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D Jovanovic

Publications and source records attributed to D Jovanovic.

At least 19 recordsLinked to original sources
PubMed2006

Interferon alpha sensitisation induced fatal renal insufficiency in a patient with chronic myeloid leukaemia: case report and review of literature.

Renal dysfunction as a sequel to extended interferon alfa (IFNalpha) treatment in chronic myeloid leukaemia (CML) has been reported previously in six patients. An additional patient is presented with Philadelphia chromosome positive (Ph+) CML and nephrotic syndrome in whom initial renal insufficiency developed after only one month of low dose IFNalpha therapy. The renal biopsy showed a focal segmental mononuclear cell infiltration, basal membrane thickening, and deposits of immunoglobulins (IgG; IgAGM IC3). In spite of discontinuation of IFNalpha, renal function deteriorated and the patient died six months later. This case represents an instance of fatal kidney insufficiency as an untoward effect of sensitisation to the IFNalpha, confirmed by modified Coombs assay.

Acute Kidney Injury↗
PubMed2006

Salvage rectal surgery--overview.

Recurrence of the disease represents the major problem in patients who undergo "curative" resection for rectal cancer, with published rate ranging from 3 to 50%. Most relapses occur within first two years of follow-up. Depending on the site of the recurrence, it can be local or distant. It also can be solitary or diffuse. In terms of potential surgical cure the best results are achieved with solitary, localized metastases. The most common sites of the solitary metastases are pelvis, liver and lung, with a fairly even distribution among these three sites. Other sites of the localized metastases can be peritoneum, lymph nodes, brain, bone, abdominal wall, ureter and kidney. These sites are less common, but not so amenable to resection. Local recurrence varies depending on the original type of surgery. It can be stated that surgical technique directly influences local recurrence rate in patients with rectal cancer. According to the results from a number of different authors 5-year survival rate after reresection is 2-13% of all patients with locally recurrent cancer, both alone and associated with distant metastases. The most important moment in this problem is to decide when not to operate. The absolute contraindications for salvage surgery are: "frozen pelvis", aneuploid tumors and those with mucinous component, clinical or CT evidence of invasion of the pelvic nerves, lymphatics or veins, or ureter bilaterally. Also, evidence of involvement of the lateral pelvic sidewalls and/or upper sacral marrow, and/or S2 is an absolute contraindication for surgery. Thus, main goals of this type of surgery are respectively: palliation of symptoms, a good quality of life and, if possible, cure with low treatment-related complication rates.

Humans↗
PubMed2005

Comparison of liquid chromatography with fluorescence detection to liquid chromatography-mass spectrometry for the determination of fluoxetine and norfluoxetine in human plasma.

A comparison study on fluoxetine (FL) and norfluoxetine (NORFL) quantitation in human plasma was carried out between the recently developed liquid chromatographic method with fluorescence detection (LC-FLD) and an earlier established liquid chromatography-mass spectrometry (LC-MS) laboratory procedure. Comparative method evaluation was based on the analysis of plasma samples obtained from Parkinsonian patients receiving 20mg of FL per day. The LC-FLD method involves a two-step liquid extraction procedure without any derivatization, followed by direct chromatography on a Zorbax C8 reversed-phase column. The analytical results are discussed in terms of the method validation and the corresponding experimental protocol (r>/=0.998; CV<9%; LOQ 20 microg/l). There was good correlation between FL, as well as NORFL, plasma levels as determined by the LC-MS and LC-FLD techniques (r=0.9597, N=16 and r=0.9852, N=14 for FL and NORFL, respectively). The results confirm that direct FL/NORFL fluorimetric determination is acceptable for routine use in pharmacokinetic and clinical studies.

Calibration↗
PubMed2005

Comparative survival analysis of urea kinetic based indices.

