Safety of the food effects

Garcinia kola is safe taken with or without other foods. Taking it an hour before or after meals may help to increase the absorption of the key ingredients. Food does not affect the metabolism of G. kola and may buffer effects of mild indigestion [17]. Garcinia kola is primarily carried bound to albumin in the blood and only a minor amount is metabolized by hepatic metabolism [18]. Kolaviron does not affect phase 1 drug metabolizing enzymes [16] but induce phase 2 enzymes [21]. It may be classified as a bifunctional inducer according to the classification of Greenwald et al 1995 [22].

Drug interactions of Kolaviron have been shown to be hepatoprotective [[7, 10, 21, 23, 24], and [25]]. It does not appear to have a pronounced effect on drug metabolizing enzymes [21] and no known interactions with orthodox medications [26]. The tablet properties could be controlled to obtain optimal release of the bioactive compounds [27].

Although surgery can relieve the pain of KOA and restore function, not all patients are candidates for surgery, and many want to avoid or delay it if possible. Therefore, alternative treatments are important [28] which could include G. kola that have not been evaluated for knee osteoarthritis. To date, there is no clinical documentation of the effect of G. kola on the knee osteoarthritis through a Medline search and locally available literatures. The research hypothesis was that G. kola have a positive effect on knee osteoarthritis as depicted in Yoruba folk songs. The objective of the study was to evaluate the clinical effects of G kola on knee osteoarthritis pain, stiffness and function. The effects of G. kola in KOA is been investigated in Nigerians through a multidisciplinary research study group based at the Obafemi Awolowo University, Ile-Ife, Osun State; Nigeria.

Inclusion criteria

Men and women between the ages of 18 and 80 years were enlisted if they had knee trauma or overuse of the knees prior to the onset of symptomatic osteoarthritis. Only uncomplicated hypertensive patients solely on Nifedipine were included. Within the routine clinical practice, many of our confirmed KOA patients do present with hypertensive heart disease on multiple therapies. Basically our research center is in resource constrained country where high technology laboratory support needed to identify specific adverse drug interactions that could be associated with multiple anti hypertensive medications is not available. It was due to this peculiar limitation and the need to enhance clarity of interpretation of subject's clinical features, study drug's efficacy and safety assessment within available international standard facilities that necessitated the inclusion of patients with uncomplicated hypertensive solely on Nifedipine.

Patient's diets were not altered from their pre study period. The other inclusion criteria in the study were – osteoarthritis of the knee verified according to the clinical, laboratory, radiographic criteria of the American College of Rheumatology (ACR) and resting visual analog scale pain intensity in the target knee > 45 mm.

Exclusion criteria

Patients with known allergic reactions (to Garcinia kola, celebrex and naproxen); Kidney failure (blood creatinine > 84 umol/L); abnormal liver function (SGOT > 35 U/L or SGPT > 35 U/L or GGT > 50 U/L); gastrointestinal ulcers (bleeding or discolored stool during the past 8 weeks); malignant diseases; systemic therapy with corticosteroids during the past 8 weeks; surgery of the test joint during the past 8 weeks; inflammatory joint diseases(ESR > 40 mm/h);chronic heart failure (NYHA grade III or IV); Chronic obstructive airway disease requiring prophylactic medication and participation on a clinical trial during the past 4 weeks. Patients with absolute indication for surgery and knee instability were excluded. Subjects with high levels of clinical disability (> 34 on the WOMAC scale) were excluded as it was unlikely that they could perform the experimental protocol consistently. Also the knee requiring no weight bearing and who had intra-articular injections into the study joint within 3 months prior to first visit were excluded. No herbal or allopathic treatment, which could influence the outcome of the study, was permitted during the course of the study. Crossing over of patients from one subgroup to another was excluded through surveillance.

Settings

Subjects were recruited into the study between February 20^th, 2004 and August 19^th, 2006 at the orthopedics and general outpatient's clinics of the Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife (OAUTHC); Nigeria.

