Development and evaluating the biopotency of ready to eat liver meat balls in fighting anaemia and vitamin A deficiency, improving selected nutritional biochemical indicators and promoting the cognitive function among mildly anaemic Egyptian children aged 3-9 years.

OBJECTIVE: Ready to eat fried liver meat balls (LMB) were developed to fight anaemia and vitamin A deficiency and promote cognitive function. DESIGN: Randomised controlled trial consisting of two arms: control group with no supplement and LMB group receiving LMB supplement three times a week for 90 d. Criteria of evaluations included dietary assessment, anthropometric measurements, laboratory investigations and cognitive function by Wechsler test. SETTING: Kinder Garten and primary school in Urban Giza. PARTICIPANTS: Sixty boys and girls aging 3-9 years. RESULTS: The LMB supplement contributed to significant increases in the intakes of high bioavailable Fe and vitamin A in the diets of all children. Initial overall prevalence of mild and moderate anaemia was 43 %, which disappeared completely from all children aging < 72 months and from 88 % of children ≥ 72 months after the 90 d dietary intervention with the LMB. Faecal systemic immune globulin A, urinary hydroxyproline index and urinary iodine excretion increased significantly (P < 0·05) only after the dietary intervention with the LMB supplement for 90 d. The standard scores of verbal and non-verbal cognitive function tests (Δ day 90-day 0) increased significantly (P < 0·05) among the LMB group compared with the respective changes observed among the control group. The increase in height-for-age Z score and blood Hb were good predictors for improvement in cognitive function. CONCLUSION: LMB supplement is effective sustainable nutritious biotherapeutic food in fighting hidden hunger and promoting the cognitive function.

Pirfenidone ameliorates pulmonary inflammation and fibrosis in a rat silicosis model by inhibiting macrophage polarization and JAK2/STAT3 signaling pathways.

Macrophages play an important role in causing silicosis eventually becoming an irreversible fibrotic disease, and there are no specific drugs for silicosis in the clinic so far. Pirfenidone has consistently been shown to have anti-inflammatory and anti-fibrotic effects, but the specific mechanism by which it ameliorates fibrosis in silicosis is unclear. A rat silicosis model was established in this study, and lung tissues and serum were collected by batch execution at 14, 28, and 56 days. Also, the effects of Pirfenidone on macrophage polarization and pulmonary fibrosis were evaluated in silicosis with early intervention and late treatment by histological examination, Enzyme-linked immunosorbent assay, Hydroxyproline assay, Western blot and Quantitative reverse transcription polymerase chain reaction. The results showed that Pirfenidone significantly reduced pulmonary fibrosis in rats with silicosis, and both early intervention and late treatment effectively inhibited the expression of α-SMA, Col-I, Vimentin, Hydroxyproline, IL-1ß, IL-18, and the M2 macrophage marker CD206 and Arg-1, while only early intervention effectively inhibited E-cad, TGF-ß1, TNF-α, and the M1 macrophage marker iNOS, CD86. Furthermore, Pirfenidone dramatically reduced the mRNA expression of the JAK2/STAT3. These findings imply that Pirfenidone may reduce pulmonary fibrosis in silicosis rats by inhibiting macrophage polarization via the JAK2/STAT3 signaling pathway.

FcεRI deficiency alleviates silica-induced pulmonary inflammation and fibrosis.

