Pharmacological Toxicological Effects 51 Neurological Effects

Feverfew's mechanism of action in the prevention of migraine headaches is not known. It is speculated that feverfew affects platelet activity or inhibits vascular smooth-muscle contraction, perhaps by inhibiting prostag-landin synthesis (4). Results of in vitro studies suggest that rather than acting as a cyclooxygenase inhibitor, feverfew inhibits phospholipase A2, thus inhibiting release of arachidonic acid from the cell membrane phospholipid bilayer (11,12).

Drugs that are serotonin antagonists are used in migraine prevention (e.g., methysergide) (9). During a migraine, serotonin is released from platelets (9), and in vitro studies using a bovine platelet bioassay have shown that parthenolide, as well as other sesquiterpene lactones, inhibits platelet serotonin release (13). Both parthenolide and a chloroform extract of dried, powdered leaves were also able to inhibit serotonin release and platelet aggregation in an in vitro study using human platelets and a variety of platelet-activating agents (14). The effect of these substances on platelet aggregation caused by a variety of chemicals was tested, and was similar except that inhibition of platelet aggregation induced by the calcium ionophore A23187 by chloroform extract leveled off at a relatively low concentration and was not com plete, whereas parthenolide inhibited aggregation in a dose-dependent manner, suggesting a different mechanism of action.

Similarly discrepant results were reported in a study comparing chloroform extracts of fresh and dried feverfew and parthenolide (15). In this in vitro study, both the fresh extract and parthenolide were able to irreversibly inhibit contraction of rabbit aortic ring and rat anococcygeus muscle in a dose-dependent manner. In contrast, the extract from dried powdered feverfew leaves was spasmogenic, causing a slow, maintained, reversible contraction. The differences in pharmacological effect were explained by the differences in composition of the extracts; unlike the extract of fresh leaves, the extract of dried powdered leaves did not contain parthenolide or other sesquiterpene lactones. The specific functional group responsible for inhibition of smooth muscle contraction has been identified as the a-methylene moiety present on parthenolide and other sesquiterpene lactones (16). It has been hypothesized that the irreversible inhibition of platelet aggregation and inhibition of smooth muscle contraction are caused by covalent binding of parthenolide and other lactones to sulfhydryl (SH-) groups on proteins (15).

Another study using chloroform extract of fresh feverfew leaves demonstrated reversible blockade of open voltage-dependent potassium channels, but not of calcium-dependent potassium channels, in smooth muscle cells in vitro (17). Inhibition of potassium channels would be expected to increase the excitability of smooth muscle cells, potentiate the effects of depolarizing stimuli, and open voltage-dependent calcium channels, thus leading to muscle contraction. In the study described previously (17), the extract of dried, powdered feverfew had this very effect, which could be explained by potassium channel blockade; however, the fresh extract had the opposite effect (i.e., it irreversibly inhibited contractility). In addition, parthenolide, which was present in fresh but not dried extracts, did not appear to inhibit potassium channels. The substances in feverfew that cause potassium channel blockade and muscle contraction have not been identified, but because voltage-dependent potassium channels present in smooth muscle cells are similar to those present in neurons, it is possible that feverfew interferes with the neurogenic response in migraine (17).