BACKGROUND: Although urea kinetic modeling indices for measuring dialysis dose are recommended by world expert groups, it is not quite clear whether some of these are superior in predicting the outcome over others. This prospective, single-center study was carried out with the aim to compare predictive value of different indices and methods of measuring dialysis dose. METHODS: The analysis included 93 anuric patients having been on hemodialysis for at least 2 years who were followed-up for 75-months. The dialysis dose was measured by Kt/V (formal UKM, 3 and 2 urea samples), Kt/V (Daugirdas), Kt/V (Lowrie), eKt/V (Daugirdas), URR and TAC urea. RESULTS: Correlations between dialysis indices and survival time were significant for all indices (p<0.01) except for TAC. All indices, except for TAC urea, were significant predictors of mortality (multivariate Cox regression analysis; p<0.01) and differences of significant levels among these colinear parameters were small. CONCLUSION: All examined indices except for TAC urea were highly predictive of patient mortality. Daugirdas and Lowrie simplified Kt/V indices are as predictive of all-cause mortality as more complex formal UKM methods in long-term patients on a 3x4h/week schedule.

Adult↗
PubMed2005

Influence of carvedilol on chronic renal failure progression in spontaneously hypertensive rats with adriamycin nephropathy.

BACKGROUND: In this study, the effects of carvedilol, antihypertensive (alpha-beta blocker) agent with antiproliferative and antioxidative properties, on slowing down of chronic renal failure (CRF) progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy were examined. METHODS: Eighty adult (24 weeks) SHR were divided into four groups: CONTROL GROUP: 20 SHR; ADR group: 20 SHR treated with ADR (2 mg/kg i.v. twice in 20 days); ADR-C group: 20 SHR treated with ADR and with carvedilol (30 mg/kg/day); ADR-CC group: 20 SHR treated with carvedilol and captopril (60 mg/kg/day). Systolic blood pressure was measured every two weeks, renal blood flow (RBF), mean arterial pressure (MAP) and renal vascular resistance (RVR) were determined at Weeks 6 and 12, creatinine clearance and proteinuria at Weeks -3 (see measurements), 6 and 12. The rats were sacrificed at Weeks 6 and 12 after the second ADR injection. Glomerular sclerosis, tubulointerstitial and blood vessel changes were determined by semiquantitative scoring. RESULTS: Carvedilol decreased systolic blood pressure. It decreased RVR and MAP, and increased RBF significantly. Carvedilol also significantly decreased interstitial infiltration in the early phase of the study, slowed down the development of interstitial fibrosis and tubular atrophy and decreased blood vessel changes. The hemodynamic and morphological effects of carvedilol were associated with slowing down the CRF progression as well as a mild decrease in proteinuria. Captopril addition to carvedilol improved its effects especially on prevention of tubulointerstitial changes. CONCLUSIONS: Results of this experimental study showed beneficial effect of carvedilol and its combination with captopril on CRF progression, indicating that clinical studies are warranted.

Animals↗
PubMed2004

First thousand rectal cancer cases--local recurrence and survival.

