C
ontraindiCationsexternal use
Not for use in or near eyes (Agrawal et al. 1985; Fett 2003; Johnson 2007).
o
therP
reCautionsinternal use
In sensitive individuals, excessive doses may cause gastroin- testinal irritation or heartburn, or exacerbate gastroesopha- geal reflux (Chadha 1988; Felter and Lloyd 1898; Martindale and Reynolds 1996; Milke et al. 2006; Myers et al. 1987; Viranuvatti et al. 1972; Watt and Breyer-Brandwijk 1962).
external use
Cayenne preparations irritate the mucous membranes and injured or broken skin even at very low concentrations, and
may cause a painful burning sensation (Fett 2003; Johnson 2007).
d
rugands
uPPlementi
nteraCtionsUse of topical cayenne products may exacerbate cough caused by angiotensin-converting enzyme (ACE) inhibi- tors, although cayenne is not believed to affect the efficacy of these drugs (Stargrove et al. 2008; Yeo et al. 1994, 1995).
e
ditors’ n
oteThe German Commission E suggests that Capsicum should not be applied externally for more than 2 days, with a 14-day time lapse between applications (Blumenthal et al. 2000). However, two systematic reviews of human studies of topi- cally applied products containing the compound capsaicin (0.025–0.075%) as the active ingredient indicated that study periods were generally 4 to 8 weeks in duration (Mason et al. 2004; Zhang and Po 1994).
C
a
dversee
ventsands
idee
ffeCtsTopical application of cayenne may produce a burning sen- sation, often accompanied by erythema (redness of the skin due to capillary congestion). Repeated topical use generally causes desensitization that is reversible on discontinuation of the drug (Hautkappe et al. 1998; Johnson 2007). Cayenne preparations irritate mucous membranes even at very low concentrations, and may cause a painful burning sensation (Fett 2003).
Ingestion of cayenne may cause or exacerbate gastric irritation, heartburn, or gastroesophageal reflux (GER) in sensitive individuals (Milke et al. 2006).
P
harmaCologiCalC
onsiderationsOne study in rats indicated that cayenne reduced the bio- availability of aspirin and salicylic acid (Cruz et al. 1999). A
study in rabbits indicated that cayenne increased the plasma levels of orally but not intravenously administered theoph- ylline (Bouraoui et al. 1995). The relevance of those data to human use is not known.
P
regnanCyandl
aCtationInformation on the safety of cayenne use in pregnancy is limited. One animal study showed no adverse effects of cayenne after administration to pregnant rats for 5 d ays (Pellicer et al. 1996).
No information on use of cayenne during lactation was identified. While this review did not identify any concerns for use while nursing, safety has not been conclusively established.
R
eviewD
etailSi. d
rugands
uPPlementi
nteraCtionsClinical trials of drug or supplement interactions
Exacerbation of ACE inhibitor-induced cough by capsaicin has been reported in two small studies in humans (Yeo et al. 1994, 1995).
Case reports of suspected drug or supplement interactions
Topical application of a capsaicin-containing cream (0.075% capsaicin) induced cough in a woman taking an unspecified ACE inhibitor. The cough occurred just after the cream was applied (Hakas 1990).
animal trials of drug or supplement interactions
Coadministration of aspirin or salicylic acid and cayenne extract (300 mg/kg, 10% capsaicin) orally to rats signifi- cantly reduced the bioavailability of salicylic acid and aspi- rin. Chronic oral administration of aspirin or salicylic acid and cayenne extract (100 or 300 mg/kg) resulted in undetect- able plasma levels of aspirin and significantly reduced blood levels of salicylic acid (Cruz et al. 1999). The compound cap- saicin increased the absorption of acetaminophen in rats (Metwally and Kandil 1985).
Oral coadministration of 5 ml/kg of a cayenne suspen- sion (10% cayenne) and 20 mg/kg theophylline to rabbits significantly increased the plasma levels of theophylline (Bouraoui et al. 1988), whereas oral administration of cay- enne (5 ml/kg of a 10% cayenne suspension) and intravenous administration of theophylline (12 mg/kg) did not affect the plasma levels of theophylline (Bouraoui et al. 1995). Dosing with cayenne and theophylline for 7 days in rabbits signifi- cantly reduced urinary excretion of the theophylline metabo- lite 1-methyluric acid (Bouraoui et al. 1995).
