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Clinical evaluation of a powder of quality elk velvet antler for the treatment of osteoarthrosis in dogs Maxim Moreau, Jacques Dupuis, Norbert H Bonneau, Manon Lécuyer Abstract — A powder of quality elk velvet antler (QEVA) was evaluated on client-owned dogs with osteoarthrosis (OA) in a clinical, double-blind, and placebo-controlled study. Thirteen dogs received a placebo for 30 days and then QEVA for 60 days. Twenty-five other dogs received QEVA for 60 days. Gait analysis measured with a force plate, clinical signs assessed by an orthopedic surgeon, performances in daily life activities and vitality assessed by the owners, and complete blood analyses were obtained at days 0, after 30 days of placebo and/or 60 days of QEVA. On placebo, the 13 dogs did not show significant improvement (P  0.05); however, their gait, their performances in daily life activities, and their vitality were significantly improved on QEVA, based on changes in values exceeding those observed when placebo was administered. The 25 dogs on QEVA for 60 days showed similar improvements. No clinical changes were revealed on blood analyses. Administration of QEVA was effective in alleviating the condition in arthritic dogs.
Résumé — Évaluation clinique de l'utilisation d'une poudre faite à partir de bois de velours
de cerf de bonne qualité dans le traitement d'ostéoarthrose chez le chien. Une poudre faite à
partir de bois de velours de cerf de qualité a été évaluée chez des chiens ayant de l'ostéoarthrose lors d'une étude clinique à double insu. Trente chiens ont reçu un placebo pendant 30 jours et, par la suite, de la poudre de bois de velours pendant 60 jours. Vingt-cinq autres chiens ont reçu de la poudre de bois de velours pendant 60 jours. L'analyse de la démarche a été faite à l'aide d'une plate-forme. Les signes cliniques ont été évalués par un chirurgien orthopédiste. Les performances et l'entrain dans les activités quotidiennes ont été évalués par les propriétaires. Des analyses sanguines complètes ont été faites au jour 0, après 30 jours de placebo ou 60 jours de poudre de bois de velours. Les 13 chiens ayant reçu le placebo n'ont pas montré d'amélioration significative (P  0,05); cependant, leur démarche, leurs performances lors d'activités quotidiennes et leur vitalité se sont améliorées consi- dérablement après qu'ils eurent reçu de la poudre de bois de velours, cette conclusion repose sur les écarts de valeurs plus important que ceux observés chez les chiens ayant reçu le placebo. Les 25 chiens qui ont reçu la poudre de bois de velours pendant 60 jours ont connu des améliorations similaires. Les analyses sanguines n'ont révélé aucun changement clinique. L'administration de la poudre de bois de velours s'est avérée efficace pour améliorer l'état des chiens arthritiques.
(Traduit par Docteure Andrée Lesage) Can Vet J 2004;45:133–139 used clinically in East Asia for thousands of years in the Osteoarthrosis (OA) is a painful musculoskeletal treatment of various diseases and as a tonic (9). This condition in dogs, often being secondary to struc- traditional Chinese medicine is a nutritional supplement tural abnormalities, such as hip or elbow dysplasia or made from the inner core of elk antler in the velvet stage ligament injury. Disturbance in the normal homeostasis of growth. Observations from in vivo studies demon- of joint tissue between degradation and synthesis is strated an antiinflammatory eff f ect of a peptide (pilose involved in this degenerative process, visually character- antler peptide) isolated from velvet antler in a rodent ized by articular surface erosion, bone sclerosis, and model of inflammation (9,10). T hese studies, combined osteophyte production, leading to pain, joint stiffness, with the knowledge that chondroitin sulfate is found in and muscular atrophy (1–4).
velvet antler,r suggested that this material could be useful Research has led to the development of a broad range in the treatment of OA (11,12).
of pharmaceutical approaches to alleviate clinical signs by acting on the degenerative process, the associated the health benefits of a powder of quality elk velvet inflammatory process, or both (5–8). Elk velvet antler is antler,r referred here to QEVA V , by administering it at the a well-known Chinese materia medica, which has been manufacturer's recommended dosage to a pool of client- owned dogs afflicted with OA. The companion animal research group, Faculté de médecine Materials and methods St-Hyacinthe Quebec J2S 7C6.
