSAIDs are a large class and cover 280804* and 280805*. Either copy and paste the number(s) back into the Main Search screen using the clipboard and edit it to read 280804* or 280805*, or simply type directly in the Main Search screen in the Drug field.

Remember when searching for adverse reaction information, you do not want to use a disease term, such as ULCER, PEPTIC 533., in combination with a causative drug or drug class. The indexing practice in the IDIS database is to index the disease terms with drugs that are used to treat that disease, not drugs as the cause of the disease. Therefore you would not want to combine ibuprofen or NSAID with ULCER, PEPTIC 533., because that combination would imply that ibuprofen was being used to treat an ulcer.

To retrieve articles on the treatment of a side effect, the descriptor 93 Side EF Treatment may be used. Combine 93 with drug terms for the causative agent (e.g,. ibuprofen), or with terms for a pharmacologic-therapeutic class as detailed above.

The disease term V07. PROPHYLAXIS NEC is useful for locating articles about the prevention of NSAID-induced ulcers. You may combine V07. with 531. ULCER, GASTRIC or 532. ULCER, DUODENAL or with 533. ULCER, PEPTIC. Combine the ulcer terms with the Boolean or in parentheses, then combine with V07. using and (see Figure 1). If drug terms are used in this search, those drugs used as prophylactic agents in this condition such as misoprostol or omeprazole would give the best results, rather than drugs that cause ulcers.

Figure 1.

Another special disease term, E999. TX/AE-DRUG/CHEMICAL, would be useful to identify articles related to the treatment of NSAID-induced ulcers. The disease term E999. could be combined with the disease terms for ulcer (e.g., 531. or 532. or 533.), and terms for drugs used to treat the ulcer (e.g., misoprostol or omeprazole or ANTIULCER-H2 ANTAGONISTS [search 562604*]). Figure 2 provides an example of this search strategy.

Figure 2.

The above strategies will locate articles providing information needed to evaluate adverse drug reactions, prevention and treatment. This type of search is also addressed in the Index Notes section of the IDIS database. To view these indexing notes, click on the Index Notes tab at the bottom of the Main Search screen and type side effect. You will see titles to several notes, two of which are most relevant: Treatment of a Side Effect, and Side Effect Prevention. Click on the title in the lower half of the Result screen, and the note will be displayed in the upper half of the screen.

Kevin Moores, R.Ph., Pharm.D.


Bianchi Porro G, Parente F, Imbesi V et al. Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in longterm NSAID users. Response to omeprazole dual therapy. Gut. 1996;39:22-26. (IDIS Article Number 370133)

Chan FKL, Sung JJY, Chung SCS et al. Randomised trial of eradication of helicobactor pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet. 1997;350:975-979. (IDIS Article Number 393079)

Hawkey CJ, Karrasch JA, Szczepanski L et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med. 1998;338:727-734. (IDIS Article Number 402217)

Hudson N, Taha AS, Russell RI et al. Famotidine for healing and maintenance in nonsteroidal anti-inflammatory drug-associated gastrointestinal ulceration. Gastroenterol. 1997;112:1817-1822. (IDIS Article Number 387095)

Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279:1200-1205. (IDIS Article Number 402890)

Silverstein FE, Graham DY, Senior JR et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. Ann Intern Med. 1995;123:241-249. (IDIS Article Number 351344)

Silverstein FE. Improving the gastrointestinal safety of NSAIDs: the development of misoprostol--from hypothesis to clinical practice. Dig Dis Sci. 1998;43:447-458. (IDIS Article Number 404051)

Singh G, Ramey DR. NSAID induced gastrointestinal complications: the ARAMIS perspective--1997. J Rheumatol. 1998;25(suppl 51):8-16. (IDIS Article Number 406191)

Singh G, Ramey DR, Morfeld D et al. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis: a prospective observational cohort study. Arch Intern Med. 1996;156:1530-1536. (IDIS Article Number 370697)