Administration of 0.1 µg/kg of the compound capsa- icin to rats protected the stomach from mucosal damage by
ethanol. Doses of 10 to 30 mg/kg capsaicin, however, aggra- vated the damage caused by ethanol (Salam et al. 1995).
ii. a
dversee
ventsadverse events reported in Clinical trials
A systematic review of herbal medicines for lower back pain identified two trials of topical cayenne monoprepara- tions and reported that adverse events in cayenne treatment groups were inflammatory contact eczema, urticaria, min- ute hemorrhagic spots, and vesiculation or dermatitis. In one trial, 15 adverse events were reported in the cayenne group and 9 in the placebo group (Gagnier et al. 2007). In a clini- cal trial of a topical capsicum plaster or placebo, localized adverse drug reactions were found in 7.5% of the patients on capsicum and 3.1% on placebo (Frerick et al. 2003).
A review of clinical trials of the compound capsaicin indicated that repeated topical applications of capsaicin to the skin produce an initial burning sensation followed by gradual desensitization that is reversible on discontinuation of the drug (Hautkappe et al. 1998).
A meta-analysis of topical capsaicin for the treatment of chronic pain, including 6 studies with a total of 656 patients, reported that 54% of patients using capsaicin had one or more local adverse events compared with 15% in the pla- cebo group. Coughing was reported in 8% of patients using products with 0.075% capsaicin and none using products with 0.025% capsaicin. One active-controlled trial reported coughing in 1 of 32 patients using 0.025% capsaicin and in 7 using 0.25% capsaicin (Mason et al. 2004).
Case reports of adverse events
Topical reactions to cayenne, including contact dermatitis and urticaria, have been reported (Burnett 1989; Feldman and Levy 2003).
Capsicum spp.
C
iii. P
harmaCologyandP
harmaCokinetiCs human pharmacological studiesA review of the effects of cayenne on gastric ulcers indicated that large doses of chili pepper administered directly into the stomach of normal fasting subjects generally produced a mild response consisting of a sm all increase in gastric acid secretion and an increased blood flow (Ayad 1995). Intragastric administration of 3 g c ayenne in healthy sub- jects with varying histories of cayenne consumption caused no detectable changes in 13 of the 20 subjects, mild to moder- ate edema or increased blood flow in 6 subjects, and a hem- orrhage in 1 subject (Viranuvatti et al. 1972). An assessment of cayenne on human gastric mucosa in healthy volunteers indicated that administration of 0.1 to 1.5 g cayenne exhib- ited dose-dependent parietal secretion, pepsin secretion, potassium loss, and gastric cell exfoliation, and that the gastric effects were similar to those of aspirin (Myers et al. 1987).
Consumption of 20 g of cayenne provided a protective effect against gastrointestinal mucosal damage induced by aspirin (600 mg) in a study of healthy volunteers (Yeoh et al. 1995).
A study on the effects of chronic chili ingestion on gas- troesophageal reflux (GER) symptoms indicated that daily ingestion of 3 g o f chili (two different varieties of chilies, one with 0.048% capsaicin, the other with 0.088% capsaicin) induced GER and that the magnitude of the induced reflux was related to the kind of chili (Milke et al. 2006).
A trial of guajillo chili (a cultivar of Capsicum annuum L. var. annuum) in patients with irritable bowel syndrome (IBS) indicated that ingestion of 1 g o f guajillo chili (0.112% cap- saicin) did not change IBS symptoms but did induce upper abdominal discomfort and lowered the rectal pain thresh- old. The authors indicated that guajillo chili may induce rec- tal hyperalgesia (high sensitivity to pain) in persons with IBS (Schmulson et al. 2003).
No exacerbation of hemorrhoidal symptoms was observed after administration of 10 mg of ground cayenne pepper in patients with hemorrhoids (Altomare et al. 2006).
