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RASPBERRY LEAF

*Other Common Name:*	Red raspberry leaf
*Botanical Name:*	Rubus idaeus
*Family:*	Rosaceae
*Plant Part Used:*	Leaf

PRESCRIBING INFORMATION

Actions	Astringent, partus preparator, parturifacient, antidiarrheal
Potential Indications	Based on appropriate evaluation of the patient, practitioners should consider prescribing raspberry leaf in formulations in the context of: • Ensuring healthy uterine function at childbirth (when taken during pregnancy) (4,5) • Abnormal bleeding from the uterus, stomach, or bowels (5) • Mouth ulcers, diarrhea (5) • Dysmenorrhea (6) • Topical treatment for tonsillitis, conjunctivitis, sore throat (5,6)

Contraindications None known. Warnings and Precautions None required. Interactions None known. Use in Pregnancy and Lactation No adverse effects expected in pregnancy or lactation, but confining use to the second and third trimesters is more appropriate. Side Effects None expected if taken within the recommended dosage. Dosage Dose per day^* Dose per week^* 4.5-14 ml of 1:2 liquid extract 30-100 ml of 1:2 liquid extract

* This dose range is extrapolated from the British Herbal Pharmacopoeia 1983 and the author’s education and experience.

SUPPORTING INFORMATION

Traditional Prescribing	Traditional Western herbal medicine uses include: • Diarrhea, dysentery, cholera ^1,² • During pregnancy and to facilitate delivery,^1,² dysmenorrhea³ • Stomatitis;¹ hemorrhage from the stomach, bowel, or uterus; prolapsed uterus² • Topically for tonsillitis and conjunctivitis,¹ as a gargle for sore throats⁴ • Stomach complaints of children, topically for wounds and ulcers ⁴
Pharmacologic Research	The leaves of raspberry contain flavonoids, gallotannins, and ellagitannins.⁵ • Aqueous extract of raspberry leaf (1 g/15 ml) had little or no effect on isolated uteri from nonpregnant rats but inhibited contractions of those from pregnant rats. A variable response was obtained from uteri in induced estrus. Inhibition lasted 3 to 4 minutes, and intrinsic contractions were resumed. Epinephrine (adrenaline)-like resistance did not develop and the inhibitory effect was not prevented by propranolol. The extract contracted strips of human uterus at 10 to 16 weeks of pregnancy. For pregnant human and rat uteri, the intrinsic rhythm (over a 20-minute period while the extract remained in contact with the tissue) appeared to become more regular in most cases, and contractions were less frequent.⁶ • Aqueous extract of raspberry leaf stimulated isolated smooth muscle, particularly the uterus. When the tannins were removed from this extract, spasmolytic activity was exhibited. Both stimulant and relaxant components were present in the extract, with a weak anticholinesterase component demonstrating stimulation.⁷ • Raspberry leaf extracts relaxed isolated intestinal smooth muscle.⁸ • A concentrate of raspberry leaf infusion relaxed the uterus and intestine in situ (by intravenous injection), provided the tone of the organs was normal. For the uterus, the relaxation was occasionally followed by contraction and further relaxation. The degree of relaxation increased with successive doses. Secondary contractions were eliminated, and those that occurred were evenly spaced. The experimental model included mainly nonpregnant uteri and one animal in late pregnancy. Relaxation was also promoted in tonically contracted isolated (presumably nonpregnant) uteri, but if allowed to relax, raspberry leaf caused the organ to contract. When little tone was present in isolated uterus, raspberry leaf caused stimulation, but when the uterus was toned, raspberry leaf induced relaxation.⁹ This finding implies a regulatory action on uterine tone.
Clinical Studies	• A retrospective, observational, controlled study involving 108 women found that women can consume raspberry leaf during their pregnancy to shorten labor, with no side effects identified for the women or their babies. Ingesting raspberry leaf may also decrease the likelihood of preterm and postterm labor, evidenced by a smaller spread of the gestation period among the raspberry leaf group. An unexpected finding of the study was that women who ingest raspberry leaf might be less likely to require artificial rupture of their membranes, cesarean section, forceps, or vacuum birth. Treatment began as early as 8 weeks’ gestation, with the majority commencing at 30 to 34 weeks. The daily dose ranged from 1 to 6 cups of tea or 1 to 8 tablets, with 6 cups or tablets per day being the most popular intake. The weight of the tablets was not defined. ¹⁰ • A follow-up trial of randomized, double-blind, placebo-controlled design was conducted by the same authors and involved 192 women who were followed from 32 weeks of pregnancy to labor. The women in the treatment group received 1.2 g of raspberry leaf twice a day. No adverse effects were observed, but also, no effect on shortening the first stage of labor was indicated. A shortening of the second stage of labor occurred (a difference of 9.6 minutes) and a lower rate of forceps deliveries was noted for the raspberry leaf group compared with the control group (19.3% and 30.4%, respectively). The authors suggested that earlier intervention and a higher dose should be studied.¹¹ • A pharmacologic study conducted in the 1940s observed that uterine contractions decreased in frequency and strength in three pregnant women administered a raspberry leaf extract. Secondary contractions were also eliminated. A very slight fall in the systolic blood pressure was noticeable. The authors noted that raspberry leaf may be useful for treating irregular uterine action during labor and menstruation. The dose was recorded as 20 to 40 grains (approximately 1.3 to 2.6 g) of crude extract of dried raspberry leaves, containing fragarine. “Fragarine” is the term the authors proposed for the active principle of this crude extract of raspberry leaves.³ This term has been used in popular and scientific literature ever since, but no evidence has been found to verify the existence of fragarine, let alone its chemical structure.