Silicosis is one of the most important occupational diseases worldwide, caused by inhalation of silica particles or free crystalline silicon dioxide. As a disease with high mortality, it has no effective treatment and new therapeutic targets are urgently needed. Recent studies have identified FCER1A, encoding α-subunit of the immunoglobulin E (IgE) receptor FcεRI, as a candidate gene involved in the biological pathways leading to respiratory symptoms. FcεRI is known to be important in allergic asthma, but its role in silicosis remains unclear. In this study, serum IgE concentrations and FcεRI expression were assessed in pneumoconiosis patients and silica-exposed mice. The role of FcεRI was explored in a silica-induced mouse model using wild-type and FcεRI-deficient mice. The results showed that serum IgE concentrations were significantly elevated in both pneumoconiosis patients and mice exposed to silica compared with controls. The mRNA and protein expression of FcεRI were also significantly increased in the lung tissue of patients and silica-exposed mice. FcεRI deficiency significantly attenuated the changes in lung function caused by silica exposure. Silica-induced elevations of IL-1ß, IL-6, and TNF-α were significantly attenuated in the lung tissue and bronchoalveolar lavage fluid (BALF) of FcεRI-deficient mice compared with wild-type controls. Additionally, FcεRI-deficient mice showed a significantly lower score of pulmonary fibrosis than wild-type mice following exposure to silica, with significantly lower hydroxyproline content and expression of fibrotic genes Col1a1 and Fn1. Immunofluorescent staining suggested FcεRI mainly on mast cells. Mast cell degranulation took place after silica exposure, as shown by increased serum histamine levels and ß-hexosaminidase activity, which were significantly reduced in FcεRI-deficient mice compared with wild-type controls. Together, these data showed that FcεRI deficiency had a significant protective effect against silica-induced pulmonary inflammation and fibrosis. Our findings provide new insights into the pathophysiological mechanisms of silica-induced pulmonary fibrosis and a potential target for the treatment of silicosis.

ß-Carotene inhibits NF-κB and restrains diethylnitrosamine-induced hepatic inflammation in Wistar rats.

ß-Carotene exhibits antioxidant and hepatoprotective activities via a multitude of biochemical mechanisms. However, the action mechanism involved in antioxidant and anti-inflammatory effects of this carotene in chronic liver diseases is not fully understood. In the present investigation, we have attempted to outline a plausible mechanism of ß-carotene action against liver fibrosis in albino Wistar rats. To induce hepatic fibrosis, diethylnitrosamine (DEN) was administered in experimental rats for two weeks. DEN treated rats were divided into four groups, wherein each group comprised of five rats. ß-Carotene supplement attenuated DEN-induced elevation in LFT markers (P < 0.05); averted depletion of glycogen (24%, P < 0.05) and, increased nitrite (P < 0.05), hydroxyproline (~67%, P < 0.05) and collagen levels (~65%, P < 0.05). Confocal microscopy of tissue sections stained with picrosirius red revealed accrued collagen in DEN-administered group, which was found to be reduced by ß-carotene supplementation. Furthermore, ß-carotene decreased the expression of iNOS/NOS-2 and NF-κB, as revealed by immunohistochemistry and Western immunoblotting. Collectively, these results demonstrate that ß-carotene mitigates experimental liver fibrosis via inhibition of iNOS and NF-κB in-vivo. Thus, ß-carotene may be suggested as a possible nutraceutical to curb experimental liver fibrosis.

Efficacy of Hydroxy-L-proline (HYP) analogs in the treatment of primary hyperoxaluria in Drosophila Melanogaster.

