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Consultant Pharmacist Forum

Use of Vitamin E and Gingko Biloba in Patients with Alzheimer Disease

The recent explosion of over-the-counter (OTC) vitamin and herbal products presents a challenge to consultant pharmacists. First, these agents offer temporary hope to many residents who have chronic or incurable diseases. Second, there is heightened awareness of natural products among the lay population, leading patients to ask if these products are viable alternatives to their medications. Third, most pharmacists receive little training or formal education on vitamin and herbal supplements.

In the long-term care environment, I have noticed increased interest in ginkgo biloba and vitamin E for residents diagnosed with Alzheimer's disease. As a result, I developed a brief summary of these agents' effects to assist patient care staff in the facilities I serve. (Table 1).

Table 1. Summary of Information on Natural Products Used in Alzheimer's Disease

Product Name	Recommended Dose	Forms Available	Comments
Vitamin E	2,000 IU daily	Tablets, capsules in various strengths, and drops	Available in various racemic mixes; dose based on IU rather than mg. May slow progression of Alzheimer's disease symptoms by seven to eight months. Is a fat-soluble vitamin, and toxicity is possible.
Ginkgo biloba	120-160 mg daily	40, 60, and 100 mg tablets, tea, and liquid	Tea and liquid do not indicate strength and thus, cannot be dosed reliably. May improve some symptoms of Alzheimer's disease. Effects may last six to 12 months. Generally recommended for patients with mild to moderate Alzheimer's disease.

There is some information available in the medical literature to support use of both of these drugs. A brief summary of reference articles is listed at the end of this article for readers who would like additional information.

Vitamin E

Use of vitamin E is based on the principle that medications or vitamins that protect against oxidative harm may reduce neuronal damage and slow the progression of Alzheimer's disease. A study published last year in the New England Journal of Medicine reviewed outcomes of 341 patients who were assigned to one of four groups: placebo, selegiline, vitamin E, or selegiline and vitamin E together.

The study found that in patients with moderately severe impairment from Alzheimer's disease, treatment with either selegiline or vitamin E slowed disease progress. The study used death, institutionalization, loss of ability to perform basic activities of daily living, and development of severe dementia as disease progression markers.

In this study, doses of vitamin E of 2,000 units (IU) daily were administered. Vitamin E is available in a number of dosage forms, including tablets, capsules, and liquid drops. The tablets or capsules should not be crushed, but should be swallowed whole. The liquid drops are available in a strength of 50 mg dl-alpha tocopheryl acetate per milliliter, with 1 mg dl-alpha tocopheryl acetate equivalent to 1 IU of vitamin E. Thus, approximately 40 ml of drops are needed to provide 2,000 I.U. of vitamin E daily.

Vitamin E has few side effects. Overdose can cause fatigue, nausea, weakness, headache, blurred vision, flatulence, and diarrhea. Vitamin E can interact with warfarin, with a possible increase in hypoprothrombinemic effect and consequent bleeding.

Gingko Biloba

Less is known about gingko biloba, although studies are currently being conducted. Available literature suggests that it is a cognitive function enhancer. Its use is well established in Europe. Gingko biloba is promoted for vascular insufficiency that has resulted in short-term memory loss, vertigo, headache, and tinnitus; depression; intermittent claudication; early Alzheimer's disease; senility; and diabetic retinopathy.

Doses of 40 mg given three to four times a day are used. It is available as a standardized leaf extract containing 24% ginkgo heterosides. Headache and gastrointestinal discomfort have been reported as side effects, but only rarely. Improvement is not immediate. It may take two to three weeks to see improvement; longer trials (up to three or four months) may be needed.

Guidelines for Use

At a 120-bed nursing facility serviced by our pharmacy, physicians have prescribed vitamin E to 16 patients, and ginkgo biloba extract to one. To date, no patients have been taken off of these medications due to side effects. Two events stimulated consultant pharmacist action: drug information questions from consumers and health care providers increased, and scientific studies were published in noteworthy journals.

I gave attending physicians several recent articles on the use of these supplements to help them prepare for and address questions.