One of the first studies to attempt to objectively evaluate the efficacy of feverfew for migraine prophylaxis enrolled 17 patients with common or classical migraine who had been self-medicating with raw feverfew leaves (average 2.44 leaves [60 mg]) daily for at least 3 months (7). Patients were randomized to receive either 50 mg of freeze-dried feverfew powder or placebo for 6 months. One patient in each group was taking conjugated equine estrogens (PremarinĀ®) and one patient in the feverfew group was taking OrlestĀ® 21, an oral contraceptive. Efficacy was assessed using patient diaries in which patients recorded the duration and severity of headache pain, severity and duration of nausea and vomiting, and analgesic use on an ordinal scale. The frequency of migraine, nausea, and vomiting, was significantly (p < 0.02) lower in the feverfew group, but analgesic use was similar. Two patients taking placebo withdrew from the study because of recurrent severe migraine. Patients taking feverfew reported a similar number of migraine attacks during the study compared to before the study, when they were self-medicating with feverfew. Conversely, placebo patients reported a frequency of headache that was greater than when they were self-medicating, and similar to the frequency of headache before beginning feverfew self-treatment. At the end of the study, the patients assessed the overall efficacy of the treatment; feverfew had a more favorable rating than placebo (p < 0.01). Because there was underreporting of headache in the placebo group, the difference between feverfew and placebo may have been even greater. Adverse events were not reported in the feverfew group, but patients did complain of the product's taste. A potential problem with this study was blinding; most patients guessed correctly which treatment they were receiving. Another criticism of this study is that because the participants were recruited from a population already taking feverfew and who presumably felt they were benefiting from feverfew, the investigators were in effect selecting known "feverfew responders" for their study. Such a selection process limits the extent to which these study results can be extrapolated to the general population.

In a subsequent study, efficacy of feverfew in migraine prophylaxis was further assessed in a double-blind, randomized, crossover design (9). One capsule of dried feverfew leaves (70-114 mg, average 82 mg) was compared to placebo in 72 adult volunteers with classical or common migraine. All subjects had migraine of at least a 2-year duration, and suffered at least one attack per month. Patients were excluded if they were being treated for any other disease, but women taking oral contraceptives were eligible for the study if they had been on the same contraceptive for at least 3 months. Females of child-bearing potential were excluded unless they were using adequate contraception. All migraine-related drugs were stopped at the beginning of the trial, which commenced with a 1-month single-blind placebo run-in period. Patients were then randomized to placebo or feverfew for 4 months each. Efficacy was assessed based on a patient diary in which patients recorded the number, severity, and duration of any migraine attacks, as well as the presence of nausea and vomiting, on a scale from 0 to 3. In addition, every 2 months, the patient's overall impression of migraine control was assessed using a 10-cm visual analog scale. There was a significant difference (p < 0.05) between placebo and feverfew in number of attacks only after month 4, but there wasa significant difference between the two groups in overall impression after month 4 (p < 0.05) and after month 6 (p < 0.01) when assessed via the visual analog scale. Feverfew decreased the number of classical migraine attacks by 32% (95% confidence interval [CI] 11-53%, p < 0.05), but the effect on the number of common migraine attacks was not statistically significant (p = 0.06). When assessing the responses of patients who had never used feverfew before study enrollment (n = 42/59), the number of attacks was reduced by 23% (95% CI 10-33%, p = 0.06). This nonsignificant result gives credence to the concerns about selection bias in the study by Johnson and colleagues. The overall impression of both patients with common and classical migraines was favorable based on the visual analog scale (p < 0.01). Vomiting associated with attacks was also decreased with feverfew, and there was a trend toward reduction in migraine severity. Duration of attacks was unchanged. Incidence of adverse effects, including mouth ulceration, indigestion, heartburn, dizziness, lightheadedness, rash, and diarrhea was low and comparable to placebo.

Another randomized, double-blind, crossover study assessed the efficacy of 100 mg of feverfew (0.2% parthenolide) daily compared to placebo in 57 patients (8). Efficacy was assessed using a questionnaire. Feverfew was superior to placebo in reducing intensity of migraine pain and other symptoms. Unfortunately, no results were reported for the actual number of headache attacks occurring during the study. An alcoholic extract of feverfew providing 0.5 mg of parthenolide daily for 4 months was not superior to placebo in the number of migraine attacks in a randomized, double-blind, crossover study in 44 evaluable patients (18).

