Queen’s Delight

Summary and Pharmaceutical Comment

The Euphorbiaceae plant family is characterised by the diterpene esters. These compounds, known as phorbol, ingenane or daphnane esters depending on their skeleton type, have been investigated as constituents of genera such as Euphorbia and Croton, and some of them have been found to be co-carcinogenic and highly irritant to mucous membranes.(G33) No scientific evidence was found to justify the reputed herbal uses. In view of the lack of data on pharmacological effects, efficacy and safety, and the potential toxicity of queen’s delight, the appropriateness of medicinal use of queen’s delight should be considered; and excessive use, at least, and use during pregnancy and lactation should be avoided.

Species (Family)

Stillingia sylvatica L. (Euphorbiaceae)

Synonym(s)

Ditrysinia sylvatica (L.) Raf., Excoecaria sylvatica (L.) Baill., Queen's Root, Sapium sylvaticum (L.) Torr., Stillingia, Stillingia sylvatica var. genuina Müll. Arg, Yaw Root

Part(s) Used

Root

Pharmacopoeial and Other Monographs

BHP 1996(G9)

Legal Category (Licensed Products)

GSL(G37)

Constituents

Terpenoids Gnidilatin, a daphnane diterpene.(1) Eight compounds, termed stillingia factors S1–S8, have been isolated and identified as daphnane-type and tigliane-type esters carrying saturated, polyunsaturated or hydroxylated fatty acids.(2)

Other constituents Volatile oil 3–4%, fixed oil, acrid resin (sylvacrol), resinic acid, stillingine (a glycoside) and tannin.

Other plant parts Hydrocyanic acid (leaf and stem).(2)

Food Use

Queen's delight is not used in foods.

Herbal Use

Queen's delight is stated to possess sialogogue, expectorant, diaphoretic, dermatological, astringent, antispasmodic and, in

Figure 1 Selected constituents of queen’s delight.

large doses, cathartic properties. Traditionally, it has been used for bronchitis, laryngitis, laryngismus stridulus, cutaneous eruptions, haemorrhoids, constipation and specifically for exudative skin eruption with irritation and lymphatic involvement, and laryngismus stridulus.(G7, G64)

Q

Figure 2 Queen’s delight (Stillingia sylvatica).

494 Queen’s Delight

Figure 3 Queen’s delight – dried drug substance (root).

Dosage

Dosages for oral administration (adults) recommended in standard herbal reference texts are given below.

Dried root 1–2 g as a decoction three times daily.(G7)

Liquid extract 0.5–2.0 mL (1 : 1 in 25% alcohol) three times daily.(G7)

Tincture 1–4 mL (1 : 5 in 45% alcohol) three times daily.(G7)

Pharmacological Actions

None documented.

Clinical studies

There is a lack of clinical research assessing the effects of queen's delight and rigorous randomised controlled clinical trials are required.

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Side-effects, Toxicity

Clinical data

There is a lack of clinical safety and toxicity data for queen's delight and further investigation of these aspects is required.

Overdose of queen's delight is reported to cause vertigo, burning sensation of the mouth, throat and gastrointestinal tract, diarrhoea, nausea and vomiting, dysuria, aches and pains, pruritus

and skin eruptions, cough, depression, fatigue and perspiration.(G22) The diterpene esters are toxic irritant principles known

to cause swelling and inflammation of the skin and mucous membranes.(2, G33)

Preclinical data

The leaves and stem are documented to be toxic to sheep because of the hydrocyanic acid content.(3)

Contra-indications, Warnings

In view of the irritant nature of the diterpene esters, queen's delight may cause irritation to the mucous membranes. In view of the lack of data on pharmacological effects, efficacy and safety, and the potential toxicity of queen's delight, whether or not queen's delight is appropriate for medicinal use should be considered.

Pregnancy and lactation In view of the irritant and potentially toxic constituents, the use of queen's delight during pregnancy and lactation should be avoided.

References

1 Dictionary of Natural Products. Chapman & Hall, 1982–2005.

2Adolf W, Hecker E. New irritant diterpene-esters from roots of

Stillingia sylvatica L. (Euphorbiaceae). Tetrahedron Lett 1980; 21:

2887–2890.

3Lewis WH, Elvin-Lewis MPF. Medical Botany. New York: Wiley Interscience, 1977.