Address all correspondence and reprint requests to Dr.r Maxim Dogs weighing more than 20 kg and older than 18 mo Moreau; e-mail: m.moreau@umontreal.ca were included in the study.
y All dogs had radiographic A in 1 or more joints. The OA This study was generously supported by Qeva V Corporation, Calgary, have been determined to be the cause of the clinical Can Vet J Volume 45, February 2004 signs, including an algetic gait, by a complete orthopedic group their dog had been assigned, and about the contents examination performed by an orthopedic surgeon (JD or of the capsules administered to their dog. Surgeons were NHB). The algetic gait reported by the owner had to be unaware of the GRF, had no communication with the chronic and stable. Dogs with rupture of the cranial owners, and did not know about the assigned group. Dogs cruciate ligament were admitted, if the rupture had been meeting all enrolment criteria were randomly assigned to surgically repaired more than 1 y previously. Dogs were 1 of these 2 experimental groups.
also included if a complete cranial cruciate ligament rupture had been diagnosed more than 1 y previously and Placebo-QEVA group
had not been surgically corrected at that time and if they Dogs weighing between 20 and 39.9 kg, 40 and 59.9 kg, were without evidence of gross instability (drawer and 60 and 79.9 kg received 2, 3, and 4 capsules of placebo, movement) at the time they were presented for the study. respectively, PO, q12h for 30 d, starting on day 0. Following Concurrent treatment for OA was not permitted during this, dogs weighing between 20 and 39.9 kg, 40 and 59.9 kg, the course of the study. If dogs had previously received and 60 and 79.9 kg received 2, 3, and 4 capsules of QEVA, treatment, the following predetermined withdrawal respectively, PO, q12h for 60 d, from days 31 to 90. Each periods were observed: 2 wk for oral nonsteroidal capsule of placebo contained a mixture of flour (unbleached antiinflammatory drugs, 3 wk for oral corticosteroids, r anic romano bean), powder (arrowroot, roaster and 12 wk for injectable corticosteroids. A 4-week with- drawal period was required following oral administration contained 280 mg of a pure powder of elk (Cornu cervi) of glucosamine, chondroitin sulphate, or both, while a velvet antler (Cartiplex; Qeva Velvet Products, Calgary, 24-week withdrawal period was required following injectable polysulfated polysaccharide. Pregnant bitches and dogs suffering from neurologic or other musculo- 30 d had changed. The following 60 d were used to evalu- skeletal lesions were excluded. Dogs that had undergone ate the effects of QEVA.
orthopedic surgery within the past year were also excluded. Recruitment was done through telephone calls Quality elk velvet antler group
to clients selected from the medical files of the Veterinary Dogs between 20 and 39.9 kg, 40 and 59.9 kg, and 60 to Teaching Hospital of the Université de Montréal and 79.9 kg received 2, 3, and 4 capsules of QEVA, respectively, advertisements in newspapers. Dog owners involved in PO, q12h for 60 d, starting on day 0. Each capsule contained the study were required to sign a consent form.
280 mg of QEVA.
returned to the V T aching Hospital for 2nd and The experimental protocol was approved by the Animal 3rd visits on days 30 and 90, respectively.
Care and Use Committee of the Université de Montréal and dogs included in the QEVA A group returned to the was in accordance with the Guidelines of the Canadian T aching Hospital for a 2nd visit on day 60. Council for Animal Care (13). On day 0, owners and dogs At the time of these visits, owners were asked again to attended the Veterinary Teaching Hospital for the first visit. Owners were asked to score performances in daily an assessment of increasing vitality by using a dichoto- life activities by using an owner's assessment form mous key (yes or no) and to report side eff f ects related to (Appendix 1). Scores for each activity were then summated treatment. Dogs were weighed, their gait was analyzed, to generate a score for activity performances. Dogs were and an orthopedic examination was carried out. Owners weighed and their gait was analyzed by using ground were asked to return any unused medication, so that it reaction forces (GRF) obtained by a biomechanical force could be verified that it had been given as prescribed. plate (Model OR6-6; Advanced Mechanical Technology, Watertown, USA). Visual examination of the gait and Equipment and gait analysis protocol