Before using either supplement for the treatment of Alzheimer's disease, a Mini-Mental State Examination (MMSE) should be conducted to determine the patient's baseline condition. The examination assesses orientation, short-term memory, attention, concentration, language skills, and visual/spatial abilities. Alzheimer's disease causes global brain failure, and repeated application of the MMSE every three to six months can help determine disease progression. Patients with Alzheimer's disease can be expected to lose points in all areas of the MMSE. Use of vitamin E or ginko biloba may slow decline in some of the areas tested.

Consultant pharmacists will have many questions as they begin using natural products for this and other conditions. Some suggestions and points of interest are presented here:

• Consistent use of products from the same manufacturer may be wise. This minimizes manufacturer-to-manufacturer variability, and reduces the possibility of reaction to different preparations or diluents.
  
• Provide information to health care providers at the initiation of treatment.
  
• Early education can improve care and decrease the possibility of adverse events.
  
• Depending on the third-party payer involved, reimbursement for OTC supplements is still in question for many residents.
  
• Vitamin E is available in various racemic mixes and strengths. Whenever a product is used, the labeling should be checked for correct conversion to international units.
  
• Some liquid nutritional supplements contain vitamin E. If the patient is receiving liquid nutrients, examine the labeling for the presence and amounts of vitamin E.
  

Health care providers have to be familiar with all products being used to treat residents. Careful review of lay and scientific literature keeps consultant pharmacists on the cutting edge of practice. Dissemination of this information helps other health care professionals stay abreast of change, order natural products appropriately, administer them correctly, and monitor for problems.

William M. Steffen, PharmD, FASCP
Medcenter One Health Systems
Bismarck, North Dakota

References and Suggested Readings

1. Lebars PL, Katz MM, Berman N et al. A placebo-controlled, double blinded, randomized trial of an extract of ginkgo biloba for dementia. JAMA 1997;278:1327-1332.

2. Sano M, Ernesto C, Thomas RG et al. A controlled study of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med 1997;336(17):1216-22.

3. Kettl PA. Alzheimer's disease: an update. Hosp Med 1997;33(10):12-4,17-GE 6.

Streamlining and Individualizing

Anticonvulsant Therapy

Only the number of patients suffering from epilepsy rivals the number of "gold standard" methods for treating the condition. Patients must be assessed and monitored on a highly individualized basis in order to receive optimal treatment. A method that controls seizures in one patient may be completely ineffective in another. Even in individual patients, the formula for seizure control will vary over time and with circumstances.

Clinical Case History

Clinical pharmacists were asked to perform a drug regimen review on JI, a 57-year-old male with a two-month history of increased seizure activity. Past medical history was significant for dementia resulting from alcohol abuse and hemiparesis caused by stroke. Both of these conditions made communication with this patient difficult.

After interviews with medical and nursing staff, a pattern of this patient's complex partial seizures was established. Seizure episodes lasted between five and 45 minutes, sometimes progressing to a generalized seizure requiring four to seven staff members to restrain the patient. Discomfort seemed to precipitate seizures in this particular patient. Staff had noticed that arthritis pain and/or cold temperatures frequently preceded seizures. They also noted that JI was spending more and more time confined to a wheelchair or posey because of his unsteady gait.

When the increased seizure frequency was noted, the patient was taking phenytoin, phenobarbital, and carbamazepine for seizure control. Prior to the drug regimen review, the treatment team's neurologist decided to discontinue carbamazepine, initiate gabapentin (titrating upward), and taper off phenobarbital (to eventual discontinuation). The staff neurologist recommended initiation of lorazepam 4 mg every four hours as needed for seizures, raising concern among some team members. Hesitancy of the staff to administer such large doses of lorazepam actually prompted the original call to the pharmacy. Various pain medications were being used on an as-needed basis.

Other medications of interest included daily aspirin therapy, benztropine, and supplements of multivitamins, folic acid, and thiamine. Liquid nutritional supplements (either Resource or Ensure) were taken three times daily.