REFERENCES

1 British Herbal Medicine Association’s Scientific Committee. British herbal pharmacopoeia. Bournemouth: BHMA, 1983.

2 Felter HW, Lloyd JU. King’s American dispensatory, ed 18. Portland: Eclectic Medical Publications, 1905. rev 3, reprinted 1983

3 Whitehouse B. Br Med J. 1941;2:370-371.

4 Grieve M. A modern herbal. New York: Dover Publications, 1971.

5 Wagner H, Bladt S. Plant drug analysis: a thin layer chromatography atlas, ed 2. Berlin: Springer-Verlag, 1996.

6 Bamford DS, Percival RC, Tothill AU. Br J Pharmacol. 1970;40(1):161P-162P.

7 Beckett AH, et al. J Pharm Pharmacol. 1954;6:785-796.

8 Patel AV, et al. J Pharm Pharmacol. 1990;47(12B):1129.

9 Burn JH, Withell ER. Lancet. 1941;2(6149):1-3.

10 Parsons M, Simpson M, Ponton T. J Aust Coll Midwives. 1999;12(3):20-25.

11 Simpson M, et al. J Midwifery Womens Health. 2001;46(2):51-59.

RED CLOVER

*Botanical Name:*	Trifolium pratense
*Family:*	Leguminosae
*Plant Part Used:*	Flower

PRESCRIBING INFORMATION

Actions	Depurative, antitumor (traditional use)
Potential Indications	Based on appropriate evaluation of the patient, practitioners should consider prescribing red clover in formulations in the context of: • Skin disorders, including eczema, psoriasis, and ulcers (5) • Respiratory conditions, especially with spasmodic cough, including bronchitis (5)

Contraindications None known. Warnings and Precautions None required. Interactions None known. Use in Pregnancy and Lactation No adverse effects expected. Side Effects None expected if taken within the recommended dose range. Dosage Dose per day^* Dose per week^* 1.5-6.0 ml of 1:2 liquid extract 10-40 ml of 1:2 liquid extract

* This dose range is extrapolated from the British Herbal Pharmacopoeia 1983, the British Herbal Compendium 1992, and the experience.

SUPPORTING INFORMATION

Traditional Prescribing	Traditional Western herbal medicine uses include: • Chronic skin disease, including eczema, psoriasis, leg ulcers, and burns ^1,² • Bronchitis, whooping cough, laryngitis ^1,² • Cancer ²
Pharmacologic Research	Red clover flowers contain isoflavones, including biochanin A, formononetin, and genistein.³ Isoflavones have demonstrated weak estrogenic activity and under certain circumstances exert an antiestrogenic competitive activity.⁴ However, in 25% aqueous ethanolic extracts of red clover flowers, these constituents are present in low quantities. ³
Clinical Studies	Trials using concentrated extracts of red clover leaf and flower, standardized for isoflavone content have been conducted. However, given that traditional liquid extracts are low in isoflavones, this information has not been reviewed here.