BACKGROUND: Substrate reduction therapy with analogs reduces the accumulation of substrates by inhibiting the metabolic pathways involved in their biosynthesis, providing new treatment options for patients with primary hyperoxalurias (PHs) that often progress to end-stage renal disease (ESRD). This research aims to evaluate the inhibition efficacy of Hydroxy-L-proline (HYP) analogs against calcium oxalate (CaOx) crystal formation in the Drosophila Melanogaster (D. Melanogaster) by comparing them with Pyridoxine (Vitamin B6). METHODS: Three stocks of Drosophila Melanogaster (W118, CG3926 RNAi, and Act5C-GAL4/CyO) were utilized. Two stocks (CG3926 RNAi and Act5C-GAL4 /CyO) were crossed to generate the Act5C > dAGXT RNAi recombinant line (F1 generation) of D. Melanogaster which was used to compare the efficacy of Hydroxy-L-proline (HYP) analogs inhibiting CaOx crystal formation with Vitamin B6 as the traditional therapy for primary hyperoxaluria. RESULTS: Nephrolithiasis model was successfully constructed by downregulating the function of the dAGXT gene in D. Melanogaster (P-Value = 0.0045). Furthermore, the efficacy of Hydroxy-L-proline (HYP) analogs against CaOx crystal formation was demonstrated in vivo using D. Melanogaster model; the results showed that these L-Proline analogs were better in inhibiting stone formation at very low concentrations than Vitamin B6 (IC50 = 0.6 and 1.8% for standard and dietary salt growth medium respectively) compared to N-acetyl-L-Hydroxyproline (IC50 = 0.1% for both standard and dietary salt growth medium) and Baclofen (IC50 = 0.06 and 0.1% for standard and dietary salt growth medium respectively). Analysis of variance (ANOVA) also showed that Hydroxy-L-proline (HYP) analogs were better alternatives for CaOx inhibition at very low concentration especially when both genetics and environmental factors are intertwined (p < 0.0008) for the dietary salt growth medium and (P < 0.063) for standard growth medium. CONCLUSION: Addition of Hydroxy-L-Proline analogs to growth medium resulted in the reduction of CaOx crystals formation. These analogs show promise as potential inhibitors for oxalate reduction in Primary Hyperoxaluria.

Ganoderma modulates allergic asthma pathologic features via anti-inflammatory effects.

Ganoderma, a fungal genus, is a traditional medicine with immuno-modulating effects. Asthma is an inflammatory disease of airways, and the main trigger of asthma is allergic inflammation. In this study, the effects of Ganoderma (an anti-inflammatory agent) given via oral administration (G/O) or intraperitoneal injection (G/IP) on asthma was evaluated. Forty BALB/c mice were divided into four groups, including the control, OVA-challenge, OVA-challenge + G/O, and OVA-challenge + G/IP. To determine AHR, the MCh challenge test was done. The levels of IL-1ß, -4, -5, -6, -8, -10, -12, -13, -17, -25, -33, -38, Cys-LT, LTB4, and hydroxyproline were measured. Finally, lung histopathology was evaluated to determine eosinophilic inflammation, goblet cell hyperplasia, and mucus hyper-secretion. Treatment with G/O and G/IP could significantly reduce the levels of IL-1ß, -5, -6, -8, -17, -25, -33, and -38; the levels of IL-4 and IL-13 had no significant changes, but the levels of IL-10 and IL-12 were enhanced. The mice treated with G/O and G/IP showed decreased levels of Cys-LT, LTB4, peribronchial and perivascular inflammation, but no significant changes were observed in AHR, hydroxyproline level, goblet cell hyperplasia, and mucus hyper-secretion. Ganoderma can be applied as an immunomodulatory and anti-inflammatory agent for managing asthma.

[Hydroxynitone suppresses hepatic stellate cell activation by inhibiting TGF-ß1 phosphorylation to alleviate CCl4-induced liver fibrosis in rats].

OBJECTIVE: To investigate the effect of hydronidone on CCl4-induced liver fibrosis in rats and explore the possible mechanism. METHODS: Sixty-six male SD rats were randomized into 5 groups, including a control group (n=10), a liver fibrosis model group (n=20), 2 hydronidone dose groups (100 and 250 mg/kg; n=12), and a pirfenidone (250 mg/kg) treatment group (n= 12). Rat models of liver fibrosis were established by subcutaneous injection of CCl4 in all but the control group. Hydronidone and pirfenidone were given daily at the indicated doses by intragastric administration for 6 weeks. After the treatments, serum samples were collected from the rats for detecting liver function parameters, and hydroxyproline content in the liver tissue was determined. Inflammation and fibrosis in the liver tissue were observed using HE staining and Sirius Red staining. In the cell experiment, human hepatic stellate cell line LX-2 was stimulated with TGF-ß1 and treated with hydronidone or pirfenidone, and the expression levels of α-SMA, collagen type I and phosphorylated Smad3, phosphorylated p38, phosphorylated ERK1/2 and phosphorylated Akt were detected with Western blotting. RESULTS: In the rat models of liver fibrosis, treatment with hydronidone obviously improved the liver functions, reduced the content of hydroxyproline in the liver tissue, and significantly alleviated liver fibrosis (P < 0.05). In LX-2 cells, hydronidone dose-dependently decreased the expression levels of α-SMA and collagen type I. In TGF- ß1-stimulated cells, the phosphorylation levels of Smad3, P38, ERK, and Akt increased progressively with the extension of the treatment time, but this effect was significantly attenuated by treatment with hydronidone (P < 0.05). CONCLUSION: Hydronidone can inhibit the phosphorylation of the proteins in the TGF-ß signaling pathway, thereby preventing TGF-ß1-mediated activation of hepatic stellate cells, which may be a possible mechanism by which hydronidone alleviates CCl4-induced liver fibrosis in rats.