In the period 1990 - 2002, 1674 patients with colorectal carcinoma were operated in the First Surgical Clinic, Third Department for Colorectal Surgery. In 1264 cases (75.5%) rectal carcinoma was the indication for surgical treatment. Sphincter saving procedures (SSP) were performed in 824 (65.2%), abdominoperineal resections (APR) in 340 (26.9%) and resections of rectum with definitive stoma (Hartmann procedure) in 100 (7.9%) patients. We analyzed 1095 cases where curative SSP or APR were performed. All cases where curative resection was not possible because of liver metastases or inability to excise all macroscopic disease were excluded. In the group of patients where SSP was performed (767 cases), there were 26.6% high colorectal anastomoses (8cm from anal verge), 65.4% with low (4-8cm from anal verge) and 8.0% with intersphincteric coloanal anastomosis (cm from anal verge). Patohistological exam showed 5.3% Dukes A, 53.1% Dukes B, 36.5% Dukes C and 4.9% Dukes D. In the APR group (328 cases) there were 1.,5% Dukes A, 32.4% Dukes B, 62.1% Dukes C and 3.5% Dukes D. In this study we analyzed local recurrence and five-year survival in both groups. Recurrence of the disease was registered in 325 (29.6%) out of 1095 patients. Local recurrence was found in 81 (7.,4%) patients. In the SSP group recurrence occured in 215 (28.0%) out of 767 curative resections. Local recurrence alone was found in 53 patients (6.9%). SSP group was also divided into two subgroups; in the first group TME was performed and in second transection of mesorectum was carried out. Analyzing local recurrence in these two groups, in the TME group it was 7.6% and in the transection group 5.6%. In the APR group recurrence was registered in 110 (33.5%) out of 328 patients while local recurrence alone was found in 28 (8.5%) cases. Analyzing mortality we found that 234 (21.4%) out of 1095 patients died during follow-up. In the SSP group 154 out of 767 patients (20.1%) died. In the TME group mortality was 21.7% and in the transection group 16.9%. Mortality in the APR group showed that 80 out of 328 (24.4%) patients died during follow-up. Analysis by the Kaplan-Meier's test shows cumulative survival of 0.69 for all cases. In the SSP group cumulative survival is 0.72 and in the APR group 0.64 with statistically significant difference (p .001). In the TME group cumulative survival is 0.75 and in the transection group 0.,72 with statistically significant difference (p .05). We believe that performing SSP should be encouraged whenever it is possible because there is no difference in local recurrence rates and survival compared to APR. Transection of mesorectum can safely be performed in most cases with tumors located more than 8 cm form anal verge. We believe that exact preoperative staging and preoperative radiotherapy could improve results.

Adolescent↗
PubMed2001

Effects of atropine, trimedoxime and methylprednisolone on the development of organophosphate-induced delayed polyneuropathy in the hen.

In this study we have examined the effects of atropine, trimedoxime (TMB-4) and methylprednisolone (MP) on the development of organophosphate-induced delayed polyneuropathy (OPIDP) in the hen. The birds were treated with standard neuropathic dose of diisopropylfluorophosphate (DFP) (1.1 mg/kg, sc), which produced OPIDP that could be graded as 5 on the 8-point scale, and the development of OPIDP was observed for the next 22 days. The results obtained have shown that atropine (20 mg/kg, ip), TMB-4 (15 mg/kg, im) and MP (2 or 10 mg/kg, ip) either alone or in different combinations are able to improve the condition of the birds. The most potent effect was obtained with atropine, TMB-4 (given 20 min before DFP) and MP (2 mg/kg, sc, given 20 min before and at 48 hour intrevals after poisoning) since the signs of OPIDP could hardly be seen (grade 1 at the 8-point scale). When TMB-4 and MP were given 15 or 40 min after DFP the protective/therapeutic effects of these drugs appeared to be diminished since walking disorders were more serious and graded as 2 or 4, respectively. The possible mechanisms of the action of the drugs in respect to OPIDP are discussed. In conclusion, the results of this study have shown that it is possible to prevent the development of DFP-induced OPIDP in the hen by treatment with atropine, trimedoxime and methylprednisolone when they were given before or soon after DFP.

Animals↗
PubMed2000

Nonlinear model for coherent electric field structures in the magnetosphere

A new pseudo-three-dimensional electron hole in a magnetized plasma is possible when the low-frequency ion dynamics is taken into account. The newly found nonlinear Bernstein-Greene-Kruskal stationary solution, whose parallel phase velocity ranges between almost zero and the electron thermal speed, has the form of a cylinder that is tilted relative to the magnetic field. These structures are interpreted as three-dimensional electron holes coupled with hydrodynamic vortices, and provide a possible theoretical explanation for the POLAR and FAST satellite observations of coherent structures characterized by bipolar spikes of the parallel electric field and large perpendicular ion kinetic energies.