Ingestion of iron with a meal supplemented with 4.2 g of freeze-dried chili significantly inhibited iron absorption (Tuntipopipat et al. 2006).
A “sensory hyperreactivity” cough induced by inha- lation of the compound capsaicin has been described (Millqvist 2000; Millqvist and Bende 2001; Millqvist et al. 2000). Cough was reported as an adverse event in a study of topical application of a c apsaicin cream (0.075% capsa- icin) (Ellison et al. 1997). The effects are believed to be due to aerosolization and subsequent inhalation of particles of dried cream (McKenna et al. 2002). Capsaicin activates the type 1 vanilloid receptor, a sensory receptor that stimulates coughing (Kissin 2008; Knotkova et al. 2008; Morice and Geppetti 2004; Nagy et al. 2004; Pingle et al. 2007; Szolcsanyi 2004).
animal pharmacological studies
Topical application of cayenne tinctures at concentrations of 0.1 to 1% to rabbits indicated that such concentrations were nonirritant (Maruzen Pharmaceuticals 2002).
in Vitro pharmacological studies
The compound capsaicin inhibits the drug-metabolizing isoenzyme CYP2E1 (Surh and Sup Lee 1995).
In human ileocarcinoma cells, cayenne increased cell permeability (tight junction gap increase) (Jensen-Jarolim et al. 1998).
iv. P
regnanCyandl
aCtationA study on the administration of cayenne (2.75 mg capsa- icin) daily for 5 days to rats during pregnancy indicated no adverse developmental effects on the fetus. Offspring of the rats showed a delayed response to acute heat stimuli. The authors of this study indicate that the compound capsaicin is capable of crossing the placental barrier (Pellicer et al. 1996).
No effects on parturition time, skeletal development, or weight of offspring was observed in rats subcutane- ously administered 50 to 200 mg/kg of the compound cap- saicin every other day on gestational days (GD) 7 t hrough 15 (Perfumi and Sparapassi 1999). In rats subcutaneously administered 50 mg/kg capsaicin on GD 14, 16, 18, or 20, or on days 15 and 16, or 16 and 17, a reduced crown-rump length of fetuses was observed only in dams injected on day 18, and a decrease in fetal spontaneous activity and loss of fetal responsiveness to morphine were observed in offspring of mothers treated on days 16 and 17, but not on days 15 and 16. No skeletal or soft tissue malformations, differences in fetal weight or average number of fetuses, or incidences of resorption were observed (Kirby et al. 1982). Capsaicin was shown to cross the placenta in rats subcutaneously admin- istered the compound at doses of 20 to 50 mg/kg (Atkinson and Chaggar 1983).
No information on the safety of cayenne during lacta- tion was identified.
v. t
oxiCitys
tudiesacute toxicity
The LD50 of cayenne extract orally administered to rats is
23.58 ml/kg (Winek et al. 1982). The LD50 values of the com-
pound capsaicin in mice via various routes of administra- tion are 190 mg/kg (oral), 7.65 mg/kg (intraperitoneal), and 0.56 mg/kg (intravenous) (Glinsukon et al. 1980).
short-term toxicity
In mice fed a diet of up to 10% cayenne for 4 weeks, only minor effects of cayenne were observed, including a slight glycogen depletion and anisocytosis of hepatocytes. General health, body weight, and food intake were apparently not affected, and no treatment-related changes were observed in any of the tissues examined (Jang et al. 1992).
C
subchronic toxicity
In rats intragastrically administered 0.5 g/kg cayenne pow- der daily for 60 days, some reduction in growth rate was observed as compared to control but no significant differ- ences from control were observed in rectal temperature, water intake, plasma chemistry, urine dilution and concen- tration, or relative organ weights (Monsereenusorn 1983).
No significant adverse effects were observed in rats fed a diet of 2% cayenne for 8 weeks. In rats fed a diet of 10%, however, feed intake and growth rate were depressed and exfoliation of the intestinal epithelium into the lumen, cyto- plasmic fatty vacuolation, and necrosis of the centrilobular hepatocytes were observed (al-Qarawi and Adam 1999).
