DE LAS MEDIDAS DISCIPLINARIAS

Natural antioxidants obtained from ‘citrus oils’ have been shown to inhibit oxidation of LDL cholesterol in in vitro studies (Lv et al 2012, Takahashi et al 2003), possibly due to the gamma-terpinene content. Terpinolene and alpha-terpinene also have antioxi- dant properties. Takahashi et al suggested gamma- terpinene could be added to foods and beverages to prevent oxidation. Sellar (1992) suggested that sweet orange oil aids the absorption of vitamin C. Certain types of tissue damage are mediated by reactive oxygen species (free radicals) such as superoxide. Research suggests reactive oxygen metabolites (ROMS) are associated with inflammatory tissue injury and some antioxidants attenuate the inflam- matory process by reducing ROMs, thereby attenu- ating the tissue injury (Lv et al 2012). Lv et al suggested a diet containing C. aurantium might improve oxidative injury and improve immunity in acute otitis media in rats. They showed essential oils obtained from orange peel reduced serum and cochlear malondialdehyde (MDA), immunoglobu- lins A (IgA), G (IgA) and immunoglobulin M (IgM) and increased the activity of antioxidant enzymes in rats. The clinical application requires further study.

CLINICAL USE

Bitter orange extract and the isolated constituent

p-synephrine (oxedrine) are used in oral weight-

loss and weight management supplements, cholesterol-lowering herbal mixtures, and in sports supplements.

Orange essential oil is available in tablets, capsules and liquid oil.

Heartburn and dyspeptic symptoms

A key indication for bitter orange tincture or extract is heartburn (Blumenthal et al 2000). The dried peel is officially listed in the British Pharmacopoeia (British Herbal Medicine Association Scientific Committee 1983) as a bitter tonic, and empirical evidence suggests that it acts as a carminative agent. Commission E approved the use of cut peel for loss of appetite and dyspeptic symptoms (Blumenthal et al 2000).

Weight loss

Citrus aurantium extract is growing increasingly

popular as an ingredient in weight loss products, and is being substituted for the banned herbal product ephedra in the United States. The main active ingredient, p-synephrine, produces effects on human metabolism that could theoretically reduce fat mass in obese humans because it stimulates lipolysis, raises metabolic rate and increases fat oxidation through increased thermogenesis. Interestingly, m-synephrine is a more potent adrenergic stimulant than p- synephrine and although not thought to be found thermogenesis in humans, hamsters and guinea pigs

(Carpene et al 1999). The dose-dependent effect is suggested because a later study found neither a single administration of 300 mg/kg of p-synephrine orally nor bitter orange extracts (5000 and 10,000 mg/ kg standardised to contain 2.5% of p-synephrine) significantly altered body temperature in mice (Arbo et al 2008).

A controlled in vivo study of C. aurantium fruit hydro-alcoholic extracts standardised to synephrine 4% (Ci. au. 4%) and 6% (Ci. au. 6%) found that repeated administration of the extract significantly and dose-dependently reduced food intake and body weight (Calapai et al 1999). More recently, a reduc- tion in body weight gain was seen in an animal study for p-synephrine 30 or 300 mg/kg given by oral gavage over 28 consecutive days (Arbo et al 2009).

Due to these combined actions, it appears to have potential benefits for use in obesity and weight management.

Antibacterial

Seville orange has strong in vitro antibacterial activ- ity against Escherichia coli and Staphylococcus aureus (Melendez & Capriles 2006).

Antiviral

The fruit of C. aurantium has a potent inhibitory activity on rotavirus infection (Kim et al 2000). The active components are neohesperidin and hesperidin.

Antifungal

Bitter orange essential oil has been shown to be effective against resistant fungal skin conditions (Ramadan et al 1996).

Digestive effects

The essential oil of C. aurantium var. dulcis is believed to aid digestion by stimulating the flow of gastric juice and has antispasmodic and carminative actions. The essential oil of C. aurantium var. amara is con- sidered to be a liver stimulant, reduces gastric spasm and relieves symptoms of indigestion (Price & Price 1995, Wichtl & Bisset 1994). It is also thought to lower cholesterol.

Aromatherapy effects

The essential oil of C. aurantium var. dulcis is con- sidered to convey warmth and happiness and improve mood (Battaglia 1997), reduce stress, aid sleep by reducing stress (Miyake et al 1991) and aid concentration. The essential oil of Citrus auran-

tium var. amara is considered to have a calming

anxiolytic effect (Faturi et al 2010) and is consid- ered one of the most effective sedative essential oils (Battaglia 1997, Price & Price 1995,

Wichtl & Bisset 1994). Anecdotally, many aroma- therapists regard orange as the ‘oil of joy and communication’.

group using the 20% oil in alcohol preparation also experienced substantial cure rates, but took longer to achieve. Application of the undiluted oil success- fully cured 33% of subjects within the first week, 60% within 1–2 weeks and 7% in 2–3 weeks. The only side effect reported was mild irritation when the undiluted oil was used.