cis-Hydroxyproline-mediated pancreatic carcinoma growth inhibition in mice.

PURPOSE: This study addressed the question of whether the collagen metabolism modulator cis-4-Hydroxy-L-proline (CHP) is applicable for potential use as a therapeutic inhibitor of pancreatic carcinoma cell growth. METHODS: Cell proliferation, as well as quantification of apoptosis of murine Panc02 cells, was assessed after CHP treatment. Supplementary, the effect of CHP on tumor growth was examined in the subcutaneous Panc02 model in vivo. Mice received daily intraperitoneal injections of CHP (300, 400, and 500 mg/kg bw). In addition to the assessment of systemic parameters (blood count, enzyme activities), histology (HE) and immunohistochemistry (Ki-67) were performed from resected tumor specimens. RESULTS: Like reduction of metabolic activity, CHP also induced inhibition of cell growth in a dose-dependent manner, with however only slight increases in apoptosis. In vivo treatment of Panc02 tumors with CHP resulted in pronounced delay of tumor growth and decreases in tumor cell proliferation. Moreover, these effects were accompanied by a massive systemic leukocytosis as well increased leukocyte infiltration into the tumors subsequent to CHP therapy. CONCLUSIONS: CHP inhibits the proliferation of Panc02 tumor cells in a dose-dependent manner both in vitro and in vivo. Our presented data show that modulation of the collagen metabolism is an interesting strategy for treatment of pancreatic carcinoma.

A systematic review and meta-analysis of oxaceprol in the management of osteoarthritis: An evidence from randomized parallel-group controlled trials.

Oxaceprol, a derivative of l-proline, is an established drug for managing osteoarthritis (OA) with better safety profile than non-steroidal anti-inflammatory drugs (NSAIDs). This systematic review and meta-analysis, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, evaluated the efficacy, safety and tolerability of oxaceprol in OA. Electronic databases for published and grey (unpublished) literature were searched to identify parallel-group randomized controlled trials (RCTs) evaluating the impact of oxaceprol in patients with OA. Risk of bias was assessed using the Cochrane collaboration's tool. A total of seven parallel-group RCTs involving 1087 participants were included in the systematic review. Meta-analysis, in Review Manager, demonstrated numerically greater/significant improvements compared to active control [diclofenac/ibuprofen]/placebo in pain and function of joint; similar improvement vs. active control in global treatment efficacy; no difference/significant difference vs. active control/placebo in NSAIDs as rescue medication. Treatment with oxaceprol showed numerically less adverse events (AEs) than active control (diclofenac: risk ratio [RR], 0.71; 95% confidence interval [CI], 0.45 to 1.11; p=0.14: ibuprofen: RR, 0.73; 95% CI, 0.30 to 1.78; p=0.49) and significantly fewer AEs compared to placebo (RR, 0.76; 95% CI, 0.63 to 0.92; p=0.004). Given the nature of small-to-moderate sample size and short duration of eligible studies, the available clinical evidence of oxaceprol in the management of OA is modest - though looks promising. New and better RCTs with larger sample size and longer follow-up are warranted to strengthen the use of oxaceprol in clinical setting for managing OA.