Taha AS, Hudson N, Hawkey CJ et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. New Engl J Med. 1996;334:1435-1439. (IDIS Article Number 365196)

Wilcox CM. Relationship between nonsteroidal anti-inflammatory drug use, Helicobacter pylori, and gastroduodenal mucosal injury. Gastroenterology. 1997;113:S85-S89. (IDIS Article Number 397743)

Yeomans ND, Tulassay Z, Juhasz L et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med. 1998;338:719-726. (IDIS Article Number 402216)

IDIS System/CD-ROM and Year 2000 Compliance

IDIS System/CD-ROM is Year 2000 compliant. The publication year is the only date field in the database and is currently in four-digit format. There is no code in the retrieval software which is affected by the system date. Please contact us if you need additional information.


Keyword Searching vs. Controlled Vocabulary

Finding Information on Drug Hypersensitivity

Descriptor SIDE EF IMMUNOLOGIC 90 is used to identify articles that report instances of a drug causing a hypersensitivity reaction. When searching for information on drug-induced hypersensitivity, combine Descriptor SIDE EF IMMUNOLOGIC 90 with a drug term.

A good example is Article Number 406428, titled "Hypersensitivity to Azathioprine." This article may be found by entering "azathioprine" in the Drug field and "side ef immunologic 90" in the Descriptor field (include the quotation marks, as shown in Figure 1).

Figure 1.

A total of 222 records are found using this strategy (see Figure 2).

Figure 2.

A title search using the words "hypersensit*" and "azathioprine" would pull the same article, but only six other desirable titles. A title search alone does not retrieve all of the records in which an allergic reaction to azathioprine was reported as the title may not include these specific words. Keyword searching in the Title and Abstract fields often provides precise results but may miss important relevant citations. Descriptor searching, on the other hand, yields broader, more encompassing results. The trade-off for a more encompassing search is more information to sift through and more false hits. Searching with "azathioprine" and "side ef immunologic 90" retrieves a number of records listing drugs other than azathioprine. The hypersensitivity denoted by descriptor 90 may relate to one of the other drugs in the article.

Keyword searching in the Title and Abstract fields is extremely useful. A main advantage of the IDIS database, however, is the controlled vocabulary, which consists of valid drug, disease and descriptor terms. IDIS indexers, selecting articles for the database, use the valid drug, disease and descriptor terms to identify the specific information contained in an article. These vocabularies provide access to information not revealed in the title or abstract. There are often several ways to search a topic. Ultimately, whether it is best to keyword search or search using the controlled vocabularies depends on the topic and the amount of information available

Brad Gilchrist, R.Ph.

You're Invited ...

Visit the IDIS/IDIN booth at the upcoming professional meetings:

American College of Clinical Pharmacy (ACCP)
Annual Meeting
November 8-11
Cincinnati, Ohio

American Society of Health-System Pharmacists (ASHP)
Midyear Clinical Meeting (MCM)
December 6-10
Las Vegas, Nevada

Perspectives From IDIS Subscribers

Editor=s Note: From time to time, we publish articles contributed by IDIS subscribers. Two separate articles are included in this issue: one from Dave Mace, B.S.(Pharm.) and the other from Adnan Gauhar, B.S.(Pharm.). These authors are from institutions that are long-standing IDIS subscribers, utilizing the database on a regular basis. Their examples illustrate IDIS database use contributing directly to improvement of patient care outcomes. The author alone is responsible for the content, which does not necessarily represent hospital views and recommendations. They hope you find the information interesting and useful and welcome comments. If you are interested in sharing your experiences using the IDIS database, please contact

Strange Musculoskeletal Syndrome Involving Swollen Hands, Fatigue and Joint Pain. Toxic?