Summary and Pharmaceutical Comment

Limited phytochemical information is available for raspberry leaf. The presence of tannin constituents supports some of the reputed traditional uses, although it is unsuitable to use as a herbal remedy to treat eye infections, such as conjunctivitis. Raspberry leaf is widely recommended to be taken during pregnancy to help facilitate easier parturition. However, evidence from rigorous randomised controlled clinical trials to support the efficacy of preparations of raspberry leaf to facilitate parturition is lacking; the sole clinical trial reported a lack of effect for a raspberry leaf preparation on several outcome variables. Further investigation to assess the effects of well-characterised raspberry leaf preparations in welldesigned randomised controlled trials involving sufficient numbers of participants is required. There is limited evidence from in vitro studies that raspberry leaf has effects on uterine tissue.

There are only limited data on safety aspects of raspberry leaf preparations, including when taken during pregnancy. In view of this, raspberry leaf should not be taken during pregnancy unless under medical supervision. Raspberry leaf preparations should be avoided during breastfeeding. Use of raspberry leaf preparations at doses higher than those recommended and/or for excessive periods should be avoided until further information is available on their safety with long-term use. In view of the documented pharmacological actions of raspberry leaf preparations, the potential for interactions with other medicines administered concurrently, particularly those with similar or opposing effects, should be considered.

Species (Family)

Rubus idaeus L. (Rosaceae)

Synonym(s)

Rubus

Part(s) Used

Leaf

Pharmacopoeial and Other Monographs

BHP 1996(G9)

Martindale 35th edition(G85)

Legal Category (Licensed Products)

GSL(G37)

Constituents

Flavonoids Total flavonoid content in dried leaves 0.46–1.05%(1) and up to 5%.(2) Derivatives of kaempferol and quercetin,(1)

including quercetin-3-O-b-D-glucoside,(3) quercetinand kaemp- ferol-3-O-b-D-galactosides, kaempferol-3-O-b-L-arabinopyrano-

side and kaempferol-3-O-b-D-(60-p-coumaroyl)-glucoside (tiliroside).(4)

Polyphenols Galloand ellagi-tannins 2.06-6.89%(1) and up to 10%.(5)

Other constituents Volatile components, e.g. E-2-hexenal and Z- 3-hexenol, glycosides of C13-norisoprenoids, vitamin C.(G75)

Other parts of the plant Berries contain anthocyanins, hydrolysable tannins, sanquin H6, a dimeric ellagitannin, lambertianin (a tetrameric ellagitannin), triterpenoids a- and b- amyrin, stigmasterol, campesterol, cycloartenol, cholesterol,(6) and raspberry ketone.(7)

Related species Mono-, sesqui-, diand tri-terpenoids are present in several species, and five labdane-type diterpenes have been isolated from R. suavissimus.(8)

Food Use

Both the leaf and fruit are listed by the Council of Europe as natural sources of food flavouring (categories N2 and N1, respectively). Category N2 allows the addition of the leaf to foodstuffs in small quantities, with a possible limitation of an active principle (as yet unspecified) in the final product. Category N1 indicates that no restrictions apply to the fruit.(G16) Raspberry fruit is commonly used in foods.

Herbal Use

Raspberry is stated to possess astringent and partus praeparator properties. Traditionally, it has been used for diarrhoea, pregnancy, stomatitis, tonsillitis (as a mouthwash), conjunctivitis

R

Figure 1 Selected constituents of raspberry.

496 Raspberry

Figure 2 Raspberry (Rubus idaeus).

(as an eye lotion), and specifically to facilitate parturition.(G2, G7, G64) Modern interest is focused on the use of raspberry leaf to

stimulate and facilitate labour and to shorten its duration.

Dosage

Dosages for oral administration (adults) for traditional uses recommended in standard herbal reference texts are given below.

Dried leaf 4–8 g as an infusion three times daily.(G7)

Liquid extract 4–8 mL (1 : 1 in 25% alcohol) three times daily.(G7)

Pharmacological Actions

There is only a limited amount of basic and clinical research exploring the effects of raspberry leaf preparations.

