Zingiber officinale (ginger)
Ginger, the rhizome of Z. officinale [Figure 1(F)], is one of the most widely used species of the ginger family (Zingiberaceae) and is a common condiment for various foods and beverages. Ginger has a long history of medicinal use dating back 2,500 years in China and India for conditions such as headaches, motion sickness, nausea, vomiting, vascular conditions, cold and arthritis, and as a antimicrobial and antifungal [reviewed in White, 2007; Afzal et al. 2001]. Characterized in traditional Chinese medicine as spicy and hot, ginger is claimed to warm the body and treat cold extremities, improve a weak and tardy pulse, address a pale complexion, and strengthen the body after blood loss [Chang et al. 1995]. The major constituents of ginger include volatile oils, oleoresin (gingerol), linoleic acid and trace elements such as magnesium, phosphorus, and potassium. The pungent phenolic constituent of ginger, -gingerol, inhibited LPS-induced iNOS expression and production of NO and other reactive nitrogen species in macrophages and blocked peroxynitrite-induced oxidation and nitration reactions in vitro [Ippoushi et al. 2003]. These results suggest that -gingerol is a potent inhibitor of NO synthesis and also an effective protector against peroxynitrite-mediated damage. Another in vitro study showed that ginger extract was effective in inhibiting the production of PGE2, TNFα, and COX-2 expression in human synoviocytes by regulating NF-κB activation and degradation of its inhibitor IkB-α [Thomson et al. 2002]. Similarly, ginger extract decreased the IL-1β and LPS-induced production of NO and PGE2 in OA cartilage [Shen et al. 2003]. It has also been reported to decrease the IL-1β-induced expression of TNFα expression and TNFα-induced production of COX-2 and activation of NF-κB in synoviocytes [Frondoza et al. 2004]. Use of ginger extract also decreased carrageenan-induced edema in rats [Jana et al. 1999].
Ginger is on the US FDA’s generally recognized as safe (GRAS) list. The British Herbal Compendium documents no adverse effects of ginger consumption [Bradley, 1990]. Ginger extract has been studied as an alternative to NSAID therapy for arthritic conditions and had moderately positive results (Table 1) [Altman and Marcussen, 2001; reviewed in Ameye and Chee, 2006]. A randomized, placebo-controlled, crossover study comparing ginger extracts and ibuprofen was performed and included 75 people with OA of the hip or knee [Bliddal et al. 2000]. Patients received 170 mg ginger extract, 400 mg ibuprofen, or placebo three times per day and were followed for 3 weeks. The study revealed significant improvement in symptoms for both groups before crossover; however, at the study’s end there was no difference between ginger and placebo. No side effects were noted in the ginger group [Bliddal et al. 2000]. A randomized, double-blind, placebo-controlled trial studied the effects of ginger in the treatment of knee OA in 261 patients. During the treatment period patients ingested 255 mg of EV.EXT 77, a patented ginger and galangal, a spice that is closely related to ginger and is of the ginger extract, which contained 500–4000 mg of dried ginger rhizomes and 500–1500 mg of dried galangal rhizomes and was given twice daily. The primary endpoint of the study was pain on standing after 6 weeks. In the ginger extract group 63% versus 50% in the placebo group showed improvement (p < 0.048). The study failed to show improvement in quality of life, decrease in the consumption of the rescue analgesic (acetaminophen). The dosage of medications used in this study was based empirically on what is typically consumed in Europe. Those receiving the ginger extract experienced more gastrointestinal side effects (116 events in 59 patients, 45%) than those who received placebo (28 events in 21 patients, 16%) [Altman and Marcussen, 2001]. While a significant number of patients experienced side effects, they were mild and mostly gastrointestinal conditions, dyspepsia, and nausea. In some studies, consumption of ginger extract was found to alleviate pain and associated symptoms in patients with OA. At present, ginger extract appears to be of limited efficacy for OA and current evidence is weak. However, these results are strong enough to advocate and support further studies using different doses and duration of treatment to assess the efficacy of ginger extract alone or in combination with other drugs for the treatment of OA.