Journal Article↗
PubMed2000

Kinetic vortex chain solution in the drift-wave plasma regime

A fully nonlinear Bernstein-Greene-Kruskal stationary solution is found in the form of a quasi-three-dimensional chain of electron holes coupled to hydrodynamic vortices. This new coherent structure is enabled by the trapping and depletion of resonant particles, and the cyclotron dissipation of the singular current sheets. It is expected to play an important role in the collisionless magnetic field line reconnection in the drift-wave plasma regime, where it represents a plausible saturated state.

Journal Article↗
PubMed2000

Vortices in relativistic electron beams

We demonstrate that a relativistic electron beam is properly described in the moving frame by the electron-magnetohydrodynamic equations of plasma physics. For large beam currents, the accelerator magnetic field is expected to be unstable to the fast magnetic reconnection. We present a plausible saturated state of the fast reconnection, in the form of a complex vortex pattern. The nonlinear dispersion equations of the vortex are derived and the relationship between the vortex structure and the background magnetic field is discussed.

Journal Article↗
PubMed1999

Mitogen-activated protein kinase and nuclear factor kappaB together regulate interleukin-17-induced nitric oxide production in human osteoarthritic chondrocytes: possible role of transactivating factor mitogen-activated protein kinase-activated proten kinase (MAPKAPK).

OBJECTIVE: To explore the signaling pathways by which the proinflammatory cytokine interleukin-17 (IL-17) may contribute to cartilage catabolism in osteoarthritis (OA) by inducing inducible nitric oxide synthase (iNOS) expression in chondrocytes. METHODS: We examined the IL-17-induced NO production in human OA chondrocytes, in combination with the proinflammatory cytokines IL-1beta, tumor necrosis factor alpha (TNF alpha), and leukemia inhibitory factor (LIF); the antiinflammatory cytokines IL-4, IL-10, and IL-13; and IL-1 receptor antagonist (IL-1Ra). Further, we explored the major intracellular signaling pathways through which IL-17 induced iNOS expression and NO production. RESULTS: Treatment with IL-17 induced a dose-dependent increase in the level of NO. When IL-17 was combined with the above factors, it resulted in a synergistic effect with TNF alpha, an additive effect with LIF, and no further effect than when used alone with IL-1beta. IL-4, IL-10, IL-13, and IL-1Ra had no true effect on IL-17-induced NO production. The cAMP mimetics, 3-isobutyl-1-methyl xanthine plus forskolin, completely blocked IL-17-induced NO production. KT-5720, genistein, and Calphostin C, inhibitors of protein kinase A (PKA), tyrosine kinase, and protein kinase C, respectively, reduced the IL-17-induced NO production by 72%, 56%, and 42%, respectively. Within minutes, IL-17 induced the phosphorylation of mitogen-activated protein kinase kinase-1/2 (MEK-1/2), -3/6 (MKK-3/6), p44/42, p38, and inhibitor of nuclear factor kappaB (I kappaB)-alpha, as well as the activation of mitogen-activated protein kinase-activated protein kinase-1 and -2 (MAPKAPK-1 and -2). Interestingly, IL-17 induced phosphorylation of the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) (p54/46) only when PKA was inhibited. Specific protein kinase inhibitors for MEK-1/2 (PD98059), p38 (SB202190), and nuclear factor kappaB (NF-kappaB) (pyrrolidine dithiocarbamate) each markedly decreased the IL-17-increased iNOS level and NO production. Inhibiting MAPK, including MEK-1/2 and p38, had no effect on the IL-17-induced activation of IkappaB-alpha, but reversed the IL-17 activation of MAPKAPK-1 and -2, respectively. CONCLUSION: These findings show that the stimulation of NO production by IL-17 is mediated mainly by a complex activation of kinases, especially PKA, NF-kappaB, and MAPK. NF-kappaB appears to require MAPK activation, with downstream activation of MAPKAPK probably acting as a transactivating factor, to induce iNOS expression.

Aged↗
PubMed1999

Reduction in the structural changes of experimental osteoarthritis by a nitric oxide inhibitor.

