The objective of the current study was to determine the effects of the botanical product, compared with placebo and loratadine, upon the clinical and inflammatory responses to nasal allergen provocation. We demonstrated that the CBP significantly reduced nasal symptoms during hours 2 through 8 following the challenge and blocked the post-allergen rise in prostaglandin D2. Subjectively, the magnitude of the difference between placebo and the CBP was about 1.5 points on the 11-point Nasal Symptoms Scale (NSS), which is greater than The smallest clinically meaningful difference in allergy treatment effects is about a 0.5 score step on an composite scale like the NSS . Thus, the clinical results with the CBP were not only statistically significant but also clinically meaningful, a conclusion also supported by the comparison to loratadine, which was associated with symptom relief greater than placebo but not significantly different from the CBP.
Our study had limitations. In particular, the study population was small, and without having any knowledge of the pharmacokinetics of the botanical product, it is difficult to say whether a washout period of 3 to 7 days between treatments was sufficient to prevent carry-over effects. In addition, while our data indicate significant differences between the experimental therapy and placebo, it is important to note that these effects were statistically assessed using one-tailed paired t-tests without corrections for multiple comparisons, as befits the pilot nature of this study. Finally, the generalizability of these laboratory-based results could be investigated in further laboratory-based or native disease studies.
While the combination was shown to have selected effects upon allergic pathophysiology, we are unable to determine which of the three components contributed most to these effects. Our choice of botanical substances for this study was based upon prior in-vitro experiments which demonstrated potentially beneficial effects with either the individual components used in the CBP or phytochemicals derived from these substances. A species of cinnamon related to that found in the CBP, Cinnamomum cassia, has been found to inhibit complement-dependent allergic reaction by reducing immunological hemolysis, chemotactic migration of neutrophils, and the generation of chemotactic factors by mast cells in response to complement-activated serum . Acerola contains vitamin C, which has been shown to reduce concentrations of histamine [8, 9]. Spanish Needles (Bidens pilosa) has also been found to have anti-allergic effects on mast cells and synthesis of several inflammatory mediators . Quercetin, a flavonoid found in Spanish Needles [11, 12], has been shown to stabilize mast cells and basophils, decrease leukotriene synthesis and reduce the release of histamine and other mediators . Spanish Needles also contains ethyl caffeate which has been shown in vitro to possess a variety of anti-inflammatory effects [4, 11]. Spanish Needles has been shown to inhibit nuclear transcription factor kappaB and its downstream inflammatory mediators in vitro [4, 5]. The actual active ingredients are unknown, however, which is typical for botanical products . For example, St-John's Wort, a single-ingredient botanical for depression which was once thought to possess a single active molecule, is now known to possess several active constituents , and its anti-depressant activity can only be ascribed to the total extract, not to any specific molecule or combination of molecules . While this general state of affairs accords well with the ancient concept of botanical therapeutics, whereby the efficacy of any botanical – and its possible advantage over a traditional single-compound pharmaceutical – stems from its complex action against multiple pharmacological targets , this poses manufacturing and quality control challenges . The solution adopted by painstaking manufacturers in the industry entails a combination of analytical techniques and bioassays to ensure product standardization [18, 19]. The manufacture of the present CBP involves testing for the marker substances chlorogenic acid and cynarin for the Spanish Needles powder, cinnamic acid for the cinnamon extract, and ascorbic acid for the acerola extract, all verified by HPLC; as well as total polyphenols for the finished tablet, verified by UV/Vis spectroscopy. Microbiological monitoring is also involved in quality control in according with Good Manufacturing Practices.
While prior experiments using the individual components or relevant isolated phytochemicals had particularly prominent effects on histamine release and leukotriene synthesis, in the current study the combination of the three botanical products had no detectable effects on tryptase or leukotriene C4 concentrations in nasal lavage fluid nor any effect on the acute clinical response to allergen challenge. A possible explanation for this discrepancy between previous in vitro data and the current results in allergic patients may relate to pharmacokinetic issues, including the attainment of adequate tissue levels of the active ingredients, or may reflect biologic differences between basophil or animal mast cell systems and human mucosal mast cells .
While the immediate, or early nasal response to allergen provocation was not affected by the botanical preparation, we did note a significant reduction in nasal symptom scores during the 8 hour time period following nasal challenge. The most likely explanation for this was the apparent reduction in increased PGD2 secretion in the CBP-treatment condition, compared to the loratadine- or Placebo-treatment conditions, noted immediately after allergen exposure. To our knowledge, no prior studies have examined the acute effects of PGD2 administration upon nasal symptoms or function in humans. However, injection of PGD2 into the skin of nonallergic patients has been shown to cause induration which lasted up to 6 hours . In addition, one prior clinical trial in patients with seasonal allergic rhinitis demonstrated that the addition of an oral cyclooxygenase-1 inhibitor (naproxyn sodium) to a combination of oral H1-antihistamine plus decongestant (chlorpheniramine plus pseudoephedrine) augmented nasal symptom control significantly . Both of these experimental findings suggest the role of PGD2 in eliciting tissue inflammation and the potential importance of blocking its effects in patients with allergic nasal disease.
Consistent with our prior knowledge of these phytochemicals, no clinical or laboratory adverse events were noted during this short-term trial. Although toxicity is considered unlikely, longer-term studies with the botanical product would help to clarify its place in the clinician's armamentarium for treating patients with persistent symptoms.
The medical speciality of allergy and immunology has recently seen an increase in the use of complementary and alternative medicine by both patients and physicians . Rational and effective use of such therapies requires controlled clinical trials to demonstrate safety and efficacy. However, because of the multifarious nature of botanicals compared to pure single pharmaceuticals, some adjustments are required to principles of Good Clinical Practice . In the present study, these are centered on the identity of the active ingredients in the CBP, which are unknown.