LAI scores (algofunctional indices) have been validated for use in assessing the severity of osteoarthritis of the hip and knee [9
]. LAI scores, which incorporate points for pain, maximum distance walked and activities of daily living, typically range from 1 to 14. Scores of 1 to 4 indicate a minor handicap while a score of 14 indicates an extremely severe handicap. Clinical studies used to assess the potential benefits of drugs on osteoarthritis typically start with subjects who have scores of 9 to 11 (SD 2.3 to 3.8). Upon administration of non-steroidal anti-inflammatory drugs (NSAIDS) for one or two weeks, those scores usually decrease by 2.5 to 4 points: decreases of approximately 25 to 40%. In this study, the groups had mean scores within the range of 11 to 13 (SD 1.2 to 2.4) at baseline, which indicates a very severe handicap from osteoarthritis of the knee. After 8 weeks there was a decrease of 3.7 ± 2.1 points in the normal weight treatment group and a decrease of 5.4 ± 2.2 points in the overweight treatment group. The degree of improvement observed with NP 06-1 is comparable to that reported for NSAIDS.
CRP is an acute phase protein that is produced by the liver during an inflammatory reaction. Serum CRP levels are often higher in those with osteoarthritis and are associated with joint pain, as well as the severity and progression of the disease [10
]. Recent studies have indicated that the correlation between CRP levels and osteoarthritis involves other variables besides the disease state [12
]. Body weight has been determined to influence CRP levels due to mechanical effects, as well as the production of inflammatory mediators by adipocytes. A systematic review of the literature covering weight reduction in obese subjects diagnosed with osteoarthritis of the knee concluded that the disability associated with the disease could be significantly improved with a loss of over 5.1% body weight [13
]. In contrast with the improvement in disability, loss of body weight did not necessarily predict relief from pain. Another systematic review reported that weight loss in the general adult population is associated with reductions in CRP levels. This analysis concluded that for each 1 kg of weight loss, the mean change in CRP level was decreased by 0.13 mg/L (weighted Pearson correlation, r = 0.85) [14
]. A study investigating the correlation between CRP and osteoarthritic disease progression found that subjects with inflammatory infiltrates within the synovial membrane had a mean CRP level of 4.7 ± 5.0 mg/L, while those without infiltrates had a mean CRP level of 1.7 ± 3.6 [11
In the present study, the mean levels of CRP at baseline for the four groups ranging from 0.76 to 1.3 mg/L indicated a relatively low level of inflammation. In spite of this, there was a reduction in CRP for the overweight participants with treatment compared to placebo. There was no comparative treatment effect for the normal weight participants. However there was an effect of treatment over time for both the overweight and normal weight groups. The overweight treatment group experienced a weight loss of 5.1% after 8 weeks. The normal weight subjects also lost body weight, but to a lesser degree. It appears from current literature, that the decreases in CRP in this study may have been influenced by loss in body weight [13
]. Also the reduction in weight may have had an influence in the reduction in LAI scores [13
NP 06-1 contains standardized amounts of berberine, a constituent of the Phellodendron extract, and PMFs from citrus. Both of these components have demonstrated anti-inflammatory activity. Plant extracts containing berberine have traditionally been used in rheumatic and other chronic inflammatory diseases [15
]. In support of the traditional use, extracts containing berberine have demonstrated anti-inflammatory activity in animal models [16
]. In vitro studies indicate that berberine inhibits the production of inflammatory mediators prostaglandin E2
and interleukin (IL)-12 [18
]. Berberine also reduced the levels of expression of mRNA for pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha, IL-6, CRP and haptoglobin [20
Berberine has also been shown to reduce body weight in mice and rats [21
]. Histological studies indicated that berberine reduced adipocyte size but not cell number. Measurements of metabolic gene expression in adipose and muscle tissue indicated that berberine up regulated genes involved in energy expenditure and down regulated the expression of genes involved in lipogenesis. In vitro
studies determined that berberine increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 adipocytes and L6 myotubes, as well as reduced lipid accumulation in 3T3-L1 cells. In addition, berberine reduced secretion of leptin, which regulates appetite and energy metabolism, from 3T3-L1 adipocytes.
Citrus PMFs have been reported to exhibit anti-inflammatory activity in vivo
and in vitro
. PMFs regulated levels of adipocytokines through suppression of TNF-alpha, interferon-gamma, IL-1 beta and IL-6 expression [22
]. PMFs also suppressed TNF-alpha expression by monocytes, perhaps due to inhibition of phosphodiesterase activity [23
This pilot study has a number of weaknesses. The most obvious weakness is the number of dropouts. There was no clear evidence of difference or bias in the demographics of the dropouts compared to those who stayed in the study; however, there was insufficient information to run an analysis of the two groups. Care must be taken with respect to dropouts when a full blown study is conducted. We also acknowledge that we have no information on patient compliance with treatment protocol.
In summary, it appears from the results of this pilot study that NP 06-1 may benefit subjects with osteoarthritis of the knee through an anti-inflammatory action as well as through a loss of body weight. In addition to increased osteoarthritis-related disability, obesity is correlated with an array of conditions associated with a high risk of diabetes, hypertension and/or cardiovascular disease called metabolic syndrome [24
]. Symptoms of metabolic syndrome include abdominal obesity, dyslipidemia and elevated blood pressure and insulin resistance.
We have previously reported that administration of NP 06-1 is associated with a general improvement in lipid levels, with reductions in triglycerides and low-density lipoprotein (LDL)-cholesterol and an increase in high-density lipoprotein (HDL)-cholesterol [7
]. In that same report, we also reported treatment-related decreases in blood pressure and a decrease in fasting glucose levels in an overweight population. Thus additional studies are indicated to explore the use of NP 06-1 for osteoarthritis and for metabolic syndrome.