The clinical syndrome of causalgia (reflex sympathetic dystrophy [RSD]) is said to have been first described by Mitchell et al. (1864) in a text on gunshot wounds and other nerve injuries. This syndrome often affects the shoulder and hand (shoulder-hand syndrome [SHS]) and may progress to ankylosis of the joints and atrophy of the subcutaneous tissue and bone. SHS has been associated with many causes including trauma, stroke, cervical spondylosis, epilepsy and brain tumor (Taylor, 1989). Veldman and colleagues (1993) described the reported incidence of RSD after various insults as follows: fractures (1B2%), peripheral nerve injury (2B5%) and Colles= fracture (7B35%). Changes similar to RSD may appear after myocardial infarction (5%), local cold injury and revascularization of an ischemic extremity. In 0-26% of cases no precipitating factor can be found (Veldman, 1993). The remainder of the discussion will focus on SHS associated with epilepsy, specifically the cases in patients on prolonged phenobarbital regimens.

In the early twentieth century when the association between RSD and alcoholism was well known, a study by Féré and Francillon (1902) found only one case among epileptics. Their work dates from the time before phenobarbital was introduced for the treatment of epilepsy. During the 1930s an association between barbiturate therapy and SHS called Aphenobarbital rheumatism@ was described (Taylor, 1989). This association remained unreported in the English language until 1966 when Van der Korst and colleagues reported that 25 of 75 SHS hand patients seen in a rheumatology clinic had a history of phenobarbital therapy compared with only 1% of their control group. Taylor and Posner (1989) saw nine patients in two years who had a brain tumor and developed SHS. All were taking phenobarbital. In 1941 Lund reported only five of 38 epileptics treated with phenobarbital for two years had the earliest changes associated with palmar aponeurosis. He would have expected 18 such findings among epileptics treated with phenobarbital for many years (Pojer, 1972). Horton and colleagues (1984) studied the development of SHS in patients treated with phenobarbital. They followed six patients over time documenting remission of symptoms within two months after barbiturate withdrawal, return of symptoms with phenobarbital rechallenge and remission again when phenobarbital was discontinued a second time.

Falasca and colleagues (1994) have recently described four patients with SHS while on barbiturates for seizure disorders. They suggest that SHS associated with phenobarbital may not be rare, but only rarely recognized. The recognition of SHS associated with barbiturate therapy is important, because the condition usually responds to steroid therapy, but if not addressed can result in permanent disability.

Patient Medical History

A 69 YO M with NKDA; HTN [11 yr]; NIDDM [6 yr]; open angle glaucoma [on drops]; s/p knee surgery and cholecystectomy [1965]; hands began to shake in 1987; anemia/small amount of bright red in stool [GI workupCerosive gastritis/duodenitis]; essential tremor [1997].


7/21/97: Patient referred for evaluation of hand tremor syndrome worse on R than L. Aggravating factors include writing and lifting a full glass of water. Denies vocal tremor or other changes in speech. No complaints of pain. PE [neurologic] is unremarkable except slight vibration sense loss in the LE and the coarse tremor of the hands. Diagnostic impression: essential tremor; treatment with primidone, began in 7/97 at a dose of 50B100 mg HS; since 12/2/97 his daily primidone dose has been 250 mg TID.

10/14/97: [Clinic visit] To get medications refilledCno complaints.

ADMISSION: [1/space2B1/13/98] For evaluation of generalized weakness with increased tremor in the UE and increased weakness in the LE for the month preceding admission and 30 lb weight loss over the year prior to admission. [No mention of edema in the hands or shoulder pain.]

1/29/98: [Clinic visit] On PE, R shoulder pain notedCibuprofen prescribed. No mention of restricted range of motion in the shoulder or swelling of the hands.

2/19/98: [Primary care visit] Patient complains of pain in R arm and L leg (duration of leg pain 1 year); also complains of loss of energy and insomnia H 1 yr. [On paroxetine 20 mg daily since 1/13/98.]