Surprisingly, melatonin, a human pineal hormone, has been identified in fresh green feverfew leaves at a concentration of 2.45 ^g/g, and in a commercially available feverfew tablet (Tanacet, Ashbury Biologicals, Inc., Toronto, CA) at a concentration of 0.143 ^g/g. Each Tanacet tablet contains 70-80 ng of melatonin, and the recommended dose is one or two tablets daily. Freeze-dried green leaf contains 2.19 ^g/g of melatonin, fresh golden feverfew leaf contains 1.92 ^g/g, oven-dried green leaf contains 1.69 ^g/g, freeze-dried golden leaf conatins 1.61 ^g/g, and oven-dried golden leaf contains 1.37 ^g/g. Because chronic migraine headaches are associated with lower circulating melatonin levels, it is possible that melatonin plays a role in feverfew's purported efficacy in preventing migraine headache. This finding underscores the need to fully characterize the ingredients in herbs and medicinal preparations made from them (19).

A concentrated CO2 extract of T. parthenium (feverfew) indentified as MIG-99 was evaluated in a 12-week, double-blind, multicenter, randomized, placebo-controlled, dose-response study involving 147 patients (20). The clinical effectiveness of three dosage levels of MIG-99 (2.08, 6.25, and 18.75 mg) administered three times daily was studied. In general, the compound failed to demonstrate a significant prophylactic effect in any treatment group. Only the maximum migraine intensity, severity, and the number of attacks with confinement to bed were reduced by MIG-99. In the intent-to-treat analysis, MIG-99 was shown to be effective only in a small, predefined subgroup of patients receiving the 6.25-mg dose. These patients were noted to have a total of four attacks reported in a baseline period. Regarding toxicity and safety, the incidence of adverse events was similar between all treatment groups as compared to placebo, and the incidence of patients reporting at least one adverse effect was lowest in the patients receiving the highest dose. Additionally there were no negative laboratory investigations or changes in vital signs during the treatment regimen in any patient group.

A randomized, double-blind, placebo-controlled trial comparing the effects of a compound containing a combination of riboflavin (4000 mg daily), magnesium (300 mg daily), and feverfew (100 mg standardized to 0.7 mg parthenolide daily) to placebo (25 mg riboflavin) showed a placebo effect comparable to the combination compound (21). In this particular study, the placebo effect exceeded that reported for any other placebo in migraine prophylaxis trials. The trial was undertaken to study patient response to a "natural" multicombination product containing ingredients with previously demonstrated efficacy in at least one double-blind, placebo-controlled trial. Although there was no statistical difference between groups during the 3-month trial, both groups were superior to baseline in reduction of number of migraines, migraine days, and migraine index, but not superior to previously reported positive results for any of the agents alone. Possible reasons for the high placebo response (44%) included a potential therapeutic effect of the small dose of riboflavin in the placebo group, adverse interaction between the three agents used in the combination product, and a short duration of study (3 months).

In a study designed to evaluate the pharmacokinetics and toxicity of parthenolide, the active component of feverfew, doses of 1, 2, 3, and 4 mg were studied in a dose escalation fashion (22). Administration of feverfew in escalating doses up to 4 mg showed no toxicity and a maximum tolerated dose was not reached. Despite a parthenolide detection level of 0.5ng/mL, no measurable concentrations of this component could be measured at any of the administered doses levels.

Larger studies are needed to definitively determine the efficacy of feverfew in the prevention of migraine and to identify the component or components responsible for its pharmacologic effects. Although parthenolide is considered the active constituent of feverfew, the pharmacokinetics of this constituent have not been characterized, and challenges remain in detecting this component analytically to allow evaluation of its metabolic fate.

Herbal Remedies For Acid Reflux

Herbal Remedies For Acid Reflux

Gastroesophageal reflux disease is the medical term for what we know as acid reflux. Acid reflux occurs when the stomach releases its liquid back into the esophagus, causing inflammation and damage to the esophageal lining. The regurgitated acid most often consists of a few compoundsbr acid, bile, and pepsin.

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