An inhibitor of the matrix metalloproteinase synthesized by rabbit corneal epithelium.

Normal and abnormal processes of cellular invasion often are initiated by degradation of basement membranes. The process of corneal ulceration might operate via similar mechanisms; degradation of the corneal stroma is not seen until after the basement membrane underlying the corneal epithelium in the preulcerative lesion is lost. Recent data implicate a member of the matrix metalloproteinase (MMP) family of enzymes, 92 kD gelatinase/type IV collagenase (MMP-9) in both cellular invasion processes and degradation of epithelial basement membrane before corneal ulceration. This suggests that use of nontoxic substances that block activity of MMP-9 might be useful in preventing or inhibiting pathologic invasion processes in vivo. An agent that fits these criteria is N-[D,L-2-isobutyl-3(N'-hydroxycarbonylamido)-propanoyl]-O- methyl-L-tyrosine methylamide, which previously has been characterized as an inhibitor of tumor cell collagenases. In this study, the authors show that the inhibitor can efficiently block activity of MMP-9 purified from cultures of rabbit corneal epithelial cells. Results suggest that the recently reported efficacy of a closely related inhibitor in blocking progression of alkali burns to ulceration might be attributable to its action against MMP-9.     

Release of indomethacin from ultrasound dry granules containing lactose-based excipients.

Physical mixtures were prepared containing indomethacin and beta-lactose and alpha-lactose-based excipients (Ludipress and Cellactose). The mixtures were compacted with the aid of ultrasound, obtaining tablets, which were milled and sieved. Granules thus obtained were examined by optical microscopy and differential scanning calorimetry. The intense yellow color of the granules and the absence of indomethacin peak in thermograms suggest important modifications of indomethacin physical state; the drug thus modified appears to be spread on the excipient particle surface as a thin film, giving a lustrous appearance. No influence of ultrasound was observed on phase transition concerning lactose; only loss of water was important under high energy ultrasound. Dissolution profiles suggest an increased release of the drug from the systems treated with ultrasound at high energy, with respect to a traditional compaction; while no difference could be evidenced among the three excipients that, however, appear all suitable for this ultrasound-aided direct compression process.     

Venous damage prevention by defibrotide in vinorelbine-treated patients

GOALS: The aim of our study was to evaluate the incidence of venous toxicity induced by vinorelbine administration in patients who received a preventive therapy with defibrotide. PATIENTS AND METHODS: From July 1996 to July 2002 we treated 203 patients with vinorelbine, 51 with vinorelbine alone and 152 with vinorelbine in combination with other drugs via peripheral vein infusion. Of the 203 patients, 123 were male and 80 female with a median age of 67 years (range 18 to 82 years), and 118 were chemotherapy-naive. Defibrotide was delivered i.v. at a dose of 400 mg in 250 ml normal saline. After infusion of 125 ml over about 15 min, vinorelbine mixed with 10 ml normal saline was delivered as quick brief repeated pulses over 5 min through the plastic tube, followed by infusion of the remaining defibrotide. The specific Rittenberg scale was used to assess venous irritation episodes. RESULTS: Among a total of 1336 vinorelbine infusions, with a median of five infusions per patient, the incidence of venous irritation episodes graded according to Rittenberg scale was 1.1% (15), of which 0.6% (8) were grade 2 and 0.5% (7) grade 1. Globally, 15 patients (7.3%) developed venous toxicity after a median of 3 infusions (range 1-14), but no patient had more than one event. CONCLUSION: Our findings support the use of defibrotide as an effective, safe and low-cost means for preventing vinorelbine-related venous damage.     

The metabolic syndrome in women: implications for therapy

It is becoming increasingly clear that hypertension and metabolic risk factors in women are inter-related and often share underlying causes. Menopause acts explicitly as a risk factor by reducing the direct beneficial effect of ovarian hormones upon cardiovascular functions and indirectly by negatively influencing other risk factors for coronary artery disease--i.e. hyperinsulinaemia, blood cholesterol, blood pressure, coagulation etc. Adverse changes in one factor may induce adverse changes in a variety of other risk factors and it is important to consider co-ordinated changes when evaluating these patients rather than attempt to isolate independent factors. Similarly with treatment, the prevalence of metabolic syndrome in postmenopausal hypertensive women has important implications and some antihypertensive drugs may worsen the already altered metabolic profile of these patients while others may be beneficial. Centrally-acting sympatholytic agents, e.g. moxonidine, are therefore important to consider in hypertensive postmenopausal women who experience other symptoms of metabolic syndrome.     