2/19/98: [Rheumatology visit] Patient complains of R shoulder pain for 1 month. Denies injury, etc. On PE decreased ROM for internal rotation and abduction. Patient has had a similar syndrome in the L shoulder in the past (no specific dates). Steroids were injected locally (no comment about effectiveness). Recent ibuprofen 400 mg TID no benefit; heat no benefit. Lidocaine and Aristospan given into the R shoulder joint with relief.

Diagnostic impression: rotator cuff/impingement syndrome. Get XRAY & FU 6B8 weeks.

4/17/98 [Clinic visit] Patient presents with continued swelling of the R hand, not much change since he saw Dr. ---. Now patient complains of difficulty using his RUE. On PE tenderness R shoulder; and R hand is swollen. No neurologic deficit[s] found in the RUE.

4/28/98 [Clinic visit] Patient presents with bilateral hand swelling of 2 months= duration. Hand syndrome has not changed much in past week. [Why no mention of L hand swelling in 4/17/98 note?] Over past 18 months his weight is down from 235 to 185. Diagnostic impression: amyloid vs polymyalgia rheumatica vs RA vs unknown syndrome. Start trial of low-dose steroids 15 mg prednisone daily.

5/12/98 [Rheumatology clinic] Patient fell on R hand 5 weeks prior to visit, which is a confounding factor. Patient did not injure L hand during fall. He has been on prednisone 15 mg daily for 2 weeks without benefit. Denies any other pain or tenderness. On PE, patient has pain and stiffness in the right hand. Only after he fell, has he noticed hand problems. On PE + finger/knuckle swelling of the R hand; diffuse type swelling; no hyperhidrosis; no vasomotor changes, no joint swelling elsewhere.

Diagnostic impression: no definitive diagnosis to date; patient has wt loss, increased ESR, hand pain and swelling, and monoclonal gammopathy. He did not respond to prednisone. Would taper and discontinue his steroid regimen. Another bone scan scheduled. The possibility of shoulder-hand syndrome (reflex sympathetic dystrophy) was considered, but weight loss and ESR would not be explained. Cannot use either hand normally. Concerned about the possibility of permanent damage to the hands.

5/12/98 [Primary care // later that day] No change in syndrome. Surgery consult tomorrow. Taper prednisone; rule out amyloidosis.

Critchley and colleagues (1976) studied chronic epileptics and found a 56% incidence of Dupuytren=s disease in a population of 361. Bilateral lesions were described in 70% of affected males and in 60% of females. Plantar nodules were also present in 30% and knuckle pads in 41% of those affected. There was no relationship between the etiology of the epilepsy and the occurrence of Dupuytren=s disease. There was no relationship between the EEG pattern and the incidence of Dupuytren=s disease. A definite correlation was reported for the occurrence of Dupuytren=s disease and the duration of treatment. After 20 years there is greater than 50% chance of a male developing Dupuytren=s disease. When two drug combinations were analyzed, only combinations containing phenobarbital or primidone or phenytoin showed a high incidence (66% to 69%) of Dupuytren=s disease. However, if phenobarbital is removed from the analysis, the risk falls greatly. Only two of 21 not receiving phenobarbital had evidence of Dupuytren=s disease and they were both taking primidone, for which phenobarbital is a major metabolite. They believe the increased incidence of Dupuytren=s disease is probably a sequel to long-term use of phenobarbital.

Horton and Gerster (1984) studied 149 consecutive cases of RDS and found 25 (16.8%) of them were treated with barbiturates at the time the RDS symptoms began. The group was unusual due to the absence of provocative events in 32%, high number of diseased joints bilaterality (76%), involvement of the upper extremities (76%) and Dupuytren=s disease (52%). They suggested that barbiturates may be the principal initiating event in some cases of SHS. In their view improvement depended on the withdrawal of the barbiturate.