OBJECTIVE: To evaluate the in-vivo therapeutic efficacy of N -iminoethyl-L-Lysine (L-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS) in a dose response study, on the progression of lesions in the experimental osteoarthritic (OA) dog model. DESIGN: The sectioning of the anterior cruciate ligament of the right stifle joint of mongrel dogs was done by a stab wound. Dogs were separated into experimental groups: Group 1 received no treatment, Groups 2, 3, and 4 received oral L-NIL (0.3, 1 or 10mg/kg/day, respectively) starting immediately after surgery. The OA dogs were killed at 12 weeks after surgery. RESULTS: Macroscopically, L-NIL decreased the size of the cartilage lesions on condyles and plateaus. The histologic severity of the cartilage lesions was decreased in the L-NIL-treated dogs. This effect was more pronounced at the highest dosage tested (3 and 10mg/kg/day). CONCLUSIONS: This study confirms the effectiveness of L-NIL, a selective inhibitor of iNOS, in attenuating the progression of experimental OA. It also clearly shows that the effect is dose-dependent.

Animals↗
PubMed1999

Selective inhibition of inducible nitric oxide synthase in experimental osteoarthritis is associated with reduction in tissue levels of catabolic factors.

OBJECTIVE: We used the experimental dog model of osteoarthritis (OA) to examine the in vivo effects of N-iminoethyl-L-lysine (L-NIL), a selective inhibitor of the inducible nitric oxide synthase (iNOS), on the tissue level and distribution of interleukin-1beta (IL-1beta), collagenase-1, stromelysin-1, cyclooxygenase-2 (COX-2), iNOS and nitrotyrosine, through immunohistochemical and morphometric analysis. METHODS: Cartilage and synovial membrane specimens were obtained from 3 experimental groups of dogs: Group I--unoperated dogs that received no treatment; Group II--dogs subjected to a sectioning of the anterior cruciate ligament of the right knee and given no treatment; and Group III--operated dogs that received oral treatment with L-NIL (10 mg/kg twice daily/po) for 10 weeks starting immediately after surgery. The operated dogs were killed 10 weeks post-surgery. The tissue distributions of IL-1beta, metalloproteases (MMP), COX-2, iNOS and nitrotyrosine were documented by immunohistochemistry using specific antibodies, and quantified by morphometric analysis. RESULTS: In cartilage, the cell scores (percentage of chondrocytes staining positive for the antigen) for iNOS and 3-nitrotyrosine were dramatically enhanced in OA specimens compared to normal (p < 0.0001). However, the cartilage of dogs treated with L-NIL showed significantly lower cell scores for iNOS (p<0.0001, condyle; p<0.001, plateau), nitrotyrosine (p<0.0004; p<0.0001) and COX-2 (p<0.0001; p<0.001) compared to that of untreated OA dogs. Similar findings were observed for collagenase-1 and stromelysin-1, where the increased cell scores of these 2 MMP in OA cartilage were reduced after treatment with L-NIL (collagenase: p<0.002, condyle; p<0.0003, plateau; stromelysin: p<0.006; p<0.0001). The increased cell scores for the IL-1beta, COX-2, iNOS and nitrotyrosine found in the synovial lining and mononuclear cell infiltrate of operated animals were also found to be markedly reduced in dogs treated with L-NIL. CONCLUSION: Our study demonstrates for the first time in vivo in an experimental model of OA, that a selective inhibition of iNOS by L-NIL and the subsequent decreased production of NO also results in a marked decrease in production of major catabolic factors such as MMP, IL-1beta and peroxynitrite, as well as a reduction in COX-2 expression.

Animals↗
PubMed1998

Reduced progression of experimental osteoarthritis in vivo by selective inhibition of inducible nitric oxide synthase.

