Synthesis of a NO-releasing prodrug of rofecoxib.

[reaction: see text] A newly developed synthesis of a NO-releasing prodrug of rofecoxib is described. The highly productive process consists of five chemical steps and produces prodrug 1 in an overall 64% yield from commercially available 3-phenyl-2-propyn-1-ol (4). The synthesis is highlighted by the carbometalation reaction of propargyl alcohol 4 to generate the tetrasubstituted olefin core, sulfone acid 2. Additionally, two alternate end-game strategies to prepare NO-COXIB 1 from this intermediate were explored and developed: (1) a convergent synthesis where a bromonitrate side chain is introduced in one step and (2) a two-step sequence that first installs the requisite six-carbon ester side chain followed by chemoselective nitration.

[PSA recurrence after primary curative therapy--local or systemic? When is a second curative therapy still possible?]. / PSA-Rezidiv nach primär kurativer Therapie - lokal oder systemisch? Wann ist eine kurative Zweittherapie noch möglich?

PSA recurrence after primary curative therapy for localized prostate cancer is a common problem. Further curative treatment is only reasonable in the case of local recurrence. Therefore, minimizing the likelihood of metastatic disease is crucial. So far, imaging techniques cannot distinguish between local recurrence and distant metastasis. It is therefore reasonable to orientate on PSA kinetics and pathological criteria. Histologic confirmation of suspected local recurrence after radical prostatectomy before salvage therapy is not required. However, after initial radiation therapy histologic confirmation of suspected isolated local recurrence should be obtained. The optimal treatment for a PSA recurrence depends on the initial therapy and the life-expectancy of the patient.

Cyclopropane structural units from homoaldol adducts.

[reaction: see text] An efficient two-step homologation of aldehydes to cyclopropylaldehydes has been developed. Activation of homoaldol adducts derived from O-enecarbamates and N-enecarbamates provided high yields of cyclopropylaldehydes with good to excellent levels of trans/cis selectivity. Trapping of the intermediate oxonium ion and iminium ion intermediates has also been demonstrated, leading to direct isolation of cyclopropyl carbinol and cyclopropylamine products.

Kinetically controlled cross-metathesis reactions with high E-olefin selectivities.

[reaction: see text] Homoallylic alcohols with anti-allylic substituents display enhanced E-olefin selectivity in cross-metathesis (CM) reactions with allyltrimethylsilane. The high selectivity can be explained via a five-membered chelate intermediate in which the hydroxyl group of the homoallylic alcohol coordinates to the ruthenium metal center of Grubbs' catalyst.

The roles of activins in repair processes of the skin and the brain.

A recent study from our laboratory demonstrated a strong upregulation of activin expression during cutaneous wound healing. To further analyze the role of activin A in skin morphogenesis and wound repair, we generated transgenic mice that overexpress activin A under the control of the keratin 14 promoter. The latter targets expression of transgenes to the basal, proliferating layer of the epidermis. Hetero- as well as homozygous transgenic animals were viable and fertile. However, they were smaller than non-transgenic littermates and they had smaller ears and shorter tails. Histological analysis of their skin revealed dermal hyperthickening, mainly due to the replacement of fatty tissue by connective tissue, and an increase in suprabasal, partially differentiated epidermal layers. After cutaneous injury, a strong enhancement of granulation tissue formation was observed. Furthermore, the extent of re-epithelialization was increased in some of the wounds. These data demonstrate that activin A is a potent stimulator of the wound healing process. Using an in vivo model of local brain injury, we found that activin A also plays a significant role in the early cellular response to neuronal damage. Expression of activin mRNA and protein is markedly upregulated within a few hours of injury. If applied exogenously, recombinant activin A is capable of rescuing neurons from acute cell death. Studying the interaction between bFGF, a well-established neuroprotective agent, which is currently being tested in stroke patients, and activin A, we arrived at the unexpected conclusion that it is the strong induction of activin A by bFGF which endows the latter with its beneficial actions in patients. These findings suggest that the development of substances directly targeting activin expression or receptor binding should offer new possibilities in the acute treatment of stroke and brain trauma.

Expression and function of keratinocyte growth factor and activin in skin morphogenesis and cutaneous wound repair.