complete orthopedic and neurologic examinations were then Ground reaction forces were obtained by using a carried out by 1 of 2 surgeons. After the examination, the permanently mounted biomechanical force plate that had surgeon attributed scores for the clinical signs of the most been levelled with the floor in a 10-m runway and severely affected joint by using a surgeon's assessment form interfaced with a dedicated computer and software (Appendix 2). In both assessment forms, higher scores V tforce; Sharon Software, Michigan, USA) specially meant severe clinical signs. Radiographic evaluations of designed for the acquisition, numerical conversion, and elbows, hips, and stifles were performed under routine storage of values. Tr T ot was maintained at a constant sedation in all dogs; if necessary, additional radiographs velocity between 1.9 and 2.2 m/s. A A chronometer was were obtained for specific joints. A radiographic score of used to ensure that the dogs crossed the 10-m runway in OA was attributed to each joint only on day 0 (Appendix 3). between 4.5 and 5.2 s. The objective gait analysis Blood samples were obtained by jugular venipuncture for hematological and biochemical analyses to detect any pre- f ected joint, responsible for most of the clinical signs study abnormalities and to obtain basal values. Owners were and algetic gait, as determined by the orthopedic informed that dogs selected for the study would receive examination. In the vertical axis, GRF obtained for the either a placebo or an OA medication over 2 or 3 visits. evaluated limb were the peak (maximal force) and Orthopedic examinations were successively conducted impulse (force integrated over time). In the craniocaudal during a period of 6 mo and included between clinical cases, axis, the peak and impulse for the braking (cranial) thus confounding observation on day 0 and at re-evaluations. and propulsive (caudal) portions of this GRF were also obtained. At least 5 valid trials with a stance time Can Vet J Volume 45, February 2004 Table 1. Mean and standard error (s) of the mean changes from pretreat-
ment for ground reaction forces and surgeon and owners' assessments in
13 dogs with osteoarthrosis after 30 d of treatment with placebo and then
60 d of treatment with a powder of quality elk velvet antler (QEVA)
A
Changes from pretreatment Ground reaction forces 30 d of placebo 60 d of QEVA Vertical peak 0.047, s = 1.500 4.102, s = 1.000a impulse 0.094, s = 0.214 0.091, s = 0.163Craniocaudal braking portion peak 0.151, s = 0.202 0.870, s impulse 0.009, s = 0.017 0.052, s = 0.057Propulsive portion peak 0.412, s = 0.330 0.313, s = 0.356 impulse 0.056, s = 0.039 0.020, s = 0.033 Changes from pretreatment Assessments (scores) 30 d of placebo 60 d of QEVA Surgeon clinical signs 0.00, s = 0.43 0.15, s = 0.49 visual appreciation 4.30, s = 5.70 6.38, s = 5.56Owner activity performances 1.00, s = 0.63 6.92, s = 1.45aaPretreatment values significantly different from posttreatment values with changes significantly different from those of placebo (P  0.05) determined by the software of 0.650 s were retained; in the placebo-treated group by using a chi-square test. invalid trials were rejected, as previously described (14). Probability (P) values less than 0.05 were considered Normalized values in percentage of body weight for the evaluated limb were averaged and analyzed from the first 5 valid trials. Vertical GRF peak was designated as the primary outcome measurement of the study. Age, weight, GRF, duration of clinical signs, radio- graphic findings, and assessment scores were not Forty-five (45) dogs afflicted with OA were included significantly diff f erent between groups, and the weights in the study; 5 (11%), 22 (49%), 13 (28%), 1 (2%), and of dogs obtained at each visit did not diff f er significantly.
4 (9%) dogs with clinical and radiographic evidence of Table 1 presents the changes from pretreatment observed OA of the elbow, hip, stifle, shoulder and tarsus, respec- in the placebo-QEVA A group for GRF and assessments tively. There were 33 purebred and 12 mixed breed dogs after 30 d of treatment with placebo and then after 60 d with ages ranging from 21 to 148 mo, with an average of treatment with QEVA. of 82 mo. Their weight ranged from 25 to 71 kg, with an average of 42 kg.