In vitro and animal studies

A conference abstract published in the older literature describes utero-activity for a raspberry leaf infusion (1 g dried leaves infused with 15 ml of saline for 10 minutes at 958C, then filtered) when applied to rat and human uterine tissue. The extract had little or

no effect on the uterine strips from non-pregnant rats, but

(9)

Rextract had no effect on strips from non-pregnant human uteri, but initiated contractions in strips from human uteri obtained at 10–16 weeks of pregnancy. The intrinsic rhythm of the uterine tissue in which a pharmacological effect was observed (pregnant

rat and human uteri) was reported to become more regular, with contractions, in most cases, less frequent.(9) No data are provided in a report of these experiments, and no statistical analyses appear to have been carried out; replication of this work is necessary in order to confirm or refute the findings.

A methanol extract of fresh, dried R. idaeus leaves relaxed transmurally stimulated guinea-pig ileum in vitro, whereas no

response was seen with exposure of the system to extracts prepared with less polar solvents (n-hexane and ethyl acetate).(10) Subsequent methanol extraction and bioassay-guided fractionation revealed activity associated with fractions eluted with trichloromethane/methanol (95 : 5) and trichloromethane/methanol (50 : 50). The two most active fractions relaxed transmurally stimulated guinea-pig ileum in a concentration-dependent manner.

Aqueous extracts of raspberry leaves have been reported to contain a number of active constituents, including a smoothinhibited contractions of those from pregnant rats. Similarly, the

muscle stimulant, an anticholinesterase, and an antispasmodic that antagonised the stimulant actions of the two previous fractions. The smooth muscle stimulant fraction was more potent towards uterine muscle.(11)

Flavonoids isolated from 70% ethanol extracts of the leaves from four varieties of raspberry (species not stated) collected in Russia have antioxidant activity in vitro, as assessed in a system involving measurement of the rate of oxygen absorption during initiated oxidation of isopropylbenzene.(2)

Hypoglycaemic activity has been documented for extracts of the leaves of a related species, Rubus fructicosus L., in both nondiabetic and diabetic (glucose-induced and alloxan-induced) rabbits.(12) The reduction in blood glucose concentrations, compared with controls, was greatest in glucose-induced diabetic rabbits. In addition, blood insulin concentrations increased significantly, compared with baseline values, following administration of an ethyl ether extract of R. fructicosus leaf to hyperglycaemic rabbits.(12) However, confirmation of these findings using more robust experimental methods is required. In vitro antiviral activity documented for raspberry fruit extract has been

attributed to the phenolic constituents, in particular to tannic acid.(13)

Tannins are known to possess astringent properties.

Clinical studies

The effects of a raspberry leaf preparation on labour, birth and the post-partum period were investigated in a randomised, double-blind, placebo-controlled trial involving 240 low-risk, nulliparous women. Participants received tablets containing 1.2 g raspberry leaf extract, one tablet twice daily, taken from 32 weeks' gestation until the onset of labour (regular contractions).(14)

In total, 192 women (n = 96 per group) completed the study; the 48 withdrawals were evenly distributed across the two groups. There were no statistically significant differences between the two groups with respect to the length of gestation (p = 0.51), likelihood of medical augmentation of labour (p = 0.91), need for pethidine (meperidine) (p value not stated), need for artificial rupture of membranes (p = 0.35), time spent in first, third (p value not stated) and second stages of labour (p = 0.28), proportion of normal vaginal births (62.4% and 50.6% for the raspberry leaf and placebo groups, respectively; p = 0.19) and emergency caesaerean section rate (p value not stated). There were also no statistically significant differences between the two groups with respect to safety outcomes in labour, including blood loss > 600 mL (p = 0.86), neonatal birth weight (p = 0.46), Apgar score

Figure 3 Raspberry – dried drug substance (leaf).

at five minutes (p = 0.11) and occurrence of meconium-stained fluid (p value not stated).(14) However, a higher proportion of women in the raspberry leaf group developed pre-eclampsia (4.2% and 2.1% in the raspberry and placebo groups, respectively), and a higher proportion of babies admitted to special care units was born to mothers from the raspberry leaf group than to those from the placebo group (p values not stated). Several of the above parameters showed a tendency (although not statistically significant at p < 0.05) for more favourable outcomes in the raspberry leaf group and, on this basis, further research investigating other dosage regimens may be worth while.(14)