OBJECTIVE: To evaluate the in vivo therapeutic efficacy of N-iminoethyl-L-lysine (L-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS), on the progression of lesions in an experimental osteoarthritis (OA) dog model. The effect of L-NIL on metalloprotease activity, levels of interleukin-1beta (IL-1beta), prostaglandin E2 (PGE2), and nitrite/nitrate in synovial fluid was determined. METHODS: The OA model was created by sectioning the anterior cruciate ligament of the right stifle joint of mongrel dogs by a stab wound. Dogs were separated into experimental groups: Group 1 was made up of unoperated dogs that received no treatment, group 2 were operated dogs with no treatment, and group 3 were operated dogs that received oral L-NIL (10 mg/kg/twice daily) starting immediately after surgery. The OA dogs were killed at 10 weeks after surgery. RESULTS: Experiments showed that dog OA cartilage explants in culture produced an increased amount of NO (nitrite). Immunohistochemical study demonstrated that this was due to an increased level of iNOS in chondrocytes. OA dogs treated with L-NIL showed a reduction in the incidence of osteophytes compared with the untreated OA dogs (58% versus 92%) as well as in their size (mean +/- SEM 1.92 +/- 0.58 mm versus 5.08 +/- 0.66 mm). Macroscopically, L-NIL decreased the size of the cartilage lesions by approximately 50% both on condyles and plateaus. The histologic severity of both the cartilage lesions and synovial inflammation was significantly decreased in the L-NIL-treated dogs. Treatment with L-NIL also significantly decreased both collagenase and general metalloprotease activity in the cartilage and the levels of IL-1beta, PGE2, and nitrite/nitrate in synovial fluid. CONCLUSION: This study demonstrated the effectiveness of a selective inhibitor of iNOS, L-NIL, in attenuating the progression of experimental OA. The data suggest that L-NIL may act by reducing the activity of metalloproteases in cartilage and the production of IL-1beta by synovium, both of which are known to play a major role in the pathophysiology of OA structural changes.

Animals↗
PubMed1998

Effect of IL-13 on cytokines, cytokine receptors and inhibitors on human osteoarthritis synovium and synovial fibroblasts.

OBJECTIVE: In this study we investigated the effect of interleukin-13 (IL-13), an anti-inflammatory cytokine, for potential therapeutic use in osteoarthritis (OA). DESIGN: We examined the effect of IL-13 on the synthesis and expression of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), IL-1 receptor antagonist (IL-1Ra) and stromelysin-1 on human OA synovial membrane in ex vivo cultures. In addition, we explored the effect of IL-13 on both the IL-1 receptor (IL-1R) and TNF-receptor (TNF-R) systems on OA synovial fibroblasts. This included determination of the levels of IL-1 beta and TNF-alpha receptor binding, IL-1Ra and TNF-soluble receptors 55 and 75 (TNF-sR55 and TNF-sR75). RESULTS: In OA synovial membrane treated with LPS, IL-13 inhibited the synthesis of IL-1 beta, TNF-alpha and stromelysin-1, but increased IL-1Ra production. In addition, IL-13 reduced the level of IL-1 beta mRNA and stimulated the level of IL-1Ra mRNA. In synovial fibroblasts, IL-13 decreased the level of IL-1 binding, an effect related to the increased production of IL-1Ra. Although IL-13 had no effect on the TNF-R level, this cytokine markedly decreased the shedding of TNF-R75. CONCLUSION: These experiments suggest that IL-13 is potentially useful in the therapeutic treatment of OA, as it could regulate the major pathological process of this disease by reducing the production of proinflammatory cytokines and metalloproteases, and favoring the production of IL-1Ra.

Aged↗
PubMed1998

Effects of captopril on morphologic changes in kidney of spontaneously hypertensive rats with adriamycin nephropathy.

