Ticlopidine

Brand Names: Ticlid

Clinical Names: Ticlopidine

Summary

generic name: Ticlopidine hydrochloride

trade names: Ticlid®

type of drug: Platelet aggregation inhibitor.

used to treat: Stroke prevention; intermittent claudication.

mechanism: Ticlopidine irreversibly inhibits ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions. This produces a time and dose-dependent inhibition of both platelet aggregation and release of platelet factors, as well as a prolongation of bleeding time.

caution: Ticlopidine carries a significant risk of neutropenia or agranulocytosis; consequently it should only be used with individuals who are intolerant to aspirin therapy. Use with caution in individuals with ulcers.

overview of interactions:
• herb/food affecting drug performance and toxicity: Allium sativum (Garlic)

• herb affecting drug performance and toxicity: Cinchona species (Quinine)

• herb affecting drug performance and toxicity: Ginkgo biloba (Ginkgo)

• herb affecting drug performance and toxicity: Harpagophytum procumbens (Devil’s Claw)

• herb affecting drug performance and toxicity: Panax ginseng (Chinese Ginseng)

• herb affecting drug performance and toxicity: Salvia miltiorrhiza (Dan Shen)

• herb affecting drug performance and toxicity: Zingiber officinale (Ginger)

• herbal constituent affecting drug performance and toxicity: Coumarin-containing Plants

• herbal constituent affecting drug performance and toxicity: Platelet Aggregation Inhibitor-containing Plants (Platelet Interactors)

Note: See also Chinese Herbs topic: Blood-moving Herbs and Dan Shen

• herb group affecting drug performance: Salicylate-containing Herbs

• diet affecting drug toxicity: Food



Interactions

herb/food affecting drug performance and toxicity: Allium sativum (Garlic)

• mechanism: Garlic has gained much notoriety for its potential value in reducing cardiovascular risk, especially due to atherosclerosis, by inhibiting the ability of platelets to adhere to one another. One consequence of this process is that it can also enhance the tendency for bleeding due to decreased clotting.
Note: see below: Plants with possible potentiation action due to Platelet Aggregation Inhibitors:

• research: Reports of medicinal garlic contributing to excessive bleeding are rare but have been published. Likewise, case reports have been published of incidents where an interaction between garlic and anticoagulant drugs has resulted in increased anticoagulant activity.
(Rose KD, et al. Neurosurg 1990;26:880-882; Gadkari JV, Joshi VD. J Postgrad Med 1991 Jul;37(3):128-131; Sunter WH. Pharm J 1991;246:722; Burnham BE. Plast Reconst Surg 1995;95:213; Jain RC. Am J Clin Nutr 1977 Sep;30(9):1380-1381; Chutani SK, Bordia A. Atherosclerosis 1981 Feb-Mar;38(3-4):417-421.)

• herbal/nutritional concerns: The clinical significance and frequency of occurrence of this interaction are uncertain even though the theoretical foundation for this interaction is sound and some related case reports have come forth. These findings are important since many individuals being treated by their physicians with ticlopidine might also consider using garlic for cardiovascular benefits. Individuals using ticlopidine should be aware of the possible risk of adverse interactions when taking both garlic and ticlopidine and should consult their prescribing physician before beginning supplementation with medicinal dosages of garlic. Pending further research, caution would be appropriate and physician supervision advised when using standardized extracts of garlic. Likewise, daily doses of more than one clove of garlic should be avoided if ticlopidine is being taken.
Note: see below: Plants with possible potentiation action due to Platelet Aggregation Inhibitors:

herb affecting drug performance and toxicity: Cinchona species (Quinine)

• mechanism: The bark of the Cinchona tree is the traditional source of quinine. Some reports have indicated the possibility that quinine, as a drug, may increase activity of anticoagulant drugs, specifically warfarin.
(Tatro D, ed. Jul 1993.)