Study medication and blinding

At the beginning of the study, no commercial preparation of Garcinia kola was available. G. kola seeds were obtained from a market in Ile-Ife, authenticated by Mr. A.T. Oladele, the herbarium, Department of Pharmacognosy, Obafemi Awolowo University.

G. kola 200 mg was given twice orally per day for six weeks. Active comparators were Naproxen 500 mg tablets twice daily, and Celebrex 200 mg twice daily were given orally. Placebo study medication was ascorbic acid, 100 mg tablet given twice daily. The patient in each group was given identical study medication of the same physical appearance aimed at eliminating psychological effects on the subjects. The subjects have not been previously exposed to research drug medications.

All study medications were prepared by a 10 years post-qualified nursing staff and administered to each patient by a senior registrar in orthopedic surgery. A family medicine physician of five year post fellowship qualification acted as a masked clinical outcome evaluator. The voluntary nursing staff, the senior registrar and masked evaluator were not part of the study group. The Nifedipine for hypertensive were supplied to patients from the teaching hospital pharmacy shop to ensure uniformity of quality control. A consultant radiologist with a neutral role status in the study screened the plain X-ray of patients and confirmed radiological features of knee osteoarthritis.

Study design

It was a randomized, double-blind, placebo-controlled, parallel-group study trial of the clinical effects of G. kola in knee osteoarthritis. The research medication dose assessor, clinical assessors, subjects and orthopedic surgeons were blinded to the treatment group for the six weeks of study. The G. kola subgroup was followed up for the midterm evaluation of therapeutic effect after the intake was discontinued.

The study was approved by the institutional medical ethics review board and was carried out in accordance with the ethical principles of the Declaration of Helsinki. A written informed consent was obtained from each patient that fulfilled the inclusion criteria before randomization.

Study randomization

To determine the presence of KOA, detailed history was obtained and clinical examination performed. Adults were classified as having clinical knee OA by using the criteria determined by the American College of Rheumatology (ACR) [29].

Randomization occurred in blocks of four within each stratum, using computer generated random numbers (Excel 5.0). The patients were grouped into four (A = placebo, B = naproxen, C = Garcinia kola, D = celebrex). Both assessors and patients were blind to the allocation and not informed about the block size until after completion of the study. Subjects were treated for six weeks and each of them had weekly follow-up visits until the time of study withdrawal. Study medications were taken in the morning and at noon, half an hour before meal times. No additional analgesics, NSAIDs or systemic corticosteroids were allowed during the study phases.

Objectives

At all visits, the patients completed WOMAC index to assess pain, stiffness, and physical function. The primary efficacy end point was the mean change from baseline in the WOMAC pain subscale VAS at six weeks. Secondary outcome measures included the stiffness and physical function.

Clinical assessments

Patients were assessed by consultant orthopedic surgeon at days -7, 0, 7, 14, 21, 28, 35 and 42.

The initial assessment (day -7) comprised of medical history, examination and WOMAC-VAS index. The "most painful knee joint" refer to the side of knee joint with the highest VAS pain score when a subject is having bilateral KOA. In bilateral knee OA, the side of the knee joint with the highest VAS pain score was the primary focus of measurement for future assessment in the study. Blood and urine samples were taken for standard laboratory tests. The onset of therapeutic effect of the study medication as used in this study was the mean time (minutes) recorded for the onset of KOA symptomatic reliefs. The duration of therapeutic effect of the study medication was the mean time (minutes) recorded for the return of KOA symptoms after a relief following study medication intake.

The radio diagnostic criterion of Kellgren and Lawrence [30]scheme was used for the knee osteoarthritis severity assessment. All patients underwent radiographic analysis of both knee joint using Kellgren-Lawrence less or equal to grade 2 as case definition.

The level of clinical disability was quantified by using the Western Ontario and McMaster University Osteoarthritis (WOMAC) index [30]. Disability was assessed using the physical function section of WOMAC, which contains 17 questions relating to functional disability, scored from 0 to 4 by the subject.