The only prospective controlled data on the subject of the association between the use of barbiturates in epileptics and connective tissue disorders was provided by the recently completed VA Epilepsy Cooperative Study (Mattson, 1989). For the first time there had been the opportunity to observe prospectively whether a specific antiepileptic drug was associated with any of the connective tissue disorders previously linked with antiepileptic drug use. Dupuytren=s contractures, frozen shoulder, Peyronie=s disease and/or other symptoms of joint pain developed in the first year of treatment in seven of the 10 patients:

Subsequent to completion of the study, a further search was made of patients seen by one investigator. Three men and two women were found whose connective tissue disorders were linked to barbiturate therapy. Several patients whose connective tissue disorder had been unresponsive for years improved dramatically when their therapy was changed from phenobarbital to another anticonvulsant.


For almost a century an increased incidence of various connective tissue disorders has been described in epileptic populations. Some authors believed they were genetically determined. Critchley and associates found a much lower incidence of Dupuytren=s disease in non-epileptics. The high incidence of SHS in the modern series is in contrast to earlier reports from the pre-barbiturate era. It would seem that Lund was probably correct in 1941 when he suggested that Dupuytren=s disease was a new symptom in epilepsy and that the administration of phenobarbital might be important.

The recent findings of the VA CO-OP Study Group confirm the association between phenobarbital and primidone and connective tissue disorders. Six percent of epileptics treated with a single barbiturate as the only antiepileptic therapy for six months or longer developed a connective tissue disorder within the mean three-year follow-up period.

The following facts support the possibility of a primidone (phenobarbital)-associated SHS in the patient whose case we consulted on (see Patient Medical History, p. 9):

1. Patient had no history of either shoulder pain or swelling of the hands prior to starting primidone therapy in July 1997.

2. Patient=s presentation is not consistent with other known factors associated with SHS.

3. Patient=s syndrome is similar to that described in the reported cases and different from RSD in several ways (Horton, 1984):

4. Isolated case reports and several small case series have described at least 68 patients with SHS refractory to conventional analgesics in patients on phenobarbital (most had epilepsy). In six of these patients there was documented remission of symptoms within two months of phenobarbital withdrawal, return of the syndrome with phenobarbital rechallenge and remission a second time when phenobarbital was discontinued.

5. The syndrome developed within the same time frame as previously reported cases and the cases from the controlled data. Patient=s R shoulder pain was noted about six months after primidone is started. About nine months after primidone was started, patient reported swelling of the R hand, which then became bilateral within two weeks. Compare patient=s experience with the time frames from the following controlled data and case series:

6. In a prospective controlled study of monotherapy to treat epilepsy, a statistically significant relationship was found between the use of barbiturates and connective tissue disorders (6% incidence) in males who had received phenobarbital or primidone for at least six months.

The following facts are against the possibility of a primidone (phenobarbital)-associated SHS in the patient:

1. SHS is among the connective tissue disorders with a higher incidence in diabetics than controls (see Rosenbloom, 1996).

2. We are uncertain to what extent, if any, the recent fall on his right hand might be contributing to the current syndrome.

We suggest the following:

A. Discontinue the primidone ASAP. Probably no need to taper, but might consider a PRN benzodiazepine order to cover any withdrawal symptoms which might emerge (e.g., valium 5 mg q8h).

B. Results of the pending bone scan should predict treatment success with steroids according to Kozin (1981).

C. Re-treat patient with another course of steroids, this time at a higher dose such as 80 mg/day (which would be almost 1 mg/kg/day) and taper as described by Kozin (1981).


6/15 Report from Dr. --- Pt. no worse; 6/22 Report from Dr. --- Pt. no worse; 6/30 Report from Dr. --- Pt. greatly improved [less than 30 days] after primidone discontinued without steroid treatment. Positive dechallenge supports the toxic cause of the syndrome. 8/17 Pt. greatly improved. He has moved out of state; will follow up with questionnaire.


Critchley EM, Vakil SD, Hayward HW et al. Dupuytren=s disease in epilepsy: result of prolonged administration of anticonvulsants. J Neurol Neurosurg Psychiatry. 1976;39:498B503.