• herbal concerns: Ticlopidine and quinine effect the coagulant properties of blood through significantly different actions so an interaction is not highly probable. Even so, individuals taking ticlopidine should avoid the consumption of quinine and be watchful for its presence on labels. Although Cinchona is not commonly prescribed as an herbal medicine, individuals using ticlopidine should consult with their prescribing physician and a healthcare professional trained in botanical prescribing before taking Cinchona or introducing other medicinal herbs into their therapeutic regime. The use of Cinchona, also known as China, as a homeopathic remedy poses no significant risk due to its presence in microdilution.

herb affecting drug performance and toxicity: Ginkgo biloba (Ginkgo)

• mechanism: Ginkgo provides many of its therapeutic benefits by facilitating peripheral circulation. One key way this occurs is through its influence in reducing the aggregation (clumping) of platelets in the blood. This effect also increases any underlying tendency toward bleeding. Furthermore, by enhancing peripheral circulation Ginkgo could reasonable expected to increase the occurrence of superficial bruising and other bleeding disorders in some patients.
Note: see below: Plants with Possible Potentiation Action due to Platelet Aggregation Inhibitors:

• reports: There have been at least two known cases of spontaneous internal bleeding associated with consumption of Ginkgo in standardized extracts. Kim et al conducted a study using rats which demonstrated that Ginkgo in high doses could increase the action of ticlopidine in a potentially dangerous manner should the drug act in a similar manner in humans. There has also been one published report of an individual who experienced bleeding after starting to use Ginkgo while taking warfarin, another anticoagulant drug.
(Kleijnen J, Knipschild P. Lancet 1992;340:1136-1139; Mathews MK. Neurology 1998 Jun;50(6):1933-1934; Rosenblatt M, Mindel J. New Engl J Med 1997 Apr 10;336(15):1108; Rowin J, Lewis SL. Neurology 1996 Jun;46(6):1775-1776; Kim YS, et al. Thrombosis Res 1998;91:33-38; Skogh M. Lancet. 1998 Oct 3;352(9134):1145-1146.)

herb affecting drug performance and toxicity: Harpagophytum procumbens (Devil’s Claw)

• reports: Devil’s Claw was associated with purpura (bleeding under the skin) in a patient treated with warfarin. Purpura is a known side effect of ticlopidine.
(Shaw D, et al. Drug Safety 1997;17(5):342-356.)

• herbal concerns: Individuals using ticlopidine should consult with their prescribing physician and a healthcare professional trained in botanical prescribing before taking Devil’s Claw or introducing other medicinal herbs into their therapeutic regime.

herb affecting drug performance and toxicity: Panax ginseng (Chinese Ginseng)

• reports: In two cases vaginal bleeding was associated with the use of substances reported to contain ginseng. Hopkins et al attributed the one instance of postmenopausal bleeding to ginseng's estrogen-like effect on genital tissues. Several case reports involving potential interactions between warfarin and Panax ginseng have been published. A case report by Janetzky and Morreale described a possible interaction between warfarin and ginseng as evidenced by a reduction of the international normalized ratio (INR), indicating a decrease in warfarin activity, in a patient on warfarin.
(Hopkins MP, et al. Am J Obstet Gynecol 1988;159(5):1121-1122; Greenspan EM. JAMA 1983;249(15):2018; Janetzky K, Morreale AP. Am J Health-Syst Pharm 1997;54:692-693.)

• herbal concerns: Individuals using ticlopidine should consult with their prescribing physician and a healthcare professional trained in botanical prescribing before taking ginseng or introducing other medicinal herbs that might alter bleeding patterns into their therapeutic regime. While the actual identity and dosage of the herbs involved in the cases found in the literature remains uncertain, they most likely involved the use of Panax ginseng, also known as Chinese or Korean Ginseng. Even so, the cautions might be extended to also cover Siberian ginseng (Eleutherococcus senticosus) even though it is a distinctly different plant and a member of a different genus.

herb affecting drug performance and toxicity: Salvia miltiorrhiza (Dan Shen)
Note: see below: Plants with possible potentiation action due to Platelet Aggregation Inhibitors

• reports: Several cases have appeared in the medical literature discussing the dangerous interaction which can result from the simultaneous use of warfarin and the Chinese herb known as Dan shen, Salvia miltiorrhiza, either alone or in formulations. This concern could be extended to ticlopidine and its affect upon bleeding even though ticlopidine and warfarin achieve their anticoagulant action through different mechanisms acts. Nevertheless, this interaction with an anticoagulant drug could potentially be anticipated from the understanding of Dan shen and its clinical uses within the prescribing traditions of Chinese herbal medicine.
(Cheng TO. Ann Thorac Surg. 1999 Mar;67(3):894; Tam LS. et al. Aust NZ J Med 25 Jun, 258, 1995; Chan TY. Int J Clin Pharmacol Ther 1998 Jul;36(7):403-405.)