At the second study visits (day 0), laboratory findings were compared with exclusion criteria and diary entries were checked. Patients who met all study criteria filled in the WOMAC questionnaire (baseline), received study medication and thereby entered the intent to treat population.

At the study visits on days 7,14,28,35, and 42, patients filled in WOMAC questionnaires, and compliance was checked by diary entries and study medication. Adverse events were recorded by checking diary entries as well as by direct questioning of the patients.

At the study visit on day 42, blood and urine samples were taken. The masked clinical outcome evaluator and consultant orthopedic surgeon independently recorded their final overall assessment of the change of disease activity by the study medication on 100 mm visual analogue scales (VAS). Direct inquiry and visual inspection of the returned sachets container were used for monitoring compliance. The osteoarthritis protocol instrument used for the study has a section on the disease symptom/symptom description. It evaluates each subject from the day 0 to the end of study at six weeks. The subjective response of the patients to the questions on walking distance was distinct. They were asked if the distance used to cover by walking has improved, or there is no change, or it deteriorated at the end of the study compared to the day 0.

Safety

The subjects who had received at least a dose of the research medication s were assessed for their safety. Tolerability evaluations consisted of determining clinical laboratory test abnormalities such as hepatic (aminotransferase activities) and renal (serum creatinine) function, adverse events, and physical examinations. Adverse events reported by the patient or observed by the investigator during clinical evaluation were recorded. In addition, patients were questioned at each visit regarding the occurrence of adverse events using a nonspecific question. Investigators rated the intensity of adverse events and their subjective assessment of the relationship to study medication while blinded to the treatment group.

Statistical analyses

All analyses were performed on the intention to treat cohort, defined as all patients who took at least a dose of study medications. Data were analyzed by using Statistic Package for Social Sciences (SPSS) version 11.0 for windows. The comparability of patients in the four treatment groups was determined from the demographic data and baseline haemodynamic values. The change in the mean of the group and mean time of study medications therapeutic duration were evaluated using 2-way ANOVA with Post Hoc comparison test. The confidence interval (CI) was at 95% and the P-value was considered significant at p ≤ 0.05.

Study limitations

Limited numbers of knee osteoarthritis patients were available for the study. Lack of research grants to provide study medications and laboratory investigations free for long term and to include larger groups of would be subjects at multiple centers in Nigeria.

Demographic characteristics

A total of 143 patients who had post traumatic knee osteoarthritis (unilateral = 94, bilateral = 98) on 192 limbs were recruited. Eighty-four patients (58.7%) with KOA in 121 limbs satisfied the selection criteria. All the patients who received at least a dose of the research drugs had adequate documentation of their data in each subgroup and were used for analysis. There were 24 males (28.6%) and 60 females (71.4%) with M: F: 1:2.5. The proportion of bilateral knees involvement is shown in Table 1 which compared patients in the four treatment groups. The effect of knee osteoarthritis bilateralism among the subjects was not significant (p > 0.913). The WOMAC score at day 0 was not significantly different among the four study groups (p > 0.05). A clinical photographs of typical Garcinia kola is illustrated in Figure 1. The major sources of trauma were Road Traffic Accident 46(54.8%), Sports injury 19(22.6%), Fall from height 18 (21.4%) and prolonged over use from driving long distance for over 25 years, 1(1.2%). Knee osteoarthritis in young adults was common after sporting knee injury and fall from height. The women often were those carried as passenger on motor cycle before they sustained injury. The mean duration of trauma before the onset of symptomatic knee osteoarthritis for males was 17.4 years +/- 7.3 and females 14.2 years +/- 8.6. There was 100% compliance rate in the control and celebrex groups. A patient (4.76%) in the naproxen group was unable to come to the hospital for the last two days evaluation due to diarrhea. He was traced home for evaluation and discovered the medication was taken. Two patients in the Garcinia kola group stopped after completion of 39 and 40 days on the medication. It was due to light headedness and palpitation in each of the patients. Both patients were hypertensive before the commencement of the study. They were lost during the mid term follow up period of the study. The data from the patients were accepted for analysis after completion of 92.8% and 95.2% of the six weeks study period.