REFERENCES

1 British Herbal Medicine Association’s Scientific Committee. British herbal pharmacopoeia. Bournemouth: BHMA, 1983.

2 Felter HW, Lloyd JU. King’s American dispensatory, ed 18. Portland: Eclectic Medical Publications, 1905. rev 3, reprinted 1983

3 Lehmann R, Penman K: Technical Report. MediHerb Pty Ltd, PO Box 713, Warwick, Queensland 4370, Australia.

4 Messina MJ. Am J Clin Nutr. 1999;70(suppl 3):439S-450S.

REHMANNIA

*Botanical Name:*	Rehmannia glutinosa
*Family:*	Gesneriaceae
*Plant Part Used:*	Root

PRESCRIBING INFORMATION

Actions	Antipyretic, adrenal tonic, antihemorrhagic, antiinflammatory
Potential Indications	Based on appropriate evaluation of the patient, practitioners should consider prescribing Rehmannia in formulations in the context of: • Rheumatoid arthritis, asthma, urticaria (4) • Chronic nephritis, in combination with other traditional Chinese herbs, including Astragalus (4) • Fevers, hemorrhage, skin rashes, diabetes, insomnia, constipation (5) • Benefit in supporting adrenal function, particularly if hypertension is present (Unlike licorice, Rehmannia is not contraindicated in hypertension.) (5,7) • Preventing the suppressive effects of corticosteroid drugs on endogenous levels of corticosteroids (7)

Contraindications None known. Warnings and Precautions None required. Interactions None known. Use in Pregnancy and Lactation No adverse effects expected. Side Effects In a small, open trial involving patients with rheumatoid arthritis, intermittent treatment with Rehmannia decoction elicited mild edema in a minority of patients. Excessive doses can cause diarrhea. Dosage Dose per day^* Dose per week^* 4.5-8.5 ml of 1:2 liquid extract 30-60 ml of 1:2 liquid extract

* This dose range is adapted from dried plant dosages administered by decoction in TCM.¹ The water is a more effective solvent than water for many phytochemicals are taken into account.

SUPPORTING INFORMATION

Traditional Prescribing

In TCM, Rehmannia in its uncured form is the dried root of Rehmannia glutinosa. The cured form consists of the clean, fresh root stewed in wine. In this process, the root is washed in wine, steamed, dried, then resteamed, and dried several times. Unless stated otherwise, liquid extracts of Rehmannia usually consist of the uncured form.

TCM uses for uncured Rehmannia include:

• Febrile diseases with reddened tongue and thirst ^1,²

• Hemorrhage ²

• Spitting of blood, skin eruptions ¹

• Diabetes caused by internal heat¹

• Conditions caused by heart fire: mouth sores, insomnia, low-grade fevers, constipation ²

• Conditions of yin deficiency with internal heat¹

TCM uses for cured Rehmannia include:

• To regulate menstruation, to promote blood production and tone the kidneys ³

• Anemia, dizziness, weakness, tinnitus ¹

• Amenorrhea, metrorrhagia ³

• Night sweats ¹

Pharmacologic Research

Pharmacologic research conducted using polysaccharides from Rehmannia in vitro and by injection has not been listed, because this activity is probably not relevant to the oral use of Rehmannia liquids prepared with ethanol. Rehmannia root contains a number of constituents, including iridoid glycosides and other glycosides.

• Uncured Rehmannia inhibited the metabolism of cortisol by hepatocytes in vitro. Oral administration in a model of adrenal cortex depletion (induced by chronic treatment with glucocorticoids) resulted in raised serum corticosterone levels. Rehmannia treatment also prevented or reversed morphologic changes in the pituitary and adrenal cortex, appearing to antagonize the suppressive effect of glucocorticoids on the hypothalamic-pituitary-adrenal axis.

• Cured Rehmannia abolished the suppressive effects of cyclophosphamide and dexamethasone on immune function and demonstrated protective effects on disturbances in hematopoiesis, immunity, and heart, liver, and kidney functions during chemotherapy in various experimental models.

• An in vitro study found that three compounds from Rehmannia demonstrated aldose reductase inhibitory activity.

• Orally administered uncured Rehmannia improved hemorrheology in experimental models of arthritis and thrombosis.

Clinical Studies

• Uncontrolled trials using uncured Rehmannia produced therapeutic effects in patients with rheumatoid arthritis, asthma, and urticaria.

• Oral administration of an herbal preparation that included Rehmannia and Astragalus demonstrated therapeutic effects in patients with chronic nephritis. Significant improvement was observed for 91% of the treatment group compared with 67% of the control group. The preparation also demonstrated antiallergic effects and promotion and modulation of immune function. The design of this clinical research was not rigorous and its results should be interpreted with caution.

REFERENCES

The following book was referred to in the compilation of the pharmacologic and clinical informationMills S, Bone K. Principles and Practice of Phytotherapy: Modern Herbal Medicine. Edinburgh: Churchill Livingstone, 2000.

1 Pharmacopoeia Commission of the People’s Republic of China. Pharmacopoeia of the People’s Republic of China, English ed. Beijing: Chemical Industry Press, 1997.