Reepithelialization and granulation tissue formation during cutaneous wound repair are mediated by a wide variety of growth and differentiation factors. Recent studies from our laboratory provided evidence for an important role of keratinocyte growth factor (KGF) in the repair of the injured epithelium and for a novel function of the transforming growth factor-beta superfamily member activin in granulation tissue formation. KGF is weakly expressed in human skin, but is strongly upregulated in dermal fibroblasts after skin injury. Its binding to a transmembrane receptor on keratinocytes induces proliferation and migration of these cells. Furthermore, KGF has been shown to protect epithelial cells from the toxic effects of reactive oxygen species. We have identified a series of KGF-regulated genes that are likely to play a role in these processes. In addition to KGF, activin seems to be a novel player in wound healing. Activin expression is hardly detectable in nonwounded skin, but this factor is highly expressed in redifferentiating keratinocytes of the hyperproliferative wound epithelium as well as in cells of the granulation tissue. To gain insight into the role of activin in wound repair, we generated transgenic mice that overexpress activin in basal keratinocytes of the epidermis. These mice were characterized by a hyperthickened epidermis and by dermal fibrosis. Most importantly, overexpression of activin strongly enhanced the process of granulation tissue formation, demonstrating a novel and important role of activin in cutaneous wound repair.

Overexpression of activin A in the skin of transgenic mice reveals new activities of activin in epidermal morphogenesis, dermal fibrosis and wound repair.

Recently we demonstrated a strong induction of activin expression after skin injury, suggesting a function of this transforming growth factor-beta family member in wound repair. To test this possibility, we generated transgenic mice that overexpress the activin betaA chain in the epidermis under the control of a keratin 14 promoter. The transgenic mice were significantly smaller than control littermates, and they had smaller ears and shorter tails. In their skin, the fatty tissue was replaced by connective tissue and a severe thickening of the epidermis was found. The spinous cell layer was significantly increased, and the epidermal architecture was highly disorganized. These histological abnormalities seem to result from increased proliferation of the basal keratinocytes and abnormalities in the program of keratinocyte differentiation. After skin injury, a significant enhancement of granulation tissue formation was detected in the activin-overexpressing mice, possibly as a result of premature induction of fibronectin and tenascin-C expression. These data reveal novel activities of activin in the regulation of keratinocyte proliferation and differentiation as well as in dermal fibrosis and cutaneous wound repair.

Ventricular meningiomas--report of 4 cases.

Four cases of rarely occurring meningiomas of the lateral ventricles are reported. These tumors are said to originate from meningeal cell clusters that have been mislocated during embryonal development. Patients of clinical history, diagnostic and surgical findings, and the postoperative course are described, with special emphasis on tumor growth aspects.

Hydrocarbon metabolism and cortisol balance in oil-exposed ringed seals, Phoca hispida.

1. Ringed seals were exposed experimentally to oil contamination, by feeding of a [14C]naphthalene marked crude oil in fish for up to 4 days at a rate of 5 ml/day. 2. Mixed function oxygenase (MFO) activity, measured as aryl hydrocarbon hydroxylase in liver and kidney, was found to be induced, in particular in kidney tissue where the activity increased 3-fold. 3. MFO induction correlated with a high degree of conversion of crude oil hydrocarbons to water-soluble metabolites. Most of the radioactivity was found in the polar fraction of plasma and urine. 4. Plasma cortisol levels were somewhat elevated by captive holding, and increased markedly after oil-exposure. Cortisol half-life decreased after oil exposure from 1 3/4 to 1 hr.

Induction of mixed function oxidases by petroleum in the American eel, Anguilla rostrata.

American eels, Anguilla rostrata, were exposed to crude oil by ingestion of a 10, 100, or 500 microliters/kg fish dose per day for five days. Depuration was followed for an additional twelve days. All oil doses caused an induction of hepatic microsomal enzymes, maximally by three days of exposure. Benzo(a)pyrene hydroxylase (BaPH) showed a dose related response, with greater induction at 100 microliters/kg than at the other doses. The highest dose was hepatotoxic. Cytochrome P-450 induction was dose independent, and remained induced maximally for the entire experimental period, in contrast to BaPH which declined in activity. Reaction optimum for BaPH was at pH 7.5 and 27 degrees C. A study of tissue distribution showed the liver to account for nearly all BaPH activity. A significant increase in the protein content of the hepatic postmitochondrial fraction of oil-exposed fish was also observed.

Plasma and tissue levels of dietary radiotocopherols in the harp seal, Phoca groenlandica.

Plasma and tissue levels of dietary radiotracer-labeled tocopherols were examined in the harp seal, Phoca groenlandica. The d-alpha form showed much higher plasma maxima and retention than d,l-gamma-tocopherol. Concentration peaks occurred somewhat later but were greater when the vitamin was fed with Tween 80 than with herring and corn oil respectively. Greater plasma levels occurred with the use of herring oil as compared with corn oil. Seals previously maintained on a vitamin E deficient diet showed greater plasma maxima than seals not so deprived. Plasma and tissues generally showed maximum levels within 24 h postingestion. Tissue levels of labelled dietary alpha-tocopherol were examined by biopsy and postmortem studies in selected tissues of vitamin E deprived seals.