Falasca GF, Toly TM, Reginato AJ et al. Reflex sympathetic dystrophy associated with antiepileptic drugs. Epilepsia. 1994;35:394B399. (IDIS Article Number 329165)

Féré C, Francillon M. Note sur al fréquence de la rétraction de l=aponéurose palmaire chez des aliénés. Rev Med. 1902;22:539B551. [cited in Pojer, 1972]

Horton P, Gerster JC. Reflex sympathetic dystrophy syndrome and barbiturates. A study of 25 cases treated with barbiturates compared with 124 cases without barbiturates. Clin Rheumatol. 1984;3:493B499.

Kozin F, Ryan LM, Carerra GF et al. Reflex sympathetic dystrophy syndrome (RSDS) III. Scintigraphic studies, further evidence for the therapeutic efficacy of systemic corticosteroids, and proposed diagnostic criteria. Am J Med. 1981;70:23B30. (IDIS Article Number 132349)

Lund M. Dupuytren=s contracture and epilepsy. Acta Psycol Neurol. 1941;16:465B492. [cited in Pojer, 1972]

Mattson RH, Cramer JA, McCutchen CB et al. Barbiturate-related connective tissue disorders. Arch Intern Med. 1989;149:911B914. (IDIS Article Number 253962)

Mitchell SW, Moorehouse GR, Keen WW. Gunshot wounds and other injuries of nerves. Philadelphia: J.B. Lipincott, 1864. [cited in Falasca, 1994]

Pojer J, Radivojevic M, Williams TF. Dupuytren=s Disease. Arch Intern Med. 1972;129:561B566. (IDIS Article Number 23765)

Rosenbloom AL, Silverstein JH. Connective tissue and joint disease in diabetes mellitus. Endocrin Metabol Clinic NA. 1996;25:473B483.

Taylor LP, Posner JB. Phenobarbital rheumatism in patients with brain tumor. Ann Neurol. 1989;25:92B94. (IDIS Article Number 249425)

Van der Korst JK, Colenbrander H, Cats A. Phenobarbital and the shoulder-hand syndrome. Ann Rheum Dis. 1966;25:553B555.

Veldman PH, Reynen HM, Arntz IE et al. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet. 1993;342:1012B1016.

Dave Mace, B.S.(Pharm.), Drug Information Specialist, graduated from the University of Iowa College of Pharmacy in 1967. Since 1982 he has served as the Director of the Drug Information Center at BPVAMC, 10,000 Bay Pines Blvd., Bay Pines, FL 33744. His responsibilities include serving as a preceptor for drug information and Pharm.D. clerkship programs and responding to complex drug information requests from clinical staff.

Dawn Cammillerri, Pharm.D. candidate, assisted in the preparation of this article.

Acetylcysteine 1% Solution Used to Treat Mucinous Obstruction of the Distal Ureter

The patient, a 30-year-old female, had mucinous obstruction of the distal ureter after a mid-ureteral replacement with ileum. Since oral acetylcysteine is not available in this country, the doctors used Ambroxol HCl (Mucosolvan) orally to decrease the secretions. However, the patient didn=t respond. The urologist searched Medline for alternative treatment information but failed to find any relevant information. He then called the Drug Information Center. IDIS was searched, and an article was retrieved in which Benderev (1988) had used acetylcysteine 1% solution effectively to relieve mucinous obstruction of the distal ureter after a mid-ureteral replacement with ileum.

Acetylcysteine 1% 300 ml was instilled via nephrostomy tube following documentation of obstruction. Patency of ureter was achieved immediately. Reobstruction ensued, but it resolved with repeat instillation of acetylcysteine. Patency was confirmed by a follow-up after the patient was discharged from the hospital.

The doctors were very impressed by the database of IDIS. We believe that drug therapy related information is more comprehensive and up-to-date in IDIS as compared to Medline and even to some extent with the Internet also.