2 Bensky D, Gamble A. Chinese herbal medicine materia medica. Seattle: Eastland Press, 1986.

3 Chang HM, But PP. Pharmacology and applications of Chinese materia medica. Singapore: World Scientific, 1987.

ROSEMARY

*Botanical Name:*	Rosmarinus officinalis
*Family:*	Labiatae
*Plant Part Used:*	Leaf

PRESCRIBING INFORMATION

Actions	Carminative, spasmolytic, antioxidant, antimicrobial, circulatory stimulant, hepatoprotective
Potential Indications 1

Based on appropriate evaluation of the patient, practitioners should consider prescribing rosemary in formulations in the context of:

• Increasing mental alertness and memory (6)

• Enhancing phase I and II detoxification by the liver (7)

• Achieving antioxidant and hepatoprotective effects, preventing atherosclerosis (7)

• Circulatory weakness, including hypotension (5,6)

• Dyspeptic conditions and particularly for improvement of hepatic and biliary function (4)

• Headache, depression, debility (5)

• Topical treatment for promoting wound healing, as a mild antiseptic, for alleviating symptoms of rheumatic diseases and circulatory problems (4)

• Topical treatment for myalgia, sciatica, and intercostal neuralgia (5)

Contraindications No known contraindications have been found for rosemary, although caution may be warranted in women wishing to conceive, based on the cineole content in its essential oil. In an embryotoxic study involving rats, rosemary aqueous extract did not cause significant changes in postimplantation loss or in the number of malformation of fetuses. Preimplantation loss increased in the treated group, although the difference was not significant compared with the control.¹ Warnings and Precautions None required. Interactions Nonheme iron absorption was significantly decreased in female volunteers who consumed a phenolic-rich extract of rosemary (8.2% by weight of polyphenols, including carnosic acid, carnosol, and rosmarinic acid). The extract was administered via the meat component of a test meal and compared with a control meal over a total of 4 days.² This finding indicates a potential interaction for concomitant administration of rosemary during iron intake. In anemia and cases for which iron supplementation is required, rosemary should not be taken simultaneously with meals or iron supplements. Use in Pregnancy and Lactation No adverse effects expected. (See also the “Contraindications” section in this monograph.) Side Effects None expected if taken within the recommended dose range. Contact allergy has been reported for rosemary and may be the result of the constituent carnosol.³ Dosage Dose per day^* Dose per week^* 2.0-4.5 ml of 1:2 liquid extract 15-30 ml of 1:2 liquid extract

* This dose range is extrapolated from the British Herbal Pharmacopoeia 1983 and the author’s education and experience.