Note: While Dan shen is a member of the Salvia genus, it is quite distinct from the common Western herb Sage (Salvia officinalis), which has not been associated with interactions involving anticoagulant drugs.
See also Chinese Herbs topic: Blood-moving Herbs and Dan Shen

• herbal concerns: Individuals using ticlopidine should consult with their prescribing physician and a healthcare professional trained and experienced in Chinese herbal medicine before taking Dan shen or introducing other medicinal herbs into their therapeutic regime.

herb affecting drug performance and toxicity: Zingiber officinale (Ginger)

• mechanism: Ginger could potentially exert an additive effect with pharmaceutical anticoagulants such as ticlopidine. In vitro tests have shown that ginger can reduce platelet aggregation. Even so, no studies have specifically demonstrated an interaction between ginger and platelet inhibiting drugs nor have any reports of adverse events of such character been published.

• herbal concerns: Even though no specific incidents of adverse interaction have been reported, individuals taking ticlopidine should consult with their prescribing physician before taking ginger in a supplemental form or consuming significant doses on a regular basis as a dietary component.

herbal constituent affecting drug performance and toxicity: Coumarin-containing Plants

• mechanism: Some coumarin-containing plants could potentially exert an additive effect with pharmaceutical anticoagulants such as ticlopidine. Even so, no studies have specifically demonstrated an interaction between coumarin-containing plants and platelet inhibitors nor have any reports of adverse events of such character been published.

• herbal concerns: Generally, excessive bleeding would not be likely to appear unless relatively large doses of coumarin-containing herbs or their combinations were consumed for an extended period of time. The combination of these plants with anticoagulant drugs such as ticlopidine inherently increases the risk of excessive bleeding or other adverse side effects but even this interaction would most likely require the consumption of sizable amounts of these herbs to produce a significant risk.

• Coumarin-containing plants capable of anticoagulant potentiation:
Aesculus hippocastanum (Horse Chestnut bark)
Anthoxanthum odoratum (Sweet Vernal grass leaves)
Asperula odorata (Woodruff plant)
Dipteryx odorata, Dipteryx oppositifolia (Tonka Bean seeds)
Galium triflorum (Sweet-scented Bedstraw plant)
Melilotus officinaIis, Melilotus alba (Sweet Clover plant)
Trilisa odoratissima (Vanilla leaf leaves)

herbal constituent affecting drug performance and toxicity: Platelet Aggregation Inhibitor-containing Plants (Platelet Interactors)

• mechanism: Some herbs that inhibit platelet aggregation could conceivably potentiate the anticoagulant activity of ticlopidine or other anticoagulant drugs. Generally, adverse effects would not be likely to appear unless relatively large doses of these herbs or their combinations were consumed for an extended period of time. The combination of these plants with anticoagulant drugs such as ticlopidine inherently increases the risk of excessive bleeding or other adverse side effects. In order for several of these plants, some being common foods, to produce a significant risk or interaction the consumption of sizable amounts over an extended period would most likely be required.

• Plants with possible potentiation action due to Platelet Aggregation Inhibitors:
Allium cepa (Onion plant)
Allium sativum (Garlic)
Ananas comosus (Bromelain, from fruit and stem)
Capsicum frutescens (Cayenne)
Carica papaya (Papain, from leaves and unripe fruit)
Curcuma longa, Curcuma aromatica (Turmeric root)
Ganoderma lucidum (Reishi fruit bodies)
Ginkgo biloba (Ginkgo)
Salvia miltiorrhiza (Dan Shen root)
Scutellaria baicalensis (Chinese Skullcap root)
Zingiber officinale (Ginger rhizome)

• herbs affecting drug performance: Salicylate-containing Herbs including:
Betula lenta (Sweet Birch)
Betula pendula (White birch)
Filipendula ulmaria (Meadowsweet)
Gaultheria procumbens (Wintergreen)
Populus balsamifera (Balsam Poplar)
Populus nigra (Black Poplar)
Populus candicans (Balm Of Gilead)
Salix alba (White Willow)
Viburnum prunifolium (Black Haw)