Oxaceprol versus tramadol for knee osteoarthritis: A randomized controlled trial.

OBJECTIVES: To assess efficacy and safety of oxaceprol, a hydroxyproline derivative with putative mechanism of action different from traditional nonsteroidal anti-inflammatory drugs, in symptomatic knee osteoarthritis, in comparison to tramadol. MATERIALS AND METHODS: A parallel group, double-blind, randomized controlled trial was conducted with ambulatory patients over 50 years age suffering from knee osteoarthritis causing pain of at least moderate intensity. Patients were randomized to receive either oxaceprol 200 mg thrice daily or tramadol 50 mg thrice daily for 12 weeks. The primary efficacy variable was symptom relief as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) version 3.1 for pain, stiffness, and physical function. Responder rate (50% pain relief), patient's Clinical Global Impression (CGI), and rescue medication use were other outcomes measured. Vital signs, routine blood counts, tests of hepatorenal function and treatment-emergent adverse events were recorded for safety assessment. RESULTS: From 91 patients recruited, 43 on oxaceprol and 36 on tramadol were evaluable. The WOMAC scores declined significantly from baseline in each arm but remained comparable between groups throughout the 12-week study period. The CGI ratings and 50% responder rates were also comparable at the final visit. Differences in dose up-titration and rescue medication requirements were statistically nonsignificant. So also were the adverse event counts. Compliance was satisfactory in both groups. CONCLUSIONS: Efficacy and tolerability of oxaceprol were comparable to tramadol, and the drug can be considered as an alternative to low-potency opioids in the management of knee osteoarthritis.

Oxaceprol--a randomised, placebo-controlled clinical study in osteoarthritis with a non-conventional non-steroidal anti-inflammatory drug.

OBJECTIVE: To evaluate efficacy of therapy with oxaceprol in the treatment of symptomatic osteoarthritis of knee or hip. METHODS: A 3-week prospective, multicentric, randomised, double-blind, placebo-controlled study with 167 patients aged between 40 and 75 years with painful and radiologically confirmed knee or hip osteoarthritis. Patients were randomly assigned to receive oxaceprol 1200 mg/day or placebo for 3 weeks. At inclusion, osteoarthritis symptoms were minimum pain following exercise (standardised as pain after climbing 12-15 stairs) of 40 to 90 mm on a 100 mm pain scale and difficulties in climbing stairs. Efficacy criteria were changes in pain shown in a visual analogue scale (VAS), in the Lequesne index, and in assessments of joint limitation, joint complaint and therapeutic success. The primary end point was the pain following exercise. The confirmatory analysis was based on the Full Analysis data set using the t-test for independent samples. RESULTS: Baseline characteristics of both groups were comparable. In the primary endpoint a clinically relevant and statistically significant superiority of oxaceprol as compared to placebo could be demonstrated (mean improvement in pain following exercise was 16.6 mm in the oxaceprol and 4.5 mm in the placebo group, p = 0.002). The safety and tolerability was good, showing no statistically significant difference between oxaceprol and placebo. CONCLUSION: A statistically significant and clinically relevant efficacy of oxaceprol was shown. The good safety and tolerability of oxaceprol was confirmed.

Proline analogues inhibit human skin fibroblast growth and collagen production in culture.