SUPPORTING INFORMATION

Traditional Prescribing	Traditional Western herbal medicine uses include: • To stimulate the mind, memory, and the senses ^4,⁵ • Flatulent dyspepsia associated with psychogenic tension ⁶ • Migrainous or hypertensive headaches ⁶ • Depressive states with general debility and indications of cardiovascular weakness ⁶ • All states of chronic circulatory weakness, including hypotension; debility; anorexia and poor digestion, particularly in older adults ⁷ • Topically for myalgia, sciatica, and intercostal neuralgia ⁶
Pharmacologic Research	Rosemary leaf contains an essential oil (1% to 2%), consisting of 1,8-cineole, borneol, bornyl acetate, α-pinene, and camphene; phenolic diterpenes, including carnosol and carnosic acid; rosmarinic acid; flavonoids; and triterpenoids. ^8,⁹ (Carnosic acid is also known as carnosolic acid or salvin.) • Rosemary is a strong antioxidant. The antioxidant activity is attributed to the phenolic diterpenes (particularly carnosic acid and carnosol), as well as rosmarinic acid. These components have inhibited lipid peroxidation, are good scavengers of free radicals, and protect red blood cells against oxidative hemolysis in vitro.^10,¹¹ Rosemary extract has inhibited oxidative alterations to skin surface lipids in vitro and in vivo. ¹² • Because of its strong antioxidant activity, rosemary is used in the food industry as a preservative, particularly for meat products.¹³ An in vitro comparison with 15 other herbs found that rosemary exhibited the highest antioxidant index in all the tested fats, particularly in animal fats.¹⁴ (Carnosol and carnosic acid are fat-soluble.) Rosmarinic acid is also a potent antioxidant, but its solubility in fat is low, thus it acts best in aqueous systems. The strong antioxidant activity toward saturated fats is unusual, given that most antioxidant plant extracts and phytochemicals demonstrate activity only in aqueous systems. This action may indicate a valuable role in treating and preventing pathologic processes that involve lipid peroxidation, such as the development of atherosclerosis. • Experimental studies indicated that oral administration of rosemary leaf is hepatoprotective, which has been attributed to the antioxidant phenolic compounds.¹⁵ Oral administration of a methanolic extract of osemary enhanced liver microsomal metabolism of endogenous estrogens. Rosemary also inhibited the uterotropic action of estradiol and estrone.¹⁶ • Oral intake of rosemary extract reduced the development of mammary carcinoma in vivo.¹⁷ Rosemary extract may assist in reversing multidrug resistance in mammary tumors, as indicated by its ability to inhibit the transmembrane transport pump activity in isolated breast cancer cells.¹⁸ • Rosemary extract, or its components, carnosol or carnosic acid, are potent inhibitors of DNA adduct formation induced by benzo(a)pyrene or aflatoxin B1 in vitro.¹⁹ These substances act by inhibiting cytochrome P-450 activity (phase I enzymes) and inducing glutathione S-transferase (phase II).²⁰ Oral administration of rosemary extract (0.25% to 1.0%) in the diet of rats increased the activity of the phase II enzymes glutathione S-transferase and NADPH-quinone reductase.²¹ Water-soluble extract of rosemary induced phase I and II enzymes in vivo (by oral route). This activity was attributed to flavones, monoterpenes, or an additive effect of all components but not to rosmarinic acid alone.²² A further in vivo study using oral doses indicated that the fraction containing the diterpenes induced phase II enzymes.²³ • Rosemary extract demonstrated in vitro antimicrobial activity toward food-borne microorganisms,²⁴ Leishmania mexicana (80% ethanol extract),²⁵ Yersinia enterocolitica (ethanol extract),²⁶ and HSV type 2.²⁷ • Rosemary oil also demonstrated antimicrobial activity in vitro toward Candida albicans²⁸ and a number of bacteria that cause respiratory and gastrointestinal disorders (e. g., Pseudomonas aeruginosa, Escherichia coli, Aspergillus fumigatus) by gaseous contact. Rosemary oil also delayed sporulation of several filamentous fungi. ²⁹ • Normal and diabetic mice with unlimited access to a rosemary infusion for 3 months had lower blood glucose levels compared with controls.³⁰ • Aqueous-alcoholic extract of rosemary (1 g/kg, orally) inhibited experimentally induced gastric lesions. This activity may be the result of enhanced mucosal defense.³¹ • Oral administration of rosemary infusion demonstrated diuretic activity in vivo.³² • Rosemary oil produced a relaxant effect on experimentally induced contractions in isolated tracheal smooth muscle,³³ aortic segments,³⁴ and intestine.³⁵ Rosemary extract demonstrated spasmolytic activity on experimentally contracted isolated ileum.³⁶ • Topical application of a chloroform extract of rosemary demonstrated a dose-dependent antiinflammatory activity in the croton oil–induced ear edema model. ³⁷ Rosmarinic acid inhibited experimentally induced anaphylaxis (by oral route). Further tests indicated a selectivity of this compound for complement-dependent (inflammatory) processes.³⁸ • Injection of freeze-dried rosemary extract (flowering stems) produced an increase in bile flow from both the liver and gallbladder in vivo.³⁹ • Both inhalation and oral administration of rosemary oil stimulated locomotor activity in an experimental model.⁴⁰
Clinical Studies	No clinical studies using rosemary leaf have been found. However, some clinical studies have used rosemary essential oil. • Inhaling rosemary leaf oil for 3 minutes by volunteers produced decreased frontal alpha and beta power (measured from electro-encephalographic [EEG] recordings), suggesting increased alertness. Anxiety scores were lowered. Volunteers reported feeling more relaxed and alert and were faster (but not more accurate) at mathematical computations compared with baseline values. The trial was randomized and controlled.⁴¹ • In an uncontrolled trial, an aqueous emulsion of rosemary oil (1:10) inhibited the growth of Candida albicans when applied to the mouths (five times per day) of 12 patients with cancer, pneumonia, and oral candidiasis, which was unresponsive to nystatin.⁴² • In Germany, the Commission E supports using rosemary leaf to treat dyspeptic conditions. Externally, rosemary leaf can be used as supportive therapy for rheumatic diseases and circulatory problems.⁴³ • ESCOP recommends rosemary leaf and flower for improving hepatic and biliary function and in dyspeptic conditions. In addition to the recommendations previously listed for topical use, which are also listed by the Commission E, rosemary can be used externally for the promotion of wound healing and as a mild antiseptic.⁴⁴