Aromatherapy

Citrus sinensis administered in massage or via inhala-

tion has been shown to improve mood and reduce anxiety in a range of health care settings. Lehrner et al (2000) demonstrated reduced anxiety and more positive mood compared to placebo, particularly for women, using 0.25 mL essential oil added to a dif- fuser in a dental waiting room (n = 72). Fitzgerald et al (2007) also showed a greater effect on mood in girls than boys in a multicultural paediatric inte- grative medicine clinic. Interestingly, the girls reported feeling more energetic after inhaling spear- mint, whereas males felt more energetic after inhal- ing ginger. Overall, ginger and lavender were the least liked oils. The self-reported reductions in anxiety were supported by objective measures of autonomous function: blood pressure, respiratory and pulse rates and skin temperature (Hongratana-

worakit & Buchbauer 2007). These subjects also rated themselves as being more cheerful. Likewise

Fewell et al (2007) reported sedative effects of sweet orange oil administered in a massage.

Faturi et al (2010) suggested the anxiolytic effects were most likely to be de to limonene in C sinensis, but anxiolytic activity may depend on the adminis- tration route.

Citrus aurantium var. dulcis

The essential oil is used to convey warmth and hap- piness and improve mood (Battaglia 1997), reduce stress and promote sleep (Miyake et al 1991). It is traditionally known as ‘the oil of communication and happiness’. It is also used to improve digestion and as a carminative to relieve gastric cramping and discomfort.

Citrus aurantium var. amara

The essential oil is used to reduce anxiety, muscle tension and promote relaxation, and best used in the bath before bedtime when treating insomnia (Batta-

glia 1997). It is used in cosmetics to repair broken capillaries, stimulate cell regeneration and to manage acne-prone skin.

OTHER USES

Distilled orange oil is often added to foods and beverages to enhance their flavour and to medicines to reduce the unpleasant taste.

Orange blossom water or hydrosol contains small proportions of essential oils and is used on the skin as an astringent and orally as a gastrointestinal car- minative (Jeannot et al 2005). There are no terpenes in orange hydrosol, so the likelihood of causing skin in nature, may be present in North American

weight-loss products in order to achieve better results (Fugh-Berman & Myers 2004).

As a reflection of clinical use, most research has been conducted with bitter orange extract in com- bination with other ingredients, making it difficult to determine the effects of bitter orange on weight loss.

A randomised, pilot study of eight healthy sub- jects with body mass indexes of 25–40 kg/m2 _com- pared Citrus aurantium to placebo over 8 weeks for effects on body weight (Greenway et al 2006). The

Citrus aurantium group gained 1.13 ± 0.27 (mean ± SEM) kg compared with 0.09 ± 0.28 kg in the placebo group (P < 0.04). Interestingly, resting met- abolic rate at baseline rose more in the Citrus auran-

tium group, 144.5 ± 15.7 kcal/24 hours, than the placebo group, 23.8 ± 28.3 kcal/24 hours (P < 0.002) at 2 weeks, but not at 8 weeks.

Previously, two small clinical studies have been published and both suggest possible weight reduc- tion (Preuss et al 2002); however, more research is required to confirm the effectiveness and safety of orange oil as an adjunct to weight loss.

Ergogenic aid — used in sports

IN COMBINATION

A nutritionally enriched JavaFrit (JF) coffee (450 mg of caffeine, 1200 mg of garcinia cambogia, 360 mg of citrus aurantium extract, and 225 mcg of chromium polynicotinate) was tested for effects on resting oxygen uptake (VO2_{), respiratory exchange ratio (RER), heart}

rate (HR) and blood pressure (BP) in 10 healthy and physically active individuals using a randomised, dou- ble-blind methodology (Hoffman et al 2006). During each session, subjects reported to the Human Perfor- mance Laboratory after at least 3 hours post-absorptive state and were provided either 354 mL (1.5 cups) of freshly brewed JF or commercially available caffeinated coffee (P). The nutritionally-enriched coffee beverage increased resting energy expenditure in individuals that were shown to be sensitive to the caffeine and other herbal ingredients in addition to elevating their systolic blood pressure.