Antihypertensive therapy has been shown to slow down the progression of chronic renal failure. Angiotensin converting enzyme inhibitors and calcium antagonists have been emphasized as the agents with the most protective effect. Our previous study showed that captopril slowed down renal function deterioration in the early course of adriamycin (ADR) nephropathy in spontaneously hypertensive rats (SHR). The present study was undertaken with the aim to examine morphologic changes associated with that slower renal function deterioration. Adult (24 weeks) female SHR were randomly divided into the following groups: the control group (n = 12) was given tap water to drink; the adriamycin (ADR) group (n = 25) was treated with ADR; the ADR-captopril (ADR-C) group (n = 27) was treated with ADR and thereafter with captopril (60 mg/kg/day). Rats were sacrificed at weeks 6, 12 and 18 and histologic analysis was semiquantitatively performed. In the control group the glomeruli exhibited only minor changes at the end of the study. In the ADR group slight glomerular mesangial hypercellularity appeared in the sixth week and progressed in focal and segmental sclerosis. Some glomeruli showed segmental proliferation and increased fibrular matrix of a tuft adherent to a fibrocellular crescents. In the ADR-C group, glomeruli with a slight increase of mesangial matrix were seen at the end of the sixth week, mesangial hypercellularity developed until the end of the sixth week, mesangial hypercellularity developed until the end of the 12th week and segmental glomerulosclerosis until the end of the study. Semiquantitative analysis revealed that the mean semiquantitative scores for mesangial expansion and glomerular sclerosis were significantly lower in ADR-C group than in ADR group throughout the study. We concluded that captopril slowed down mesangial expansion and reduced the development of glomerular sclerosis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

The effects of tenidap on canine experimental osteoarthritis: II. Study of the expression of collagenase-1 and interleukin 1beta by in situ hybridization.

OBJECTIVE: To examine the effect of tenidap on the expression of collagenase- and interleukin 1beta (IL-1beta) genes in experimental canine osteoarthritis (OA). METHODS: The anterior cruciate ligaments of the right stifle joints of experimental dogs were sectioned by a stab wound incision and tissues samples were taken. Four dogs had received no treatment, 4 were treated with oral omeprazole (20 mg/day), and another 4 were treated with tenidap (3 mg/kg/bid) and omeprazole (20 mg/day). The dogs received medication for 8 weeks; all dogs were sacrificed at the end of this period. Tissues from 4 healthy dogs were used as controls. IL-1beta and collagenase-1 gene expression were measured in synovial membrane (synovial lining cells and mononuclear cell infiltrate) and collagenase-1 expression in cartilage using in situ hybridization techniques. Results were calculated as the percentage of cells expressing the gene, and expressed as cell score. RESULTS: The collagenase-1 cell score in the full thickness samples was significantly higher in OA cartilage than in normal cartilage, both in condyles and plateaus (p < 0.0002). Tenidap treated dogs showed a significantly lower cell score in femoral condyles and tibial plateaus in the superficial (p < 0.0002), deep (p < 0.005, p < 0.002, respectively), and full thickness (p < 0.0002) layers compared to OA dogs. No staining for collagenase-1 was observed in normal membrane. In OA synovial membrane, the collagenase-1 cell score was high in both the synovial lining cells and mononuclear cell infiltrate. Tenidap treated dogs showed a significantly lower score compared to OA tissue in both the synovial lining cells (p < 0.03) and the mononuclear cell infiltrate (p < 0.03). The relative decrease in the collagenase-1 cell score in the tenidap treated dogs was more pronounced in the mononuclear cell infiltrate. Staining for IL-1beta was observed in only a few lining cells in normal synovial membrane from unoperated dogs. In OA synovial membrane from untreated dogs, staining for IL-1beta was intense and was found in all dog specimens. The cell score was significantly higher in OA lining cells (p < 0.03) and mononuclear cell infiltrate (p < 0.03) compared to normal. In tenidap treated dogs, the score for IL-1beta was significantly lower than in OA, both in synovial lining cells (p < 0.03) and mononuclear cell infiltrate (p < 0.03). CONCLUSION: Tenidap significantly reduced in vivo expression of collagenase-1 and IL-1beta in experimental OA. These data are an extension of our previous study and showed that tenidap exerts its protective effects on OA lesions, likely by reducing the catabolic pathways of the disease.

Animals↗