Several structural analogues of proline have been shown to be incorporated into proteins in place of proline. As a consequence, the proliferation of cells in culture and the extracellular deposition of collagen in animal systems are reduced. In this study, the effects of two proline analogues, cis-4-hydroxy-L-proline and L-azetidine-2-carboxylic acid, on the growth parameters and procollagen production by cultured normal human skin fibroblasts were examined. The results indicated that incubation of the cells with the analogues reduced the rate of fibroblast proliferation and lowered the plating efficiency. Further experiments demonstrated that fibroblasts in the presence of L-azetidine-2-carboxylic acid synthesized procollagen polypeptides which were not in a triple-helical conformation, as judged by limited pepsin proteolysis. Also, a significantly increased fraction of the newly synthesized collagenous peptides was in a dialyzable form, suggesting increased degradation of the nonhelical chains. The rate of translation of collagenous polypeptides and the preprocollagen messenger RNA activity in the cells were not affected by the analogues. The proline analogues thus appear to inhibit the production of procollagen on the posttranslational level by preventing the polypeptides from folding into a stable triple-helical conformation. The nonhelical polypeptides are then readily susceptible to proteolysis leading to reduced deposition of extracellular collagen fibers. Similar experiments were also performed with fibroblasts cultured from patients with active progressive systemic sclerosis. Quantitatively and qualitatively comparable inhibition of procollagen production by L-azetidine-2-carboxylic acid was noted with scleroderma cells as with control fibroblast cultures. The results suggest, therefore, that proline analogues may, in the future, prove useful in limiting excessive collagen deposition in scleroderma and other forms of dermal fibrosis.

Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor.

A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 was designed using a computer model of the active site of thermolysin. This 10-membered ring lactam represents a general mimic for any hydrophobic dipeptide in which the two amino acid side chains bind to an enzyme in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50 = 3 nM). In order to improve oral bioavailability, various functionality was attached to the macrocycle. These modifications lead to CGS 25155, an orally active NEP 24.11 inhibitor that slows down the degradation of the cardiac hormone atrial natriuretic factor, producing a lowering of blood pressure in the DOCA-salt rat model of hypertension.

Antirheumatic agents and leukocyte recruitment. New light on the mechanism of action of oxaceprol.

Most anti-inflammatory agents used in the treatment of joint diseases exert inhibitory effects on leukocyte infiltration. Methotrexate, a disease-modifying drug, and corticosteroids also inhibit leukocyte accumulation during inflammation. However, the mechanisms of action of these different compounds on leukocytes vary and in the case of non-steroidal anti-inflammatory drugs (NSAIDs) the mechanism(s) may be indirect. No current drug for inflammatory or degenerative joint disease has been proposed to act specifically by an inhibitory action on neutrophilic leukocytes. Oxaceprol is an amino acid derivative that has been used for several years for the treatment of osteoarthritis and rheumatoid arthritis, ameliorating pain and stiffness and showing good gastrointestinal safety, particularly in comparison with NSAIDs. Recent experimental studies have shown that oxaceprol does not inhibit the synthesis of prostaglandins in vitro, but markedly inhibits neutrophil infiltration into the joints of rats with adjuvant arthritis. These results support earlier screening data showing inhibition by oxaceprol of leukocyte infiltration into sites of acute inflammation. In studies on surgical ischemia reperfusion in hamsters in vivo, oxaceprol was an effective inhibitor of leukocyte adhesion and extravasation. It is proposed that oxaceprol represents a therapeutic agent for degenerative and inflammatory joint diseases, which acts predominantly by inhibiting leukocyte adhesion and migration.

An antifibrotic agent reduces blood pressure in established pulmonary hypertension in the rat.

We have shown that administration of the antifibrotic agent cis-4-hydroxy-L-proline (cHyp) to rats at the onset of exposure to hypoxia prevents collagen accumulation in pulmonary arteries and the rise in pulmonary blood pressure. In this experiment, we tested whether cHyp is effective when administered after hypertension was already established. Rats were exposed to hypoxia (10% O2) for 21 days. Groups were hypoxic animals treated with cHyp (200 mg/kg sc twice daily) on days 10-21 (hypoxic cHyp) and saline-injected hypoxic animals (hypoxic). On day 21, we measured mean right ventricular pressure, hematocrit, collagen content of main and intrapulmonary arteries, and wall thickness of arterioles. Treatment reduced right ventricular pressure from 21 +/- 1 to 17 +/- 1 mmHg (P less than 0.05), hematocrit from 66 +/- 1 to 56 +/- 1% (P less than 0.05), hydroxyproline content of intrapulmonary arteries from 30 +/- 3 to 11 +/- 2 micrograms/vessel (P less than 0.05), and wall thickness from 27 +/- 3 to 16 +/- 2 microns (P less than 0.05). These results show that vascular collagen content is increased in established pulmonary hypertension and that cHyp treatment is effective in partially preventing the hemodynamic, structural, and biochemical changes if started after pulmonary hypertension is established. cHyp may also affect the rheological properties of blood.