assessments obtained for the 13 dogs in this group were not significantly diff f erent from those obtained before treatment (day 0). Only 1 owner reported an increased The Wilcoxon rank-sum test was used to evaluate the homogeneity between groups. Posttreatment GRF and of treatment with QEVA V , the vertical GRF peak and the assessment scores were compared with pretreatment craniocaudal GRF peak for the braking portion for these (day 0 or 30) scores by using the Wilcoxon signed- rank test for paired data. Changes from pretreatment for QEVA-treated dogs were calculated and compared pretreatment scores significantly exceeded the changes with similar changes for placebo-treated dogs by using the Wilcoxon signed-rank test for paired data in the placebo-QEVA group and the Wilcoxon rank-sum test as indicated by a significant reduction, compared with in the QEVA group. An improvement was defined as an pre-treatment (day 30) in activity performance scores. increase in GRF and a decrease in assessment scores. Changes in activity performances significantly exceeded The proportion of dogs with an increased vitality in the those observed after these dogs received the placebo. In V -treated group was compared with that of dogs these 13 dogs, 9 owners reported an increasing vitality Can Vet J Volume 45, February 2004 Table 2. Mean and standard error (s) a of the mean changes from pretreatment for ground reaction forces
and surgeon and owners' assessments in dogs with osteoarthrosis after 60 d of treatment with a powder of
quality elk velvet antler (QEVA)
A
Changes from pretreatment Ground reaction forces group (25) group (38) subset (19) Vertical force peak 2.381, s = 0.717b 2.970, s = 0.590b 2.514, s = 0.726b 3.149, s = 0.588b impulse 0.160, s = 0.145 0.136, s = 0.109 0.130, s = 0.153 0.209, s = 0.132 Craniocaudal force braking portion peak 0.529, s = 0.257a 0.646, s = 0.251a 0.726, s = 0.310a 0.267, s = 0.224 impulse 0.042, s = 0.021a 0.046, s = 0.023b 0.051, s = 0.025a 0.011, s = 0.021 Propulsive portion peak 0.060, s = 0.230 0.066, s = 0.193 0.124, s = 0.304 0.515, s = 0.305 impulse 0.024, s = 0.028 0.009, s = 0.022 0.033, s = 0.033 0.045, s = 0.035 Changes from pretreatment Assessments (scores) group (25) group (38) subset (19) Surgeon clinical signs 0.68, s = 0.51 0.39, s = 0.37 0.21, s = 0.53 0.75, s = 0.68 visual appreciation 5.40, s = 4.36 5.73, s = 3.40 5.68, s = 5.10 8.00, s = 5.48 Owner activity performances 8.00, s = 1.26a 7.63, s = 0.96a 8.63, s = 1.62a 6.25, s = 1.16a aPretreatment values significantly different from posttreatment values with changes significantly different from those of placebo (P  0.05)bPretreatment values significantly different from posttreatment values (P  0.05) after 60 d of treatment with QEVA. This proportion (9/13) was significantly higher compared with the proportion group (18/25), pooled group (27/38), and hips subset (14/19), observed after treatment with placebo (1/13).
but not in the stifles subset (6/12).
Table 2 presents the changes from pretreatment scores for GRF and assessments after 60 d of treatment with Side effects and sample exclusion
QEVA. Ground reaction forces and assessments were recorded for the QEVA group of dogs and the dogs monitored revealed no evidence of abnormalities of any pooled from the placebo-QEVA and QEVA groups. clinical relevance following administration of placebo or Subsets for stifles and hips were created from this pool V , and the owners reported no side eff of 38 dogs to provide distinction in treatment effects to their administration.
according to evaluated joints. Seven dogs did not complete the study. In the placebo- The vertical GRF peak observed after 60 d of treatment A group, a pregnant bitch was withdrawn from the with QEVA was significantly improved in the QEVA group, y and another dog was withdrawn when the owner pooled group, and in the hips and stifles subsets compared decided to stop the study for reasons unrelated to the with the pretreatment peak. Also, the craniocaudal GRF peak experimental context. Also in this group, a 4-year- and impulse for the braking portion were significantly Great Pyrenees died after 30 d of QEVA improved in the QEVA group, pooled group, and hips subset, history of anorexia, lethargy history of anorexia, lethar , and vomiting. On necropsy , and vomiting. On necropsy but not in the stifles subset. Except for the braking impulse macroscopic examination revealed bilateral reduction in in the pooled group, these changes significantly exceeded size of the adrenal glands, which was confirmed by those observed in the 13 dogs that received the placebo only. microscopic examination. The final diagnosis was According to owners' assessment, activity performances chronic adrenal atrophy with degeneration and fibrosis were significantly improved in dogs in the QEVA group, the of the cortical region of the adrenal glands. In the QEVA pooled group, and in the hips and stifles subsets, as indicated group, a 10-year- r old dog died after 38 d of QEVA by a significant reduction in activity performances scores compared with pretreatment (day 0) evaluations. Changes from the surface of the right atrium and on the spleen. A from pretreatment scores significantly exceeded the changes final diagnosis of hemangiosarcoma of the right atrium observed after the 13 dogs had received the placebo. r old American bulldog developed Assessments by the surgeon did not note significant diarrhea after 2 d of QEVA V . Based on owner information differences from pretreatment scores. Eighteen, 27, 14, and a medical history that this dog had previously and 6 owners reported an increased vitality in the QEVA demonstrated enteric problems with susceptibility to group, pooled group, hips, and stifle subsets, respectively. diarrhea associated with dietary changes, the owner Compared with placebo (1/13), proportions of dogs with an decided to withdraw his dog. Following a history of Can Vet J Volume 45, February 2004 diarrhea and 40 d of QEVA, a 5-year-old bobtail died; According to the owners' 'assessment, QEVA its alkaline phosphatase prior to treatment was 531 U/L. dogs demonstrated a beneficial response. At home, Macroscopic examination revealed pulmonary congestion arthritic dogs improved their physical performances, and bilateral atrophy of the adrenal glands with a thin accompanied by an increasing vitality.