• mechanism: Concern has been raised about the theoretical possibility of an interaction between salicylate-containing herbs and ticlopidin because both interfere with the action of platelets. Salicylates are aspirin-like compounds found in many plants. Ticlopidine is a potent antiplatelet agent without interaction with prostaglandin synthesis. Ticlopidine and aspirin are often coadministered in the treatment of a variety of conditions. However, research by Abou-Khalil et al found that ticlopidine induced swelling in the mitochondrial of cells from rat livers. Salicylates are also known for their association with mitochondrial injury, though most likely by a different mechanism. Consequently the combined use of aspirin and ticlopidine on an extended basis might be approached with caution. Even so, the extent to which these concern might relate to salicylate-containing plants can only be speculative. In vitro research thus far indicates that aspirin and plant salicylates act through different mechanisms in regard to their effect on blood coagulability. Further, the risk of plant salicylates causing bleeding problems is minimal because their absorption is relatively poor and they do not tend to accumulate to a significant degree. Finally, there have been no published reports of negative interactions between salicylate-containing plants and ticlopidine or between salicylate-containing plants and aspirin or aspirin-containing drugs.
(Abou-Khalil S, et al. Biochem Pharmacol. 1986 Jun 1;35(11):1849-1853; Wichtl M, Bisset NG, eds. 1994; McGuffin M, et al. 1997, 154-155; Janssen PL, et al. Cancer Lett 1997:114(1-2):163-164.)

• herbal concerns: While concerns about potential interactions between anticoagulant drugs such as ticlopidine and salicylate-containing herbs might conceivebly have some theoretical foundation they remain highly improbable and unproven. Individuals who consume large amounts of plants containing salicylates should consider discussing this issue with their physician if they are prescribed ticlopidine. Mots likely such an interaction would most require the consumption of sizable amounts of these herbs for extended periods to produce a significant risk.

diet affecting drug toxicity: Food

• dietary concerns: The digestive upset commonly associated with taking ticlopidine can be avoided by taking the drug with food.
(Threlkeld DS, ed. Jan 1992, 85c-85g.)

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Do not rely solely on the information in this article.

References

Abou-Khalil S, Abou-Khalil WH, Yunis AA. Swelling of mitochondria by the platelet antiaggregating agent ticlopidine. Biochem Pharmacol. 1986 Jun 1;35(11):1849-1853.
Abstract: Our studies on the effects of ticlopidine on mitochondrial functions led us to an intriguing observation related to its interaction with mitochondrial membranes. Liver mitochondria were isolated from Sprague-Dawley rats and assayed for swelling by spectrophotometry. When ticlopidine was added to mitochondria preincubated in an isotonic test medium, an induced-swelling activity was observed. This activity was time and concentration dependent and occurred in different isosmotic solutions. Several analogues of ticlopidine, assayed under identical conditions, produced only a minor effect. Respiratory chain inhibitors, uncouplers, ATP, and phosphate protected the mitochondria against the ticlopidine-induced swelling, whereas oligomycin did not. Comparative studies with the drugs chloramphenicol, nitroso-chloramphenicol, and salicylate (known for their association with mitochondrial injury) showed the first two to have little effect while the third one caused swelling as expected. On the other hand, oxypolarographic tests of respiring mitochondria in the presence of ticlopidine showed that the drug is not an uncoupling agent. These results indicate that the antiaggregating agent ticlopidine interacts with mitochondrial membranes causing swelling which, in turn, may alter mitochondrial permeability; however, unlike some other swelling agents, it does not act as a classical uncoupler.

Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, Yarnold PR, Kwaan HC, Green D. Thrombotic thrombocytopenic purpura associated with ticlopidine: a review of 60 cases. Ann Intern Med. 1998;128:541-544.

Burnham BE. Garlic as a possible risk for postoperative bleeding. Plast-Reconst-Surg 1995 Jan;95(1):213.

Cheng TO. Warfarin danshen interaction. Ann Thorac Surg. 1999 Mar;67(3):894.

Chung KF, Dent G, McCusker M, Guinot P, Page CP, Barnes PJ. Effect of a ginkgolide mixture (BN 52063) in antagonising skin and platelet responses to platelet activating factor in man. Lancet 1987;1:248-251.
Abstract: Antagonism of the effects of platelet activating factor (PAF) by the ginkgolide mixture BN 52063 was assessed in a double-blind, placebo-controlled, crossover study in 6 normal subjects. Weal and flare responses to 400 ng PAF, examined 2 h after ingestion of BN 52063 (80 mg, 120 mg) were inhibited in a dose-related manner. After 120 mg the flare area was reduced by a mean 62.4% (p less than 0.005) and the weal volume by a mean 60% (p less than 0.05). Both doses of BN 52063 significantly inhibited PAF-induced platelet aggregation in platelet-rich plasma (p less than 0.001). In vitro, BN 52063 inhibited PAF-induced but not ADP-induced platelet aggregation. Thus BN 52063 seems to be an antagonist of PAF in man.