Side-effects, Toxicity

Clinical data

There is only a limited amount of information on the safety and toxicity of raspberry leaf preparations and further investigation of these aspects is required. In a randomised, double-blind, placebocontrolled trial, 240 low-risk, nulliparous women received tablets containing 1.2 g raspberry leaf extract, one tablet twice daily, taken from 32 weeks' gestation until the onset of labour (regular contractions); 192 women, 96 in each group completed the study.(14) A higher number of adverse events was reported by raspberry leaf recipients than by placebo recipients (31 and 24, for the raspberry leaf and placebo groups, respectively, corresponding to 32.3% and 25.0% of women in each group, respectively), although no statistical analysis for this comparison was reported. No congenital abnormalities were reported for either group. Also, there were no statistically significant differences between the two groups with respect to several safety outcomes in labour (see Pharmacological Actions, Clinical studies). This study provides only very limited information on the safety of raspberry leaf when taken during pregnancy (weeks 32 to labour onset) as clinical trials are designed primarily to assess efficacy, not safety, and have the statistical power only to detect common, acute adverse effects.

Contra-indications, Warnings

As excessive ingestion of tannins is not recommended, raspberry leaf tea should not be used for prolonged periods.

Drug interactions None documented. In view of the pharmacological actions described for raspberry leaf, the potential for preparations of raspberry leaf to interfere with other medicines administered concurrently, particularly those with similar or opposing effects, should be considered.

Pregnancy and lactation Preparations of raspberry leaf have been used traditionally during labour to help ease parturition. However, there is limited and conflicting scientific evidence that raspberry leaf has effects on uterine contractions. A preliminary report published in the older literature describes inhibition of contractions of tissue obtained from the uteri of pregnant rats and initiation of contractions in uterine strips obtained from pregnant

Raspberry 497

women at 10–16 weeks of pregnancy following application of a raspberry leaf infusion in vitro. These findings require confirmation. Furthermore, a randomised, double-blind, placebo-con- trolled trial found no statistically significant differences in labour outcomes for raspberry leaf extract 1.2 g twice daily taken from 32 weeks' gestation to labour onset, when compared with placebo. Hence, at present, as there is a lack of evidence to support the efficacy of preparations of raspberry leaf during late pregnancy to assist parturition, and in view of the lack of safety data, preparations of raspberry leaf should not be used during pregnancy and labour. If raspberry leaf is taken during these periods, this should only be under medical supervision.

There is a lack of information on the use of raspberry leaf during breastfeeding. Until information is available, raspberry leaf preparations should be avoided during breastfeeding.

Preparations

Proprietary multi-ingredient preparations

France: IgeE. UK: Fenneherb Monthly. USA: Women's

Menopause Formula.

References

1Gudej J, Tomczyk M. Determination of flavonoids, tannins and ellagic acid in leaves from Rubus L. species. Arch Pharm Res 2004; 27: 1114– 1119.

2 Nikitina VS et al. Flavonoids from raspberry and blackberry leaves and their antioxidant activities. Pharm Chem J 2000; 34: 596–598.

3Khabibullaeva LA, Khalmatov KK. Phytochemical study of raspberry leaves. Mater Yubileinoi Resp Nauchn Konf Farm Posvyashch 1972; Sept: 101–102.

4 Gudej J. Kaempferol and quercetin glycosides from Rubus idaeus L. leaves. Acta Polon Pharm 2003; 60: 313–316.

5 Cygan F-C. Die Himbeere – Rubus idaeus L. Portrait einer Arzneipflanze. Z Phytother 1995; 16: 366–374.

6 Puupponen-Pimia R et al. Bioactive berry compounds – novel tools against human pathogens. Appl Microbiol Biotech 2005; 67: 8–18.

7Morimoto C et al. Anti-obese action of raspberry ketone. Life Sci 2005; 77: 194–204.

8Patel AV et al. Therapeutic constituents and actions of Rubus species. Curr Med Chem 2004; 11: 1501–1512.

10Rojas-Vera J et al. Relaxant activity of raspberry (Rubus idaeus) leaf extract in guinea-pig ileum in vitro. Phytotherapy Res 2002; 16: 665– 668.

11Beckett AH et al. The active constituents of raspberry leaves. A preliminary investigation. J Pharm Pharmacol 1954; 6: 785–796.

12Alonso R et al. A preliminary study of hypoglycaemic activity of Rubus fruticosus. Planta Med 1980; 40 (Suppl. Suppl.): 102–106.

13Konowalchuk JK, Speirs JI. Antiviral activity of fruit extracts. J Food Sci 1976; 41: 1013–1017.

14Simpson M et al. Raspberry leaf in pregnancy: its safety and efficacy in labor. J Midwifery Women's Health 2001; 46(2): 51–59.