cortical region. The liver was pale and friable. Bilateral this appreciation, QEVA A prevented or decreased the atrophy of the cortical region of the adrenal glands with deleterious effect of inactivity by providing vigor mild lymphoid adrenalitis and vacuolar hepatopathy was and favoring resumption of normal activities of daily diagnosed. Finally, to avoid concomitant medication, the life. Although no improvements were observed by the investigators decided to withdraw a dog with a prior V -treated dogs, visual appreciation history of dermatological problems that required corti- showed a decrease in score, while an increase in score costeroid therapy during the course of the study.
was observed in placebo-treated dogs. Whether adjust- ment in dose to provide a greater amount of QEVA longer therapy might result in better improvement in orthopedic examination needs further investigation. Kinetic measurement of musculoskeletal limb function A were described by using subsets has been used in different ways to comparatively evaluate to determine if a distinction existed between treatment response to different treatments (15–17), impact of acute synovitis (14), and surgical procedures (18). The biome- joints. Results showed that a diff f erence in response was chanical force plate used in this study allows a noninva- in fact present, with less improvement of GRF and sive and objective quantification of the forces transmitted vitality for dogs with arthritic stifles. Based on a previous through a single limb to the ground. Concerning the limb study on the marked effect of a nonsteroidal antiinflam- with the most severely affected joint, the vertical and matory drug on canine stifles, we speculated that this craniocaudal GRF were obtained pretreatment to create f er in etiopathogenesis, resulting possibly an arthritic pattern that could be compared with the GRF in a more pronounced inflammatory process associated obtained posttreatment. The difference in GRF and in with an injury to the cruciate ligament (15). A assessments scores pre- and posttreatment represents the to this speculation, the distinction in improvement could effect of the treatment on the arthritic condition. be related to the major inflammatory process associated The efficacy of QEVA was evaluated objectively on with cruciate disease and a less eff f ective treatment with dogs afflicted with OA by using a description of the gait. A when pronounced inflammation is present. This Although some GRF were obtained and analyzed, vertical hypothesis was suggested by clinical observations, thus GRF peak was chosen as a primary outcome measure of it is limited in scope. improvement, thus limiting the probability of getting an There was no alteration in the biochemical and hemato- improvement by chance alone. The GRF generated by the musculoskeletal system and transmitted to the affected 3 deaths occurred. One of these deaths was related to a limb were increased in QEVA-treated dogs, thereby hemangiosarcoma; however, the 2 other cases showed indicating an improvement. The vertical GRF peak reflects similar postmortem lesions on microscopic examination: the maximal weight bearing of the dog. Dogs treated with atrophy of the cortical region of the adrenal glands. In one QEVA applied a greater magnitude of weight on their case, the degree of fibrosis observed suggested that the worst limb during the stance phase. This improvement in lesions were secondary to cortical necrosis. The severe weight support may be related to an increase in muscular hyperkalemia, obtained from postmortem analysis of strength, a decrease in joint inflammation, or both. Indeed, vitreous humor, supports the hypothesis of cardiogenic and when muscular mass is able to adequately support limb circulatory shock following adrenocortical insufficiency. In loading, reduction in joint loading occurs. This myotropic the other case, pulmonary and hepatic congestion suggested effect can improve the arthritic gait by limiting the delete- that death was caused by a vascular shock.
rious action of joint loading. Also, when the inflammatory process in a joint is reduced, relief of pain related to dy with 2 deaths with similar lesions, safety of hyperalgesia occurs (19). This reduction in joint inflam- this medication needed to be demonstrated further: Oral mation can improve the arthritic gait by limiting the pain related to biochemical mediators released from OA cartilage, synovial membrane, and nerve fibers from the surrounding articular tissues (20–22). rodents (Cartiplex; Qeva Ve V lvet Products, personal The craniocaudal GRF generated during the stance phase is divided into a braking and a propulsive por- gross pathologic examination revealed no evidence of tion. At the beginning of the stance phase, dogs decrease their momentum; then they propel their body forward of a rapid withdrawal of exogenous corticosteroids (24). before lifting the limb from the ground to increase their momentum (23). Dogs treated with QEVA were corticosteroid therapies had never been used previously.
able to increase their maximal braking force and also Organochlorine compounds, such as dichloro-diphenyl- increase their total applied braking force. Based on trichloroethane (DDT) and its derivatives, can produce gait analysis, QEVA-treated dogs improved their weight bearing, accepted an algetic portion of the In order to determine the presence of noxious substances stance phase, and executed the stride in a comfortable in the QEVA capsules, investigators submitted the medica- tion used in both of these dogs to an independent Can Vet J Volume 45, February 2004 laboratory (Bodycote-Envirolab, Ste-Foy, Quebec) to screen for 20 potential pesticides, including DDT and its 1. Martel-Pelletier J, Alaaeddine N, Pelletier JP.