Benderev TV. Acetylcysteine for urinary tract mucolysis. J Urol. 1988;139:353B354. (IDIS Article Number 249558)

Adnan Gauhar received a B.S.(Pharm.) from faculty of Pharmacy, University of Karachi, Pakistan, in 1993. Since 1995 he has worked as a Drug Information Specialist at the Department of Pharmacy Services, Aga Khan University Hospital. His responsibilities include responding to complex drug information requests from the medical and nursing staff, preparation of the Pharmacy Newsletter and Pharmacy Updates and conducting staff development programs and orientation/training programs for new staff.

The Aga Khan University Medical Center, Karachi, Pakistan, is a 654-bed community teaching hospital, one of the largest private sector hospitals in Pakistan. The hospital has fully automated pharmacy services. Funded by an endowment grant from the Canadian Ismaili Pharmacists group, the Drug and Poison Information Center at the Department of Pharmacy Services is a state-of-the-art facility available to general public and health care professionals. The primary focus of the center is to promote rational and cost-effective medication usage in the hospital and in the community at-large.


Generic Name

(FDA Therapeutic Classification)

Trade Name


(Approval Date)

Valid IDIS Drug Term

Drug Number

(IDIS Citations)*


Valid IDIS Disease Term

Modified ICD-9-CM Number

Candesartan Cilexetil



Astra Merck Group

(June 4)



(6 citations)

Treatment of hypertension



Citalopram HBr



Forest Laboratories

(July 20)



(106 citations)

Treatment of depression

Disorder, Depressive NEC





COR Therapeutics

(May 18)



(46 citations)

Treatment of patients with acute coronary syndrome, including patients who are to be managed medically and those undergoing percutaneous intervention (PCI), and for treatment of patients undergoing elective PCI

Removal, Obstru, Coronary


Infarction, Myocard, Acute





(June 19)



(3 citations)

Prophylaxis of serious lower respiratory tract disease, caused by respiratory syncytial virus in pediatric patients at high risk of RSV disease

Pneumonia, Syncytial Virus


Infect, Resp Syncytial Virus





Hoechst Marion Roussel

(June 22)



(14 citations)

Treatment of pulmonary tuberculosis

Tuberculosis, Resp Syst NEC


Rizatriptan Benzoate




(June 29)



(6 citations)

Treatment of acute migraine headaches with or without aura







(July 16)



(330 citations)

Acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) and as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrences



Erythema, Nodosum


Tirofiban HCl




(May 14)



(39 citations)

Approved for use in combination with heparin in the treatment of acute coronary syndrome, including patients who are to be managed medically and those undergoing PTCA or atherectomy

Infarction, Myocard, Acute


* Through August 1998 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 by FDA.



This new drug selected bibliography provides a selection of key clinical studies of new drugs approved by the FDA from mid-May through July 1998. IDIS SYSTEM/CD-ROM was searched to retrieve key articles relevant to the new drugs and their approved uses.

Candesartan Cilexetil

Meineke I, Feltkamp H, Hogemann et al. Pharmacokinetics and pharmacodynamics of candesartan after administration of its pro-drug-candesartan cilexetil in patients with mild to moderate essential hypertension-a population analysis. Eur J Clin Pharmacol. 1997;53:221-228. (IDIS Article Number 400075). A randomized, double-blind, controlled, dose-finding study (2-16 mg) was conducted in 232 patients with mild or moderate hypertension to investigate the pharmacokinetics and pharmacodynamics of candesartan after administration of the pro-drug candesartan cilexetil for 28 days.

Citalopram Hydrobromide

Castanedo de Alba L and Meixueiro-Montes de Oca R. An open-label, controlled study of citalopram versus moclobemide in patients with major depression. Curr Ther Res. 1998;59:107-115. (IDIS Article Number 402392). In a six-week, open-label, randomized clinical study, investigators compared the efficacy and safety of citalopram (20-60 mg/day) to moclobemide (300-600 mg/day) in 42 patients with major depression.