Colli A, Buccino G, Cocciolo M, Parravicini R, Elli GM, Scaltrini G. Ticlopidine-theophylline interaction. Clin Pharmacol Ther. 1987 Mar;41(3):358-362.
Abstract: Ticlopidine, a new antithrombotic agent, and theophylline, a widely used bronchodilator drug, are both almost completely metabolized in the liver. To evaluate an interaction between these two drugs, we studied theophylline pharmacokinetics before, after 10 days of ticlopidine administration, and 1 month later in 10 healthy volunteers. We found a highly significant increase in the theophylline elimination half-life (P less than 0.001) and a comparable reduction in its total plasma clearance (P less than 0.001) after ticlopidine treatment. Pharmacokinetic parameters returned to initial values within 30 days after ticlopidine withdrawal. Moreover, no changes in theophylline pharmacokinetic parameters were observed 3 months later, before and after 10 days of placebo administration. Our results seem to exclude direct liver toxicity and may suggest a reversible inhibition of the liver metabolic capacity of theophylline.

Gadkari JV, Joshi VD. Effect of ingestion of raw garlic on serum cholesterol level, clotting time and fibrinolytic activity in normal subjects. J Postgrad Med 1991 Jul;37(3):128-131.
Abstract: The effect of raw garlic on serum cholesterol, fibrinolytic activity and clotting time was studied in 50 medical students of the age group of 17 to 22 years before and after feeding raw garlic. All pre-experimental values ranged within normal limits. The volunteers were then divided into experimental and control groups. The subjects of the experimental group were given 10 gm of raw garlic daily after breakfast for two months. Fasting blood samples of all the subjects were investigated after two months. In the control group, there was no significant change in any of the above parameters. In the experimental group, there was a significant decrease in serum cholesterol and an increase in clotting time and fibrinolytic activity. Hence, garlic may be an useful agent in prevention of thromboembolic phenomenon.

Greenspan EM. Ginseng and vaginal bleeding. JAMA 1983 Apr 15;249(15):2018.

Hopkins MP, Androff L, Benninghoff AS. Ginseng face cream and unexplained vaginal bleeding. Am J Obstet Gynecol 1988 Nov;159(5):1121-1122.
Abstract: A case of postmenopausal bleeding attributed to the use of topical ginseng is reported. Ginseng appears to have an estrogen-like effect on genital tissues.

Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health-Syst Pharm 1997 Mar 15;54(6):692-693.

Janssen PL, Katan MB, van Staveren WA, Hollman PC, Venema DP. Acetylsalicylate and salicylates in foods. Cancer Lett 1997 Mar 19;114(1-2):163-164.
Abstract: Acetylsalicylic acid is effective in the prevention of cardiovascular disease. It was suggested that fruits and vegetables provide unknown amounts of acetylsalicylic acid. We could not find any acetylsalicylic acid in 30 foods using HPLC with fluorescence detection (detection limits: 0.02 mg/kg for fresh, and 0.2 mg/kg for dried products). We showed that urinary excretion of salicylates is a valid indicator for intake, and found a median salicylate excretion of 10 micromol (1.4 mg) in 24 h urine of 17 volunteers eating a variety of diets. Our data suggest that the content of (acetyl)salicylic acid of diets may be too low to affect disease risk.

Kim YS, Pyo MK, Park KM, Park PH, Hahn BS, Wu SJ, Yun-Choi HS. Antiplatelet and antithrombotic effects of a combination of ticlopidine and ginkgo biloba ext (EGb 761).Thromb Res. 1998 Jul 1;91(1):33-38.
Abstract: The antiplatelet and antithrombotic effects of the oral combination treatment of ticlopidine and Ginkgo biloba extract (EGb 761) were studied in normal and thrombosis-induced rats. The ex vivo inhibitory effect on ADP-induced platelet aggregation of a small dose of ticlopidine (50 mg/kg/day) in combination with EGb 761 (40 mg/kg/day) was comparable to a larger dose of only ticlopidine (200 mg/kg/day). Bleeding time was also prolonged by 150%. Thrombus weight was also consistently decreased by a combination of ticlopidine and EGb 761 in an arterio-venous shunt model at two doses of ticlopidine (50 mg/kg) plus EGb 761 (20 mg/kg) and ticlopidine (50 mg/kg) plus EGb 761 (40 mg/kg). A combinatory treatment in acute thrombosis model in mice also showed a higher recovery than a single treatment.