P Cytokines and their derivatives. Results obtained by gas chromatographic role in the pathophysiology of osteoarthritis. Front Biosci 1999; analyses showed no detectable traces of any pesticides. Also, in order to document the adrenocortical function of 2. Martinez SA. Congenital conditions that lead to osteoarthritis in QEVA-treated dogs, adrenal response following synthetic the dog. Vet Clin North Am Small Anim Pract 1997;27:735–758. 3. Martinez SA, Coronado GS. Acquired conditions that lead to adrenocorticotropin hormone (ACTH) injection was osteoarthritis in the dog. Ve V t Clin North Am Small Anim Pract evaluated. Five dogs receiving QEVA during 16, 20, 22, 60, and 60 d were tested: Basal and stimulated cortisol 4. Johnston SA. Joint anatomy, y and pathobiology.
concentrations were all within the normal range values, Clin North Am Small Anim Pract 1997;27:699–723.
indicating a normal adrenal function. Based on these 5. Fernandes JC, Caron JP, P Martel-Pelletier J, et al. Eff f ects of tenidap findings and with the fact that in both cases the pathologist model. Suppression of metalloprotease and interleukin-1 activity.
could not rule out shock following naturally occurring Arthritis Rheum 1997;40:284–294.
adrenocortical insufficiency, these deaths were determined 6. Johnson KA, Hulse DA, Hart RC, Kochevar D, Chu Q. Effects of an to be unrelated to QEVA treatment. However, a laboratory orally administered mixture of chondroitin sulfate, glucosamine hydrochloride and manganese ascorbate on synovial fluid chondroitin work-up must be considered for QEVA-treated dogs sulfate 3B3 and 7D4 epitope in a canine cruciate ligament transection showing clinical signs similar to those reported here.
model of osteoarthritis. Osteoarthritis Cartilage 2001;9:14–21.
Elk are farmed to produce velvet antler teas, extracts, 7. Blot L, Marcelis A, Devogelaer JP, P Manicourt DH. Effects of or capsules of raw material for human and animal health diclofenac, aceclofenac and meloxicam on the metabolism of benefits. It is well established that velvet antler contains proteoglycans and hyaluronan in osteoarthritic human cartilage. Br J Pharmacol 2000;131:1413–1421.
collagen as a major protein; a small amount of glycosami- 8. Pelletier JP, Lajeunesse D, Jovanovic DV, et al. Carprofen simul- noglycans, primarily as chondroitin sulfate (11,12); taneously reduces progression of morphological changes in a peptide of 68 amino acids called pilose antler peptide cartilage and subchondral bone in experimental dog osteoarthritis. (9,10), and an alcohol extract known as pantocrin or J Rheumatol 2000;27:2893–2902.
9. Zhang ZQ, Zhang Y, W ng BX, Zhou HO, Wa rantarin (27,28). Chondroitin sulfate possesses documented Purification and partial characterization of anti-inflammatory antiarthritic effects and is the major glycosaminoglycans peptide from pilose antler of Cervus nippon Temminck. Ya present in velvet antler (29). We consider that its presence Xue Bao 1992;27:321–324.
in QEVA was not associated with the beneficial effects 10. Zhang ZQ, Wang Y, Zhang H, Zhang W, Zhang Y, Wang BX. Anti- observed in this study, since, in another study performed f ects of pilose antler peptide. Zhongguo Ya Xue Bao 1994;15:282–284.
by our group (15), administration of a nutraceutical 11. Sunwoo HH, Sim LY T Hudson RJ, Sim JS. providing chondroitin sulfate in greater amounts than Glycosaminoglycans from growing antlers of wapiti (Cervus the raw material administered in this study failed to elaphus). Can J Anim Sci 1997;77:715–721.
demonstrate significant gait improvement. The beneficial 12. Sunwoo HH, Nakano T, Hudson RJ, Sim JS. Isolation, characteriza- effects of QEVA could be associated, in part with the tion and localization of glycosaminoglycans in growing antlers of wapiti (Cervus elaphus). Comp Biochem Physiol B Biochem Mol antiinflammatory action of pilose antler peptide and with the action of pantocrin. Therapeutic claims reported for 13. Guidelines for the Canadian Council for Animal Care. Canadian pantocrin include increased work capacity, increased Council for Animal Care, 315–350 Albert Street, Ottawa, Ontario.