Bjerkenstedt L, Flyckt L, Overo KF et al. Relationship between clinical effects, serum drug concentration and serotonin uptake inhibition in depressed patients treated with citalopram: a double-blind comparison of three dose levels. Eur J Clin Pharmacol. 1985;28:553-7. (IDIS Article Number 203353). In a four-week, double-blind, randomized trial, investigators compared the effect of 5, 25 and 50 mg once daily doses of citalopram to 16 depressed patients.


Tcheng JE, Lincoff AM, Sigmon KN et al. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet. 1997;349:1422-1428. (IDIS Article Number 385794). Investigators enrolled 4,010 patients undergoing elective, urgent or emergency coronary intervention in a Phase III multicenter, randomized, placebo-controlled trial to assess the ability of eptifibatide to prevent the development of ischemic complications of percutaneous coronary intervention.

Harrington RA, Kleiman NS, Kottke-Marchant K et al. Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol. 1995;76:1222-1227. (IDIS Article Number 360036). Seventy-three patients undergoing elective percutaneous coronary intervention were enrolled in this randomized, placebo-controlled study designed to establish more firmly the pharmacokinetic and pharmacodynamic properties of eptifibatide and to further examine the safety of four eptifibatide regimens.

Tcheng JE, Harrington RA, Kottke-Marchant K et al. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker integrin in elective coronary intervention. Circulation. 1995;91:2151-2157. (IDIS Article Number 347920). In the first report of eptifibatide use during elective percutaneous coronary angioplasty, investigators conducted a multicenter, randomized, double-blind, placebo-controlled study to evaluate glycoprotein IIb/IIIa blockade in 101 patients assigned to one of three treatment regimens: placebo; a four-hour eptifibatide infusion; or a 12-hour infusion of the drug.


Subramanian KN, Weisman LE, Rhodes T et al. Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. Pediatr Infect Dis J. 1998;17:110-115. (IDIS Article Number 401101). In a Phase I/II multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial, investigators evaluated the safety, tolerance, pharmacokinetics and immunogenicity of repeat doses of intravenously administered pavlivizumab in 62 infants at risk for serious respiratory syncytial virus (RSV) disease.


Sampaio EP, Kaplan G, Miranda A et al. The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum. J Infect Dis. 1993;168:408-414. (IDIS Article Number 318757). Investigators evaluated the effect of thalidomide (300 mg/day) on cytokine levels and clinical symptoms in 18 lepromatous leprosy patients who developed erythema nodosum leprosum.


Theroux P, Catella-Lawson F, Charbonnier B et al. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med. 1998;338:1488-1497. (IDIS Article Number 405092). The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study was a double-blind, randomized, controlled, multicenter trial in which investigators evaluated the clinical efficacy of tirofiban in the prevention of acute ischemic events during coronary angiography and angioplasty in 1,915 patients with an acute coronary syndrome.

King SB, Bertrand M, Chang PI et al. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation. 1997;96: 1445-1453. (IDIS Article Number 393118). The RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis) trial was a randomized, double-blind, placebo-controlled trial of tirofiban in 2,141 patients undergoing coronary interventions (balloon angioplasty or directional atherectomy) within 72 hours of presentation with an acute coronary syndrome.

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

1998 Subscription Confirmation Reminder

If you have not previously responded, please remember to contact our office as soon as possible to advise us of your article format preference for the July-December 1998 updates.


    Marcia Cox
Marcia Cox

Hired under the Goodwill Supported Employment Threshold Program, Marcia Cox joined the IDIS staff in November of 1997. A native Iowan, she served in the Navy during the Viet Nam era.

Marcia's responsibilities in the division include database production support activities including double data entry, proofing, copying and fill-in tasks. In her leisure time, she enjoys crocheting and spending time with her two children.

World of Drug Information is published quarterly (March, June, September, December) by the Division of Drug Information Service. Back issues are available on the IDIS web site.

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