Upon investigation, it was noted that although the patient's antipsychotic medication was recently discontinued, the companion drug, benztropine, was overlooked. No apparent rationale for continuation could be found. This highly anticholinergic agent could have contributed to JI's confusion and unsteady gait.

The clinical pharmacy staff then reviewed laboratory findings for JI. A low sodium level was noted. Some literature indicates a positive correlation between low sodium and increased seizure activity. This patient's low glucose was considered noncontributory since increased seizure activity is usually associated only with high glucose levels.

Also noted was a low albumin level, which was considered important because of its tendency to artificially deflate total phenytoin levels (active free phenytoin is actually higher than it appears in lab values). Serum drug levels were within normal limits.

Drug interactions were investigated. Anticonvulsants commonly displace each other from binding sites. The more drugs involved, the higher the chance of complicated drug interactions. If at all possible, monotherapy should be the goal. Although it was the team's goal, monotherapy for JI was not possible at this time.

Recommendations

The clinical pharmacy staff presented the following recommendations:

• Continue with plan to streamline anticonvulsant therapy (to just phenytoin and gabapentin).
  
• Draw albumin and sodium levels. If albumin remains low (under 4.4 g/dl), use the following formula provided by pharmacy to determine a corrected phenytoin level:
  corrected phenytoin level = [measured level] / [(0.2)(albumin level) + 0.1]
  

• Consider modifying the lorazepam order to: 2 mg IM STAT for seizure, may repeat in 15 minutes if seizure persists, then 2 mg every four hours as needed for post-ictal state or apprehension (no more than 12 mg as maximum daily dose). This served as an excellent compromise, accepted by both the neurologist and team members.
  
• Maintain a comprehensive record of seizures (chart provided to treatment team), with detailed attention to any possible stimuli precipitating seizure activity. Nature and duration of seizures should also be noted.
  
• Document need for benztropine or discontinue its use.
  
• Consolidate supplements. Since 100% of the RDA for vitamins and minerals is provided in the liquid supplements, the multivitamin is probably unnecessary. Adequate thiamine supplementation should be provided by the liquid supplements as well. Folic acid supplementation should continue since the patient is on anticonvulsant therapy.
  
• Update hepatic and renal function tests for this patient.
  
• Try a scheduled (rather than as needed) dose of analgesics for arthritis pain. This is especially important since this patient has difficulty communicating and may experience seizures as a result of the pain.
  
• Carefully examine this patient's need for daily aspirin therapy. Some controversy exists about the use of aspirin in patients with a history of stroke.
  

Results

All recommendations were accepted. As a result of the consult with the clinical pharmacy staff, this patient's therapy was streamlined and seizure control improved. The phenobarbital, aspirin, thiamine, multivitamin, and benztropine were all discontinued as advised. When last assessed, JI no longer needed a wheelchair and offered, with a grin, to dance for the staff. He was surprisingly communicative and seemed to be in positive spirits.

When retested, albumin levels for JI remained low. When the phenytoin level was corrected to correspond with these levels, the phenytoin level was found to be relatively high. Since this patient's seizure threshold was so precarious at this time, the phenytoin dose was left unchanged. The patient continues to be monitored for signs of toxicity.

The pharmacy staff believes the most important factor in this patient's improvement was investigation of the seizure pattern and possible precipitants to seizure activity. Once an accurate seizure record was maintained, it was obvious that the stress of arthritic pain was the primary stimulus to convulsions. Cold weather, with a probable increase in arthritis pain, also seemed to bring on seizure activity. An "as needed" dosing schedule was not the solution for this patient, especially since he had difficulty communicating. Once medication was administered regularly, the pain was controlled and the stimulus for seizure removed.

Conclusion

Many practitioners make the mistake of assuming that the key to treatment of seizure disorders lies in laboratory values. Although these values are of indisputable worth, they are not the end-all of anticonvulsant therapy. This case study is an excellent example of tailoring a patient's total therapeutic regimen by assessing individual needs and idiosyncrasies, not just drug levels. Approaches as basic as making a patient more comfortable and/or simplifying a drug regimen can have profound therapeutic results.

Christiana C. Tosatto, RPh, MPH
Alexandria, Virginia