Ginkgo An herb that has shown considerable promise in alleviating many of these

symptoms is ginkgo. A concentrated extract of the leaves of Ginkgo biloba

Chapter six: Cardiovascular system problems 105 L., family Ginkgoaceae is currently enjoying enormous popularity in

Europe as a treatment for peripheral vascular disease, particularly cerebral circulatory disturbances and certain other peripheral arterial circulatory disorders. Although the ginkgo tree has a very old history, having survived unchanged in China for some 200 million years, the herbal remedy prepared from its leaves is quite new, having been developed in the last twenty years. The leaves themselves cannot be used as an extempo- raneous herbal remedy—for example, in the form of a tea—because they would provide an insufficient quantity of the active principles. As noted, Ginkgo biloba extract (GBE) is widely used in Europe; in 1995, the most fre- quently prescribed herbal monopreparation in Germany was GBE, which

represented sales of 284 million U.S. dollars. 45 GBE is also available in Germany as an over-the-counter drug. To supply the market with adequate supplies of leaves, plantations of ginkgo trees, severely pruned to shrub height to allow mechanical pick- ing, have been established. A plantation in Sumter, South Carolina, com-

prises ten million ginkgos on 1,000 acres. 46 The leaves are picked green, dried, and shipped to Europe for processing. There, an acetone–water extract is prepared, dried, and adjusted to a potency of 24 percent flavonol glycosides and 6 percent terpene trilactones (ginkgolides and bilobalide).

Although complete analyses of GBE have not been conducted, the extract does contain a number of flavonol and biflavone glycosides, prin- cipally glycosides of quercetin and kaempferol; rutin is also present. The extract also contains 3 percent or more of a group of unique, closely related, bitter, twenty-carbon diterpene lactone derivatives known as ginkgolides A, B, C, J, and M. In addition, about 3 percent of a similar fifteen-carbon sesquiterpene designated bilobalide is present, together with 6-hydroxykynurenic acid, shikimic acid, protocatechuic acid, vanil- lic acid, and p-hydroxybenzoic acid. 47

The therapeutic effects of GBE are attributed to a mixture of these constituents, rather than to a single chemical entity. Flavonoids of the rutin type reduce capillary fragility and increase the threshold of blood loss from the capillary vessels. This tends to prevent ultrastructural (isch- emic) brain damage. They also function as free-radical scavengers and tend to inhibit the lipid peroxidation of cell membranes, to prevent oxi- dative modification of cellular proteins resulting in inactivation through cross-linking, and to prevent lesions in DNA that could lead to cell death or malignant transformation of cells.

Ginkgolides inhibit platelet-activating factor (PAF; see Figure 6.3 ). Produced by a variety of tissues, PAF not only induces aggregation of the blood platelets but also causes bronchoconstriction, cutaneous vaso- dilation, chemotaxis of phagocytes, hypotension, and the release from phagocytes of inflammatory compounds such as leukotrienes and prostaglandins as well as liposomal enzymes and superoxide. PAF appears to

106 Tyler's herbs of choice: The therapeutic use of phytomedicinals exert its actions by stimulating G protein-linked, cell-surface receptors.

This causes activation of phospholipase A 2 with resultant formation of arachidonic acid, which is converted to prostaglandins, thromboxane

A 2 , and leukotrienes. In addition, the binding of PAF to its receptor on platelets unmasks cell-surface binding sites for fibrinogen that promote platelet aggregation and thrombus formation directly. 41 In short, it mim- ics many of the features seen in allergic response. All of these actions of PAF are blocked by the ginkgolides, particularly ginkgolide B. Possibly, the ginkgolides’ most significant effect is an increase in blood fluidity, thereby improving circulation. Bilobalide acts in concert with the ginkgolides to improve the tolerance of brain tissue to hypoxia and to increase cerebral circulation.

Despite ginkgolides’ acting as potent inhibitors of PAF, no clinical effects in humans have yet been observed. An anti-PAF effect, possibly intensified by inhibition of TXA2-dependent platelet aggregation con- ferred by ibuprofen, has been suggested as responsible for fatal intrac-

erebral mass bleeding in a seventy-one-year-old man. 42 More recently, the importance of the PAF antagonistic effect of ginkgolides in hemor- rhage associated with consumption of GBE has been questioned. It was noted that inhibition of aggregation of human platelets requires ginkgolide concentrations more than one hundred times greater then peak plasma levels measured after oral intake of a standardized proprietary

extract (EGb 761) at recommended daily doses between 120 and 240 mg. 43

A systematic review of fifteen case reports describing a temporal asso- ciation between bleeding and ginkgo consumption has appeared; only six reports clearly observed that bleeding did not recur after ginkgo use was terminated. 44

Federal health authorities in Germany have declared GBE to be an effec- tive treatment for cerebral circulatory disturbances resulting in reduced functional capacity and vigilance. Some of the symptoms resulting from such disturbances are vertigo, tinnitus, weakened memory, disturbances in concentration, and mood swings accompanied by anxiety. A primary target group is patients suffering from dementia syndromes, including primary degenerative dementia or vascular (multi-infarct) dementia.