recovery from training, decreased skeletal muscle fatigue F Kincaid SA, Baird DK, Kammermann JR, V V rtical ground reaction force distribution during (adaptogenic properties), and a stimulating effect (30). To experimentally induced acute synovitis in dogs. Am J Ve reinforce our hypothesis of a myotropic effect provided by QEVA, clinical signs were analyzed separately to 15. Moreau M, Dupuis J, Bonneau NH, Desnoyers M. Clinical evalu- evaluate the effect on muscular mass in the QEVA and ation of a nutraceutical, carprofen and meloxicam for the treatment pooled groups. Although the cumulative score for clinical of dogs with osteoarthritis. Vet Rec 2003;152:323–329.
signs did not show significant improvement, palpation of f icacy in a sodium urate-induced synovitis model muscle mass revealed a significant reduction of atrophy, in dogs. Am J Vet Res 1997;58:626–631.
suggesting a myotropic effect (data not shown).
r SC, Johnston SA, Schwarz PD, DeCamp CE, Claxton The beneficial effects of QEVA on arthritic dogs were f icacy of etodolac for the treatment of osteoarthritis of the hip joints in dogs. J Am Vet Med Assoc 1999;214:206–210.
objectively and subjectively demonstrated in this study. 18. Dupuis J, Harari J, Papageorges M, Gallina AM, Ratzlaff M. Based on the improvements observed here, consideration Evaluation of fibular head transposition for repair of experimental should be given to a powder of quality elk velvet antler cranial cruciate ligament injury in dogs. Vet Surg 1994;23:1–12.
in the treatment of canine OA. Further fundamental 19. Dray A. Inflammatory mediators of pain. Br J Anaesth 1995;75: investigation in OA cartilage explants to evaluate the capacity of QEVA to reduce or inhibit the degenerative process would be interesting. Also, the long-term safety 21. Goldring MB. The role of cytokine as inflammatory mediators in of administering QEVA needs to be investigated, as does osteoarthritis: lessons from animal models. Connect Ti the magnitude of improvement with a well defined and frequently prescribed OA medication on dogs afflicted 22. Konttinen YT, r M, et al. Peripheral and spinal neural mechanisms in arthritis, with particular reference to with osteoarthrosis. treatment of inflammation and pain. Arthritis Rheum 1994;37:965–982.
23. DeCamp CE. Kinetic and kinematic gait analysis and the assessment of lameness in the dog. Vet Clin North Am Small Anim Pract 1997;27:825–840.
The authors thank Mr. Sébastien Martel for technical 24. Cotran RS, Kumar V, V Collins T.
T Robbins Pathologic Basis of Disease, 6th ed. Philadelphia: W B Saunders, 1999:11 Can Vet J Volume 45, February 2004 25. Clarke ML, Harvey DG, Humphreys DJ. Veterinary Toxicology, cervical cord and effect of Pantui extract, pantocrin. Nippon 2nd ed. London: Baillière Tindall, 1981:140–149.
Yakurigaku Zasshi 1972;68:489–493.
26. Gilman AG, Goodman LS, Rall TW, Murad F, eds. Goodman and 29. Bali JP, Cousse H, Neuzil E. Biochemical basis of the pharmaco- Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New logic action of chondroitin sulfates on the osteoarticular system. York: Macmillan Publisher, 1985:1293.
Semin Arthritis Rheum 2001;31:58–68.
27. Takikawa K, Kokubu N, Tahara N, Dohi M. Experimental whiplash 30. Di Pasquale MG. Stimulants and adaptogens. Part 2. Drugs Sports injury. 2. Evaluation of Pantui extract, pantocrine. Nippon Yakurigaku Zasshi 1972;68:473–488.
28. Takikawa K, Kokubu N, Kajihara M, Doi M, Tahara N. Experimental whiplash injury. 3. Changes in enzyme activities of Appendix 1. Owner's assessment
Appendix 2. Surgeon's assessment
Daily life activities · Walking approximately 15 minutes· Gait after 15 minutes of walking · Running approximately 10 minutes 1 — Perceivable algetic gait · Gait after 10 minutes of running 2 — Evident algetic gait · Climbing stairs· Going down stairs · Getting up after a long rest 1 — Abnormal (perceivable relief) 2 — Abnormal (obvious relief) · Climbing in the car, over objects 0 — No limit of motion1 — Reduction of 10° to 20° of motion 2 — Reduction of 20° to 50° of motion 0 — No difficulty in performing this activity 3 — Reduction of more than 50° of motion 1 — Slight and occasional difficulty in performing this activity2 — Slight and constant difficulty in performing this activity Muscular atrophya 3 — Evident difficulty in performing this activity 1 — Perceptible muscular atrophy 4 — Can no longer execute this activity 2 — Evident muscular atrophy Did you notice an increasing vitality in your dog? YES/ NO Please report side effects related to treatment 1 — Slight (complete movement with Score for each activities were added to generate a score for activity 2 — Moderate (incomplete movement with reluctance)3 — Severe (no movement allowed) 100 mm Severe algetic gait aMuscular mass atrophy was assessed by palpation.