The Role of Zinc in the Modulation of Neuronal Proliferation and Apoptosis

Although a requirement of zinc (Zn) for normal brain development is well documented, the extent to which Zn can modulate neuronal proliferation and apoptosis is not clear. Thus, we investigated the role of Zn in the regulation of these two critical events. A low Zn availability leads to decreased cell viability in human neuroblastoma IMR-32 cells and primary cultures of rat cortical neurons. This occurs in part as a consequence of decreased cell proliferation and increased apoptotic cell death. In IMR-32 cells, Zn deficiency led to the inhibition of cell proliferation through the arrest of the cell cycle at the G₀/G₁ phase. Zn deficiency induced apoptosis in both proliferating and quiescent neuronal cells via the intrinsic apoptotic pathway. Reductions in cellular Zn triggered a translocation of the pro-apoptotic protein Bad to the mitochondria, cytochrome c release, and caspase-3 activation. Apoptosis is the resultant of the inhibition of the prosurvival extracellular-signal-regulated kinase, the inhibition of nuclear factor-kappa B, and associated decreased expression of antiapoptotic proteins, and to a direct activation of caspase-3. A deficit of Zn during critical developmental periods can have persistent effects on brain function secondary to a deregulation of neuronal proliferation and apoptosis.     

The pro-myogenic environment provided by whole organ scale acellular scaffolds from skeletal muscle

In the pursuit of a transplantable construct for the replacement of large skeletal muscle defects arising from traumatic or pathological conditions, several attempts have been made to obtain a highly oriented, vascularized and functional skeletal muscle. Acellular scaffolds derived from organ decellularization are promising, widely used biomaterials for tissue engineering. However, the acellular skeletal muscle extra cellular matrix (ECM) has been poorly characterized in terms of production, storage and host-donor interactions. We have produced acellular scaffolds at the whole organ scale from various skeletal muscles explanted from mice. The acellular scaffolds conserve chemical and architectural features of the tissue of origin, including the vascular bed. Scaffolds can be sterilely stored for weeks at?+4°C or?+37°C in tissue culture grade conditions. When transplanted in wt mice, the grafts are stable for several weeks, whilst being colonized by inflammatory and stem cells. We demonstrate that the acellular scaffold per se represents a pro-myogenic environment supporting de novo formation of muscle fibers, likely derived from host cells with myogenic potential. Myogenesis within the implant is enhanced by immunosuppressive treatment. Our work highlights the fundamental role of this niche in tissue engineering application and unveils the clinical potential of allografts based on decellularized tissue for regenerative medicine.     

Prostate cancer increases hyaluronan in surrounding nonmalignant stroma, and this response is associated with tumor growth and an unfavorable outcome

Our objective was to investigate whether the presence of a tumor increases hyaluronan (HA) levels in surrounding prostate tissues and whether this extratumoral HA influences tumor growth and outcome. From a series of 287 men diagnosed with prostate cancer at transurethral resection and followed up with watchful waiting, tissue microarrays were constructed, stained, and scored for HA. A high HA staining score in the tumor stroma or in nonmalignant prostate tissue stroma were both associated positively with higher Gleason score and larger tumor volume, and was associated with a poor outcome. HA staining score was not an independent marker for outcome (multivariate Cox, with Gleason score, tumor volume, stage, and HA variables). In an orthotopic rat prostate cancer model, hyaluronic acid synthase-1 mRNA levels and HA staining were increased in normal prostate tissue surrounding prostate cancer. Orthotopic prostate cancer growth was increased by intraprostatic injection of HA. In conclusion, cancer in the prostate apparently stimulates HA synthesis both in tumor stroma and in the surrounding normal tissue. This promoted tumor growth and was associated with an unfavorable outcome.     

Biophysical stimulation in osteonecrosis of the femoral head

Osteonecrosis of the femoral head is the endpoint of a disease process that results from insufficient blood flow and bone-tissue necrosis, leading to joint instability, collapse of the femoral head, arthritis of the joint, and total hip replacement. Pain is the most frequent clinical symptom. Both bone tissue and cartilage suffer when osteonecrosis of the femoral head develops. Stimulation with pulsed electromagnetic fields (PEMFs) has been shown to be useful for enhancing bone repair and for exerting a chondroprotective effect on articular cartilage. Two Italian studies on the treatment of avascular necrosis of the femoral head with PEMFs were presented in this review. In the first study, 68 patients suffering from avascular necrosis of the femoral head were treated with PEMFs in combination with core decompression and autologous bone grafts. The second one is a retrospective analysis of the results of treatment with PEMFs of 76 hips in 66 patients with osteonecrosis of the femoral head. In both studies clinical information and diagnostic imaging were collected at the beginning of the treatment and at the time of follow up. Statistical analysis was performed using chi-square test. Both authors hypothesize that the short-term effect of PEMF stimulation may be to protect the articular cartilage from the catabolic effect of inflammation and subchondral bone-marrow edema. The long-term effect of PEMF stimulation may be to promote osteogenic activity at the necrotic area and prevent trabecular fracture and subchondral bone collapse. PEMF stimulation represents an important therapeutic opportunity to resolve the Ficat stage-I or II disease or at least to delay the time until joint replacement becomes necessary.