Kleijnen J, Knipschild P. Ginkgo biloba. Lancet 1992;340:1136-1139.

Mazur W, et al. Antiplatelet therapy for treatment of acute coronary syndromes. Cardiol Clin. 1999 May;17(2):345-357, ix. (Review)
Abstract: Acute coronary syndromes and the postpercutaneous coronary intervention state share the common feature of atherosclerotic plaque disruption and subsequent intraluminal thrombus formation. In most cases, vascular patency is maintained but partial occlusion causes myocardial ischemia and can either progress to complete occlusion or result in distal embolization with subsequent small vessel obstruction, the core section of an intraarterial thrombus is platelet-rich and can serve as a nidus for further thrombosis. Aspirin, by virtue of its anticycloxygenase activity inhibits platelet activation and aggregation to a mild degree. Clinically, aspirin has been shown to reduce the rates of myocardial infarction in patients with acute coronary syndromes and to reduce the number of ischemic complications which follow coronary angioplasty. More potent inhibitors of platelet aggregation antagonize the interaction between the platelet surface protein GP IIb-IIIa and fibrinogen. The result is profound inhibition of platelet aggregation. Three intravenous antagonists of platelet GP IIb-IIIa are clinically available and a fourth is under phase III study. When used in addition to aspirin therapy, these agents have been shown to produce further reductions in either peri-interventional infarctions or in recurrent myocardial infarctions in patients with acute coronary syndromes.

McGuffin M, Hobbs C, Upton R, Goldberg A, eds. American Herbal Product Association’s Botanical Safety Handbook. Boca Raton, FL: CRC Press, 1997, 154-155.

McPhedran P, Mukamal K. Ticlopidine for relapsing TTP. Blood. 1994;84(suppl 1):80a.

Mukamal, KJ, Wu B, McPhedran P. Ticlopidine-Associated Thrombotic Thrombocytopenic Purpura. Ann Int Med, 15 November 1998. (Letter)

Newall CA, Anderson LA, Phillipson JD. Herbal Medicines: A Guide for Health-Care Professionals. London: The Pharmaceutical Press, 1996, 135-137.

Ochoa AB, Wolfe M, Lewis P, Lenihan D. Ticlopidine-Induced Neutropenia Mimicking Sepsis Early after Intracoronary Stent Placement. Clin. Cardiol. 1998;21:304-307.
Summary: We report a case of ticlopidine-induced profound neutropenia early in the course of therapy, which was manifest as a febrile systemic illness mimicking sepsis. This clinical presentation was potentially indicative of a contaminated intracoronary stent. The patient's signs and symptoms of illness promptly resolved with removal of ticlopidine, and no infection was documented. Review of indications for ticlopidine use, potential adverse effects, and monitoring recommendations are discussed.

Rose KD, Croissant PD, Parliment CF, Levin MB. Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: A case report. Neurosurg 1990 May;26(5):880-882.
Abstract: The authors report a case of spontaneous spinal epidural hematoma causing paraplegia secondary to a qualitative platelet disorder from excessive garlic ingestion. The case also demonstrates satisfactory recovery from thoracic spinal epidural hematoma in a nonagenarian. Recovery from severe spinal cord compression can occur even in the very elderly.

Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. New Engl J Med 1997 Apr 10;336(15):1108.

Rowin J, Lewis SL. Spontaneous bilateral subdural hematoma with chronic Gingko biloba ingestion. Neurology 1996 Jun;46(6):1775-1776.

Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements: a 5-year toxicological study (1991-1995). Drug Safety 1997;17(5):342-356.