Clinical outcome

Analysis was restricted to eighty-four patients with adequate allocation concealment. All the patients that received at least a dose of the study medications had adequate documentation of their data in each subgroup. The change in the mean WOMAC pain VAS after six weeks of G. kola was significantly reduced compared to the placebo (p < 0.001, CI:-2.01_-1.15, R² = 0.8). Multiple comparisons of the mean of pain change in the G. kola group was not lowered significantly against the naproxen and celebrex groups (p > 0.05, CI:-0.56–0.85). There was no statistically significance between the change of mean VAS pain reduction of the G. kola, naproxen and celebrex groups. The mean time (minutes) of onset of symptomatic pain relief were 61.4 +/- 11.3(range: 39.0–77.2); 69.1 +/- 13.1 (range:43.2–86.3) and 55.8 +/- 8.9 (range:37.1–67.0) for the naproxen,G. kola and celebrex subgroup respectively(p > 0.05). The onset of G. kola symptomatic pain relief was faster than the placebo (p < 0.001, CI: 10.0–19.9, R² = 0.87). However, G. kola onset of action appeared to be slower than the active comparators (p > 0.05, CI:-2.4- 9.3) as shown in Figure 2.

The mean (minutes) duration of therapeutic effect of study medications were 527.28 +/- 60.01 (range: 418.0–602.0), 454.09 +/- 55.49 (range: 428.8–479.3) and 563.5 +/- 38.21 (range: 546.08–580.87) for the naproxen, G. kola and celebrex subgroup respectively. The 2-way ANOVA with post hoc comparison of the mean duration of G. kola therapeutic action showed it was less than that of naproxen (p < 0.002, CI : -41.5_ -7.3) and celebrex (p < 0.001, CI: -53.6_ -19.3, R² = 0.9). This is illustrated in Figure 3.

The duration of therapeutic effect of Garcinia kola was longer than the placebo (p < 0.001, CI: 110.2–146.8). G. kola period of effect was less than naproxen and celebrex (p < 0.001, CI:-54.6_-18.1, R² = 0.972). G. kola subjects had improved functional mean change mobility/walking after six weeks better than the control group(p < 0.001, CI:0.3–0.5, R² = 0.8). The mean change in mobility of the G. kola group when compared to the active comparators was not significantly better (p < 0.05, CI:-0.15–0.15). After six weeks of study, the Garcinia kola subjects had significant improvement in the mean change of knee joint stiffness (p < 0.001, CI:-2.5_-1.6, R² = 0.90) and a change in mean WOMAC score (p < 0.001, CI:-26.8_-22.2, R² = 0.97) when compared to the placebo. Patients on G. kola reported increased walking distance 80.9 %(p < 0.001), joint stiffness relaxation, 95.2 %(p < 0.001), and improved physical function 76.2 %,(p < 0.001) compared to the placebo.

After cessation of G. kola use, eight (38.1%) patients were lost to follow up at clinic due to farming/trading activities which took them out of the study environment. The knee joint pain relief reported by eleven (52.4%) patients that were seen at clinic lasted for a mean period of 17.3 +/- 5.2 days (range: 9.0–26.0). There was no deterioration of the disease symptoms. The two (9.52%) hypertensive subjects (a female senior lecturer and a male principal nursing staff) who had an episode of dizziness and light headedness were excluded from the mid term follow up report. The pain relief pattern post cessation of G kola is associated with the duration of therapeutic effects (p < 0.006) as illustrated in Figure 3.

No patient in any of the four subgroup experienced symptoms suggestive of hepatic failure, hepatic dysfunction or renal failure. None had aminotransferase levels ≥ twice the upper limit of the reference range or serum creatinine levels ≥ 1.5 times the upper limit of the reference range. No statistically significant differences were observed between the groups A, B, C, and D in the proportion of patients who reported at least one or more adverse events.