Superficial dermatophyte infection

The oil of bitter orange (C. aurantium var. amara) was an effective topical treatment in treatment- resistant, superficial dermatophyte infection in a study involving 60 patients (Ramadan et al 1996). Patients with tinea corporis, cruris or pedis were treated with one of three treatments based on oil of bitter orange and cure was assessed by clinical and mycological examinations. One group used a 25% emulsion of oil three times per day, the second group used 20% oil in alcohol three times per day and the third group applied pure oil once per day. Treatment with the 25% oil emulsion was the most successful and resulted in 80% of patients being cured after 1–2 weeks and 20% in 2–3 weeks. The

B

increased in fair-skinned individuals. Other photo- toxic essential oils include Citrus bergamia (bergamot) and Citrus limon (lemon). Sensitivity to sunlight or UVB light after topical application increases in the first hour after application and declines over the following 8 hours. A general caution is to avoid UV exposure for at least 12 hours after topical applica- tion and use a sunscreen during this period. An early study (Zaynoun 1977) (n = 63) showed no signifi- cant differences in phototoxic reactions to bergamot oil for eye colour, age, gender or tanning, but smaller amounts of oil produced an effect in light- skinned people. It is not clear whether this also applies to orange essential oil.

Gastrointestinal symptoms

Abdominal pain, nausea, vomiting, diarrhoea and dizziness have been reported with oral use of the oil (Citrus and Allied Essences 2004).

Cardiotoxicity

Bitter orange, standardised to 4–6% synephrine, demonstrated cardiovascular toxicity (ventricular arrhythmias with enlargement of QRS complex) and mortality in rats (Calapai et al 1999). However, a more recent double-blind, placebo-controlled trial found that bitter extract treatment delivering 98 mg

p-synephrine daily over 60 days produced no effects

to systolic or diastolic blood pressure and no adverse effects with respect to the cardiovascular, hepatic, renal or haemopoietic systems (Kaats et al 2013). Intravenous administration of synephrine raises blood pressure (Fugh-Berman & Myers 2004) and is likely to have a different safety profile to the oral use of bitter orange extract preparations as

p-synephrine has very poor oral bioavailability.

Many commercial products contain synephrine or Citrus aurantium (CA) in combination with other ingredients such as caffeine which makes it difficult to interpret case reports. In Canada, between January 1998 and February 2004, 16 cases of severe cardio- vascular symptoms associated with weight-loss prod- ucts containing CA or synephrine were reported and of these, only one contained CA as a sole ingredient. There is also some suspicion that ephed- rine, which continues to be detected in adulterated dietary supplements found in North America, may be responsible for some cardiac adverse effects and that safety issues really increase when synephrine is taken as part of a combination with other sympa- thomimetic ingredients (Rossato et al 2011).

In 2010, Health Canada published new guide- lines for the use of synephrine in natural products, establishing a daily limit of 30 mg as the maximum allowable dose for synephrine in these products and prohibiting caffeine in synephrine-containing prod- ucts unless clinical evidence of its safe use in humans was demonstrated (Health-Canada 2010).

SIGNIFICANT INTERACTIONS

There are no known interactions between the essential oils and conventional medicines; however, irritation is significantly reduced. It is also used topi-

cally as an astringent for acne-prone skin and to calm babies and induce sleep (Bellakhdar 1997,

Hmamouchi 2000).

The essential oil of C. aurantium var. amara is used as an ingredient in perfumes.

DOSAGE RANGE

Bitter orange peel products

• General dose information: 4–6 g daily of cut peel for teas or other galenical preparations used for oral administration.

• Infusion: 2 g of cut peel in 150 mL boiling water taken three times daily.

• Weight loss: bitter orange 975 mg (used with caf- feine 528 mg and St John’s wort 900 mg in a small double-blind study) — efficacy uncertain

Essential oils

• Oral LD50 dose: 5 g/kg (rat).

• Dermal LD50 dose: >5 g/kg (rabbit) (Citrus and

Allied Essences 2004).

• Oral LD50 dose for a 15-kg child: 83 g/kg. • Oral LD50 dose for a 70-kg adult: 389 g/kg. • Oral doses in teas and other preparations: 4–6 g/

day or 2 g in 150 mL of boiled water as an infu- sion (American Botanical Council 1999). The inhalation LD50 dose has not been established. • Topical application dose of bitter orange to skin

exposed to UV rays: 1.4% of a blend. However, even when topical application is combined with inhalation, blood concentrations of d-limonene, a component of most citrus oils, during 20 minutes of massage is low (≤0.008 microgram/mL). It is detectable in the blood within 10 minutes, which represents an uptake of more than 1% of the dose administered (Fewell et al 2007).

ADVERSE REACTIONS