Spaulding C, Charbonnier B, Cohen-Solal A, Juilliere Y, Kromer EP, Benhamda K, Cador R, Weber S. Acute hemodynamic interaction of aspirin and ticlopidine with enalapril: results of a double-blind, randomized comparative trial. Circulation. 1998 Aug 25;98(8):757-765.
Abstract: BACKGROUND: Coprescription of aspirin and ACE inhibitors is frequent in heart failure caused by coronary artery disease. Negative interaction between aspirin and enalapril has been reported, presumably through inhibition by aspirin of ACE inhibitor-induced prostaglandin synthesis. Ticlopidine is a potent antiplatelet agent without interaction with prostaglandin synthesis. METHODS AND RESULTS: The objective of this study was to compare the influence of a coadministration of ticlopidine or aspirin on the hemodynamic effects of an ACE inhibitor (enalapril) in patients with chronic heart failure. Twenty patients with severe heart failure were enrolled in a double-blind comparative trial and allocated to ticlopidine (500 mg daily, 12 patients) or aspirin (325 mg daily, 8 patients). Hemodynamic evaluation was performed after 7 days of treatment, every hour for 4 hours after an oral administration of 10 mg of enalapril. Significant reductions in systemic vascular resistance were observed in the ticlopidine group, in contrast to no significant decrease in the aspirin group. A significant (P=0.03) time-by-treatment interaction indicated significant aspirin-enalapril drug interaction. Total pulmonary resistance decreased significantly in both groups, with no difference between patients assigned to aspirin or ticlopidine. CONCLUSIONS: Enalapril reduced systemic vascular resistance more effectively when given in combination with ticlopidine than with aspirin. In contrast, the reduction in total pulmonary resistance is similar when enalapril is administered in combination with aspirin or ticlopidine. Negative aspirin-enalapril interaction on prostaglandin synthesis presumably alters vasodilatation in systemic vessels, whereas prostaglandin-independent actions of ACE inhibition such as pulmonary arterial vasodilatation are maintained.

Tam LS, Chan TYK, Leung WK, Critchley JAJH. Warfarin interactions with Chinese traditional medicines: Danshen and methyl salicylate medicated oil. Aust NZ J Med 1995 Jun;25(3):258.

Tatro D, ed. Anticoagulants-quinine derivatives. In: Drug Interaction Facts. St. Louis, MO: Facts and Comparisons, Jul 1993.

Threlkeld DS, ed. Blood Modifiers, Antiplatelet Agents, Ticlopidine HCl. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Jan 1992, 85c-85g.

Vale S. Subarachnoid haemorrhage associated with Ginkgo biloba. Lancet. 1998 Jul 4;352(9121):36. (Letter)
Abstract: A 61-year-old man presented in September, 1997, with a 5-day history of headache, back pain, nausea, and sleepiness. He had been previously in excellent health and enjoyed outdoor exercise. On examination no physical abnormalities were found, including his neurological status. Blood pressure was 135/85 mm Hg. He had a normal blood count and mildly increased bleeding time (6 min, normal 1-3). Serum urea, nitrogen, creatinine, bilirubin, and hepatic enzymes were normal, as were prothrombin and partial thromboplastin times. A computed tomographic cranial scan obtained without the administration of contrast material was also normal. A lumbar puncture yielded 6 mL of slightly xanthochromic fluid without gross blood. Microscopical examination revealed 6 cells per µL of which five were red cells and one was white. Glucose was 3·7 mmol/L protein 240 mg/L. A subarachnoid haemorrhage was diagnosed. Detailed questioning revealed that
he had been taking Ginkgo biloba 40 mg tablets, three or four times a day, for more than 6 months before the beginning of his symptoms. The patient recovered uneventfully. He was advised to stop the extract and in January, 1998, he was doing well. His bleeding time is now 3 min and he has refused further medical investigations.

Vianelli N, Catani L, Belmonte MM, Sermasi G, Cascione ML, Gianni L, et al. Ticlopidine in the treatment of thrombotic thrombocytopenic purpura: report of two cases. Haematologica. 1990;75:274-277.

Wichtl M, Bisset NG, eds. Herbal Drugs and Phytopharmaceuticals. Stuttgart: Medpharm GmBH Scientific Publishers. 1994.

Yu CM, Chan JCN, Sanderson JE. Chinese herbs and warfarin potentiation by “danshen.” J Intern Med 1997 Apr;241(4):337-339.
Abstract: Drug interactions with warfarin can be dangerous and although common drug interactions are now well recognized those with Chinese herbs are not widely appreciated. 'Danshen' is a herbal medicine often used for various complaints, particularly cardiovascular, in the Chinese community. We report a case of danshen-induced overcoagulation with severe and dangerous abnormalities of clotting in a patient with rheumatic heart disease.