Two recent clinical studies confirmed the efficacy of GBE in dementia of the Alzheimer type and vascular dementia. One investigation involved 216 outpatients in a prospective, randomized, double-blind, placebo-controlled, multicenter study over a twenty-four-week treatment period with

a daily dose of either 240 mg GBE or placebo. 45 The second study utilized 309 patients over fifty-two weeks assigned randomly to treatment with GBE (120 mg/day) or placebo. Although modest, the changes induced by GBE were objectively measured by the Alzheimer’s Disease Assessment Scale-Cognitive subscale and were of sufficient magnitude to be recog- nized by the caregivers. 46

Chapter six: Cardiovascular system problems 107 German Commission E has also found the extract useful for the treat-

ment of certain other types of PVD—specifically, the peripheral arterial circulatory disturbance known as intermittent claudication. This condi- tion, caused by sclerosis of the arteries of the leg, is characterized by a constant or cramping pain in the calf muscles brought on by walking a short distance. It is not uncommon among older persons and apparently responds well, at least in the initial stages, to treatment with GBE. A meta- analysis of five placebo-controlled clinical trials with GBE in which the effectiveness of treatment was measured by increases in pain-free walking distance showed significant improvement in patients after three to six months of treatment with 120 mg of GBE per day. 47

A comprehensive review of the scientific literature that has examined the neurophysiological efficacy of GBE in healthy and cognitively intact adults appeared in 2005. 48 The majority of studies examining the acute effects of GBE in healthy adults found the extract efficacious in enhancing participants’ neuropsychological functioning, particularly performance on tasks assessing attention, memory, and speed of processing. In two placebo-controlled, double-blind parallel studies, acute and chronic effects of

a standardized GBE product on attention memory and executive function were examined in a well-defined population of healthy young university students (ages eighteen to twenty-six). The acute effects of a single dose of ginkgo significantly improved performance on the sustained-attention and pattern-recognition memory tests but did not significantly improve performance on the measures of working memory, planning, mental flex- ibility, and mood. Chronic treatment (six weeks) had no significant effect on mood or any of the cognitive tests. 49

Side effects of GBE administration are neither numerous nor frequent. They may include gastrointestinal disturbances, headache, and allergic skin reactions. A case report of a hemorrhagic complication during GBE use in a patient also taking aspirin suggested that there may be an increase in bleeding tendencies if GBE is taken along with other drugs that inhibit blood platelet aggregation. 50

The extract is sold in Europe as an approved drug and is available there in a variety of dosage forms, including tablets, liquids, and paren- teral preparations for intravenous administration. It is not an approved drug in the United States, where it is sold as a dietary supplement, usu- ally in the form of tablets containing 40 mg of the extract. Recommended dosage for intermittent claudication is 120–160 mg daily in divided doses taken with meals. Daily dosage for cerebral circulatory disturbances, including early-stage dementia, is 240 mg in two or three divided doses. An initial six- to eight-week period is recommended to determine the efficacy of GBE. Seriously ill patients, such as those with stroke or advanced stages of dementia, should not replace physician care and evaluation with GBE self-medication.

108 Tyler's herbs of choice: The therapeutic use of phytomedicinals Practically all of the scientific and clinical research on GBE has been

carried out with extracts produced in Germany and designated either EGb 761 by the Dr. Willmar Schwabe GmbH & Co. or LI 1370 by Lichtwer Pharma GmbH. The bioequivalence of other GBE products has not been demonstrated.

Ginkgo leaves contain ginkgolic (anarcardic) acids (6-alkylsalicylic acids) that are allergenic and regarded as otherwise toxic but virtu- ally eliminated in the process, which produces commercial proprietary extracts. The German Commission E limits the level of ginkgolic acids to

a maximum of 5 ppm. Also present in dangerously high levels in unpro- cessed ginkgo seeds, ginkgotoxin (4 ′-O-methylpyridoxine), an antivitamin

B 6 neurotoxin, is 99 percent inactivated by boiling; ginkgo leaves contain only minute quantities of the toxin. 51

Ginkgo An herb that has shown considerable promise in alleviating many of these