bOn a 100-mm line, the surgeon identified his own appreciation of the algetic gait, the resulting numeral length (score) was further analyzed.
Score for walking gait, trotting gait, posture, mobility, muscular atrophy, and joint pain were added to generate a score for clinical signs. Appendix 3. Scoring system for radiographic evidence of osteoarthrosis
0 — Osteophytes and sclerosis absent.
1 — Acetabular remodeling, Morgan line, slight neck remodeling and slight femoral head sclerosis.
2 — Acetabular remodeling and osteophytosis, neck remodeling, enthesiophytosis, and femoral head sclerosis.
3 — Advanced acetabular and neck remodeling, severe osteophytosis and advanced femoral head sclerosis.
0 — Osteophytes absent.
1 — Osteophytes present on patella and proximal aspect of femoral trochlear groove.
2 — Osteophytes present on patella, femoral trochlear groove, medial and lateral femoral condyles, and tibial plateau.
3 — Severe osteophytes on patella, femoral trochlear groove, medial and lateral femoral condyles, and tibial plateau: subchondral sclerosis of femoral condyles and tibial plateau.
0 — Osteophytes absent.
1 — Osteophytes  2 mm on the anconeal process of ulna.
3 — Osteophytes 2 to 5 mm on the anconeal process of ulna, osteophytes on the head of radius  2 mm, and on the humeral crest  2 mm.
Tarsus and shoulder 0 — Osteophytes absent1 — Osteophytes  2 mm2 — Osteophytes 2 to 5 mm3 — Osteophytes  5 mm Can Vet J Volume 45, February 2004

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Cell Physiol Biochem 2015;37:651-665 DOI: 10.1159/000430384 © 2015 S. Karger AG, Basel Published online: September 08, 2015 Spaas et al.: Chondr ogenic Priming Enhances MSC Adhesion ed: August 04, 2015 This is an Open Access article licensed under the terms of the Creative Commons Attribution- NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to

Antiplasmodial activity, in vivo pharmacokinetics and anti-malarial efficacy evaluation of hydroxypyridinone hybrids in a mouse model

Dambuza et al. Malar J (2015) 14:505 Open Access Antiplasmodial activity, in vivo pharmacokinetics and anti-malarial efficacy evaluation of hydroxypyridinone hybrids in a mouse modelNtokozo S. Dambuza1*, Peter Smith1, Alicia Evans1, Jennifer Norman1, Dale Taylor1, Andrew Andayi2, Timothy Egan2, Kelly Chibale2 and Lubbe Wiesner1 Abstract Background: During the erythrocytic stage in humans, malaria parasites digest haemoglobin of the host cell, and the toxic haem moiety crystallizes into haemozoin. Chloroquine acts by forming toxic complexes with haem mol-ecules and interfering with their crystallization. In chloroquine-resistant strains, the drug is excluded from the site of action, which causes the parasites to accumulate less chloroquine in their acid food vacuoles than chloroquine-sen-sitive parasites. 3-Hydroxylpyridin-4-ones are known to chelate iron; hydroxypyridone-chloroquine (HPO-CQ) hybrids were synthesized in order to determine whether they can inhibit parasites proliferation in the parasitic digestive vacuole by withholding iron from plasmodial parasite metabolic pathway.Methods: Two HPO-CQ hybrids were tested against Plasmodium falciparum chloroquine-sensitive (D10 and 3D7) and -resistant strains (Dd2 and K1). The pharmacokinetic properties of active compounds were determined using a mouse model and blood samples were collected at different time intervals and analysed using LC–MS/MS. For in vivo efficacy the mice were infected with Plasmodium berghei in a 4-day Peters' test. The parasitaemia was determined from day 3 and the course of the infection was followed by microscopic examination of stained blood films every 2–3 days until a rise in parasitaemia was observed in all test subjects.Results: IC50 values of the two compounds for sensitive and resistant strains were 0.064 and 0.047 µM (compound