The effect of indomethacin, prednisolone and cis-4-hydroxyproline on pulmonary fibrosis produced by butylated hydroxytoluene and oxygen.

The purpose of this study was to examine whether development of pulmonary fibrosis in mice could be influenced by indomethacin, prednisolone or a proline analog. Pulmonary fibrosis was produced in mice treated with butylated hydroxytoluene (BHT) 400 mg/kg and immediately exposed to 80% oxygen for 3 days. This treatment regimen resulted in 47% mortality. Surviving mice exhibited significant accumulations of pulmonary collagen as evidenced by increases in total lung hydroxyproline levels. The administration of indomethacin (4 mg/kg/day) on days 1-6 after BHT decreased mortality to 14% and diminished the accumulation of collagen in lung tissue. Indomethacin also enhanced survival when administered on days 1-3 after BHT/O2 but had no effect on lung collagen levels. Treatment with indomethacin on days 4-6 after BHT had no beneficial effect. The administration of prednisolone (60 mg/kg/day) on days 1-3, 1-6, or 4-6 after BHT decreased mortality but had no effect on accumulation of lung collagen. Cis-4-hydroxyproline (400 mg/kg/day) also had no effect on pulmonary fibrosis but did enhance survival when given on days 1-3 after BHT. Administering prednisolone (60 mg/kg/day) on days 1-6 after BHT to mice left in room air produced significantly more pulmonary fibrosis than in BHT-treated mice given saline. These data support the use of the BHT/O2 model of pulmonary fibrosis for screening potential antifibrotic agents. The possibility that corticosteroid treatment may enhance pulmonary fibrosis in a damaged lung is also demonstrated.

Treatment of experimental silicosis with antifibrotic agents.

We tested the efficacy of 2 antifibrotic agents, the proline analogue cis-4-hydroxy-L-proline (cHyp) and the lathyrogen beta-aminopropionitrile (BAPN), on experimental silicosis in hamsters. Silica (75 mg) was instilled intratracheally, and 3 months later lung hydroxyproline content, the volume density of silicotic nodules in lung parenchyma, fluid-filled lung pressure-volume curves, body weight and survival were measured. Animals were injected with cHyp, 200 mg/kg body weight, or BAPN, 150 mg/kg body weight, twice daily for 3 months. Hydroxyproline contents (mg/lung) at 3 months were: control, 0.8 +/- 0.1; silica, 1.4 +/- 0.1 (P less than 0.05 compared to control); silica-cHyp, 1.2 +/- 0.2; silica-BAPN, 1.4 +/- 0.1 (both NS compared to silica). The volume density of granuloma (% of surface area) was: silica, 0.7 +/- 0.1; silica-cHyp, 5.9 +/- 1.0; silica-BAPN, 9.7 +/- 1.5 (both P less than 0.5 compared to silica). There was no difference among the groups as assessed by lung pressure-volume curves. No toxic effects were produced on the skeletal system as assessed by bone hydroxyproline content and skeletal roentgenograms. Final body weights (g) were: silica, 114 +/- 5; silica-BAPN, 108 +/- 6; silica-cHyp, 88 +/- 7 (the latter P less than 0.05 compared to silica). Survival (%) was: silica, 62%; silica-BAPN, 34%, silica-cHyp, 28% (both P less than 0.05 compared to silica). These data show that cHyp and BAPN treatment did not prevent silica-induced pulmonary fibrosis, led to more extensive silicotic nodules, and were toxic. Both cHyp and BAPN have some efficacy in other models of fibrosis, and the observations in the present study could be specific to silicosis in the hamster.