Boswellia serrata (Indian olibaum)
The Boswellia spp., which is native to India, Ethiopia, Somalia, and the Arabic peninsula, produce a gum resin that is known as olibanum (frankincense). The resin of B. carteri and B. serrata [Figure 1(G)] is used for the treatment of arthritis and other inflammatory diseases in the traditional medicine system in many countries [Safayhi and Ammon, 1997; Chevrier et al. 2005]. Besides their renowned anti-inflammatory activity, boswellic acids have been extensively investigated for their chemopreventive effects [Glaser et al. 1999; Zhao et al. 2003]. B. frereana extracts have also been reported to inhibit IL-1β and oncostatin M induced MMP-9 and MMP-13 expression in cartilage explants culture [Blain et al. 2010]. Further, boswellic acids have been reported as inhibitors of 5-lipoxygenase, the key enzyme for leukotriene biosynthesis in inflammatory disorders [Safayhi et al. 1992; Gupta et al. 1997] and human leukocyte elastase a member of serine proteases subfamily, which can hydrolyze collagen IV and elastin of the extracellular matrix [Safayhi and Ammon, 1997]. Thus, its use may be beneficial in inhibiting the progression of OA. Recently, we studied the efficacy of a herbal-leucine mix (HLM) containing B. serrata as one of the constituents. HLM was found to be an effective anti-inflammatory agent, as evidenced by strong inhibition of iNOS, MMP-9 and MMP-13 expression and NO production in IL-1β-stimulated OA chondrocytes in vitro. IL-1β-induced cartilage matrix breakdown was also inhibited by HLM, as evidenced by inhibition of glycosaminoglycan (GAG) release from human cartilage explants in vitro. These inhibitory effects of HLM on the inflammatory and cartilage catabolic factors were mediated by inhibiting the activation of NF-κB in human OA chondrocytes [Akhtar et al. 2011]. A novel composition of B. serrata extract (Aflapin, Indian Patent Application No. 2229/CHE/2008) showed anti-inflammatory and antiarthritic potential in a rat model. Aflapin showed significant protection from IL-1β-induced death of human primary chondrocytes, improved glycosaminoglycans production and inhibited MMP-3 production [Sengupta et al. 2011].
Toxicity studies of Boswellia in rats and primates showed no pathological changes in hematological, biochemical, or histological parameters at doses up to 1000 mg/kg and the LD50 was established at >2 g/kg [Singh and Atal, 1986]. A trial of a herbomineral formulation containing B. serrata as one of the components also showed significant reduction in severity of pain and disability score in OA [Kulkarni et al. 1991]. A randomized clinical trial of multiplant ayurvedic drugs containing B. serrata demonstrated the potential efficacy and safety in the symptomatic treatment of knee OA over 32 weeks of therapy [Chopra et al. 2004]. A B. serrata extract (5-Loxin, US Patent publication no.: 2004/0073060A1) alone with O-acetyl-11-keto-β-boswellic acid (AKBA) (Aflapin) or AKBA (30%; Loxin) alone was tested in patients with knee OA . Both treatments were effective in reducing pain and significantly improved physical functioning and stiffness scores. However, Aflapin was more effective than Loxin [Sengupta et al. 2010]. In a double-blind, placebo-controlled trial, Boswellia demonstrated a beneficial effect on knee OA [Kimmatkar et al. 2003]. Thirty patients were given either 1000 mg Boswellia daily or placebo in three divided doses for 8 weeks. Patients in the Boswellia group experienced a significant decrease in pain and swelling and increase in range of motion compared with placebo [Kimmatkar et al. 2003]. B. serrata extract containing 5-Loxin with 3-O-acetyl-11-keto-β-boswellic acid (30%) inhibited the 5-lipoxygenase enzyme. A 90-day, placebo-controlled study was conducted to evaluate the efficacy and safety of 5-Loxin in the treatment of OA of the knee with 75 patients. The patients received either 100 mg (n = 25) or 250 mg (n = 25) of 5-Loxin daily or a placebo (n = 25) for 90 days. Both doses of 5-Loxin conferred clinically and statistically significant improvements in pain scores and physical function scores in patients with OA. A significant reduction in synovial fluid MMP-3 was also noted. In comparison with placebo, the safety parameters were almost unchanged in the treatment groups and it was concluded that 5-Loxin reduces pain and improves physical functioning significantly in patients with OA; and it is safe for human consumption [Sengupta et al. 2008]. So far the in vitro, in vivo and clinical evidence (Table 1) for the effectiveness of Boswellia is encouraging but existing data do warrant further investigations [Moussaieff and Mechoulam, 2009].