Chronic toxicity
Chronic administration of 20 µl cayenne extract (2.5 mg/ml capsaicin) to the cheek pouch of hamsters induced shrunken eyeballs and closing of the eyelids in 23% of the animals. This effect was not observed in hamsters that received a single application of the potent carcinogen methyl(acetoxymethyl) nitrosamine prior to repeated treatment with the cayenne extract (Agrawal et al. 1985).
In rabbits administered 5 mg/kg of cayenne daily for 12 months, spleen and liver weights were increased as com- pared to control animals. Microscopic observation of these organs revealed effects at the cellular level (Lee 1963).
Genotoxicity
Mutagenic activity of chilies (species unspecified) and the compound capsaicin was observed in the Ames mutagenic- ity test with Salmonella typhimurium with metabolic activa- tion from S9 mix (Nagabhushan and Bhide 1986).
Cayenne extract and the compound capsaicin exhibited mutagenic activity in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 with metabolic activation. Capsaicin had more potent mutagenic effects than cayenne. Mutagenic activity of the same products was not observed in the micronucleus test or in the 8-azaguanine-resistant muta- genesis assay with Chinese hamster cells. Capsaicin inhibited DNA synthesis in the testes of Swiss mice injected at two dose levels (Nagabhushan and Bhide 1985).
Carcinogenicity
A case-control study of men in India with cancers of the oral cavity indicated that use of red chili powder was associated, in a dose-related manner, with an increased risk of cancers.
Tea drinking was also observed to be a risk factor for esoph- ageal cancers and, to a lesser extent, for pharyngeal cancers (Notani and Jayant 1987). Similarly, a case-control study of men and women in Mexico indicated that a d ose-related trend of increasing risk of gastric cancer was reported with consumption of chili peppers (López-Carnllo et al. 1994). Conversely, a case-control study of men and women in Italy indicated that consumption of chili peppers was associated with a decreased risk of gastric cancer (Buiatti et al. 1989).
In rats administered cayenne as 10% of the diet for 2 years, neoplastic changes in the liver were observed after 6 months of treatment, with males more prone to tumor devel- opment. In female rats, cystic cholangiomas, solid cholan- giomas, adenocarcinomas, and hepatomas were observed (Hoch-Ligeti 1951).
Rats fed 4 g/kg cayenne as part of the diet for 12 months were found to have a 35% incidence of adenocarcinoma of the abdomen, with no adenocarcinoma observed in the con- trol group (Balachandran and Sivaramkrishnan 1995). A dose of 80 mg/kg daily cayenne for 30 days was associated with an 83% incidence of intestinal tumors or polyps, a 90% incidence of tumors or polyps in the positive control group treated with the carcinogen 1,2-dimethylhydrazine (DMH), and no such abnormalities in the untreated control group (Nalini et al. 1997). In rats administered cayenne alone, DMH alone, or a combination of the two, incidences of intes- tinal and colon tumors were 90% in the cayenne group, 93% in the DMH group, and 96% in the combination group. The authors of the study concluded that cayenne promoted the carcinogenesis of DMH (Chitra et al. 1997).
A review of studies on the anticarcinogenic and carci- nogenic effects of the compound capsaicin indicated that small amounts of capsaicin had few or no deleterious effects, while heavy ingestion of the compound has been associated with necrosis, ulceration, and carcinogenesis. Capsaicin has also been shown to alter the metabolism of certain carcino- gens, acting as a chemopreventive compound (Surh and Lee 1996).
Cytotoxicity
The compounds capsaicin and resiniferatoxin (both vanil- loids) inhibit the NADH-electron transport system, activate c-Jun kinase (JNK) but not AP1, and induce apoptosis in transformed cells (Macho et al. 1998). Capsaicin, dihydro- capsaicin, and resiniferatoxin inhibit NADH oxidase and induce apoptosis (Vaillant et al. 1996; Wolvetang et al. 1996).
l
iteRatuRec
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