Oxaceprol is a well-tolerated therapy for osteoarthritis with efficacy equivalent to diclofenac.

The therapeutic equivalence and safety of treatment for 21 days with 400 mg t.i.d. oxaceprol (n = 132) and 50 mg t.i.d. diclofenac (n = 131) were assessed in a multicentre, randomised, double-blind study of a mixed population of patients with osteoarthritis of the knee and/or hip. In a per-protocol analysis of efficacy, the mean Lequesne index decreased by 2.5 points in the oxaceprol group (n = 109) and by 2.8 points in the diclofenac group (n = 109). The 95% confidence interval for the end-point difference revealed therapeutic equivalence. This was confirmed by assessments (visual analogue scale) of pain at rest, weight-bearing pain, pain on standing and pain on movement, all of which decreased to a similar extent under both treatments. The pain-free walking time increased in both groups from 10 min to 25 min by the end of the treatment period. Mobility was also increased to a similar extent by both drugs. The physicians assessed treatment as good or very good in 45-46% of patients in both groups. In all patients who received treatment, 28 and 37 adverse events were reported by 25 out of 132 (18.9%) and 33 out of 131 (25.2%) patients treated with oxaceprol and diclofenac, respectively. In 15 patients (11.4%) with 15 adverse events in the oxaceprol group and 25 patients (19.1%) with 27 adverse events in the diclofenac group, a relation to the medication was considered probable. The difference between the groups was statistically significant (p = 0.04106) for the number of these adverse events. Oxaceprol is therapeutically equivalent to diclofenac, but better tolerated than diclofenac in the treatment of osteoarthritis.

Oxaceprol is as effective as diclofenac in the therapy of osteoarthritis of the knee and hip.

In this multicentre (five centres in Germany), randomised, double-blind, comparative study, 150 patients with painful degenerative joint disease according to EULAR criteria received either oxaceprol (200 mg three times daily) or diclofenac (25 mg three times daily) for 20 days. Joint function, the primary variable, assessed according to Lequesne's indices, improved equally in both treatment groups to a clinically relevant degree. Joint mobility improved by approximately 60% in both groups. By the end of therapy in both groups, the period of pain-free walking time had more than doubled and subjectively evaluated pain perception (VAS) was reduced by almost 50% without any significant differences between the treatments. The incidence of adverse drug reactions was similar in both groups but oxaceprol induced milder symptoms. Oxaceprol is as effective and better tolerated than diclofenac in the treatment of osteoarthritis.

[Assessment of the placebo effect of symptomatic slow-acting anti-arthritics]. / Approche de l'intensité de l'effet placebo dans l'évaluation des anti-arthrosiques symptomatiques d'action lente.

OBJECTIVES: Assess the importance of the mid-term placebo effect of symptomatic slow acting drugs given for osteoarthritis. METHODS: We analyzed six controlled trials available in the literature. Trial duration ranged from 2 to 6 months. The trials had been conducted to assess the symptomatic effect of diacerhein, avocado/soya unsaponifiable chondrontin sulfate and oxaceprolin given for osteoarthritis of the hip or knee. The main clinical outcomes assessed were functional impairment using the Lequesnes index and a visual analog scale. RESULTS: Globally, the trials showed decreased function impairment with a 2 to 3 points decrease in the Lequesnes index (15 to 20%) and a 10 to 16 mm fall in the visual analog scale (-20 to -30%) in the placebo groups. CONCLUSION: Our findings confirms the importance of the mid-term placebo effect in the clinical course of osteoarthritis in patients given slow-acting drugs. This placebo effect, observed under these circumstances, is an expression of what clinicians will look for in future drugs and should be helpful for calculating the number of patients required in future trials.