Methods are provided for inhibiting stenosis following vascular trauma or disease in a mammalian host, comprising administering to the host a therapeutically effective dosage of a therapeutic conjugate containing a vascular smooth muscle binding protein that associates in a specific manner with a cell surface of the vascular smooth muscle cell, coupled to a therapeutic agent dosage form that inhibits a cellular activity of the muscle cell. Methods are also provided for the direct and/or targeted delivery of therapeutic agents to vascular smooth muscle cells that cause a dilation and fixation of the vascular lumen by inhibiting smooth muscle cell contraction, thereby constituting a biological stent.

Therapeutic inhibitor of vascular smooth muscle cells

The invention relates to novel binding domain-immunoglobulin fusion proteins that feature a binding domain for a cognate structure such as an antigen, a counterreceptor or the like, a hinge region polypeptide having either zero or one cysteine residue, and immunoglobulin CH2 and CH3 domains, and that are capable of ADCC and/or CDC while occurring predominantly as monomeric polypeptides. The fusion proteins can be recombinantly produced at high expression levels. Also provided are related compositions and methods, including immunotherapeutic applications.

Binding domain-immunoglobulin fusion proteins

Background This report describes the preclinical pharmacological profile of the new rapamycin analog, SDZ RAD, i.e., 40-O-(2-hydroxyethyl)-rapamycin. Methods The pharmacological effects of SDZ RAD were assessed in a variety of in vitro and in vivo models, which included an autoimmune disease model as well as kidney and heart allotransplantation models using different rat strain combinations. Results SDZ RAD has a mode of action that is different from that of cyclosporine or FK506. In contrast to the latter, SDZ RAD inhibits growth factor-driven cell proliferation in general, as demonstrated for the in vitro cell proliferation of a lymphoid cell line and of vascular smooth muscle cells. SDZ RAD is immunosuppressive in vitro as demonstrated by the inhibition of mouse and human mixed lymphocyte reactions and the inhibition of antigen-driven proliferation of human T-cell clones. The concentrations needed to achieve 50% inhibition in all of these assays fall into the subnanomolar range. SDZ RAD is effective in the in vivo models when given by the oral route in doses ranging between 1 mg/kg/day and 5 mg/kg/day. When compared with rapamycin, the in vitro activity of SDZ RAD is generally about two to three times lower; however, when administered orally, SDZ RAD is at least as active in vivo as rapamycin. Conclusions In conclusion, SDZ RAD is a new, orally active rapamycin-derivative that is immunosuppressive and that efficiently prevents graft rejection in rat models of allotransplantation. SDZ RAD has therefore been selected for development for use in combination with cyclosporine A to prevent acute and chronic rejection after solid organ allotransplantation.

SDZ RAD, A NEW RAPAMYCIN DERIVATIVE: Pharmacological Properties In Vitro and In Vivo

Coatings for implantable devices or endoluminal prosthesis, such as stents, are provided, including a method of forming the coatings. The coatings can be used for the delivery of an active ingredient or a combination of active ingredients.

Coating for Implantable Devices and a Method of Forming the Same

A radially expandable, endovascular stent designed for placement at a site of vascular injury, for inhibiting restenosis at the site, a method of using, and a method of making the stent. The stent includes a radially expandable body formed of one or more metallic filaments and a liquid-infusible mechanical anchoring layer attached to or formed in outer surface of the filaments. A drug coating in the stent is composed of a substantially polymer-free composition of an anti-restenosis drug, and has a substratum infused in the anchoring layer and a substantially continuous surface stratum of drug that is brought into direct contact with the vessel walls at the vascular site. Thus, the rate of release of the anti-restenosis drug from the surface stratum into said vascular site is determined solely by the composition of said drug coating.

Drug-delivery endovascular stent and method for treating restenosis

The present invention is directed to novel 0-alkylated derivatives of rapamycin of formula (I), especially 40-0-alkylated derivatives, are found to have pharmaceutical utility, particularly as an immunosuppressants.

O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants

Novel 3-mono-, 3,4-di- and 3,4,4,-tri-substituted pyrrolidine compounds, these compounds for use in the diagnostic and therapeutic treatment of a warm-blooded animal, especially for the treatment of a disease (= disorder) that depends on inappropriate activity of renin; the use of a compound of that class for the preparation of a pharmaceutical formulation for the treatment of a disease that depends on inappropriate activity of renin; the use of a compound of that class in the treatment of a disease that depends on inappropriate activity of renin; pharmaceutical formulations comprising a said substituted pyrrolidine compound, and/or a method of treatment comprising administering a said substituted pyrrolidine compound, a method for the manufacture of said substituted pyrrolidine compounds, and novel inter­mediates and partial steps for their synthesis are described. The substituted pyrrolidine compounds are especially of the formula (I), wherein the substituents are as described in the specificacion.

Pyrrolidine derivatives for the treatment of a disease depending on the activity of renin

Novel derivatives of rapamycin of formula I are found to have pharmaceutical utility, particularly as immunosuppressants.

Rapamycin derivatives and their use, particularly as immunosuppressants

FIELD: organic chemistry, antibiotics SUBSTANCE: product: compound of the formula (I)where: X means (H, H) or O; Y means (H, OH) or O; Rand Rwere taken independently from: H, alkyl, arylalkyl, hydroxyl, dihydroxyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, acylhydroxyalkyl, aminoalkyl,, alkylaminialkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and hydroxyalkoxyalkyl where "alk-" or "alkyl" means linear or branched C-alkyl, preferably, C-alkyl; Rmeans methyl or Rand Rform together C-alkylene at condition that Rand Rdo not mean H simultaneously; and at condition that alkoxyalkyl or hydroxyalkoxyalkyl do not mean alkoxymethyl or hydroxyalkoxymethyl Method of synthesis involves interaction of rapamycin, deoxorapamycin or dihydrorapamycin with organic radical Ror Rlinked to terminal group (X) Synthesized compounds were used in medicine (immunology, oncology, therapy and other branches) EFFECT: improved method of synthesis

O-alkylated derivatives of rapamycin and their use, in part, as immunodepressants

This invention provides a microemulsion pre-concentrate comprising a difficultly soluble agent and a carrier medium comprising: 1) a hydrophilic phase which comprises dimethyisosorbide and/or a lower alkyl alkanoic ester, 2) a lipophilic phase, and 3) a surfactant. The active agent may be a cyclosporine or a macrolide. In another aspect, this invention provides a pharmaceutical composition for enteral or parenteral administration comprising a macrolide and an acid.

Cottens Sylvain

Papers

O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants

Pyrrolidine derivatives for the treatment of a disease depending on the activity of renin

Rapamycin derivatives and their use, particularly as immunosuppressants

O-alkylated derivatives of rapamycin and their use, in part, as immunodepressants

Pharmaceutical compositions comprising a macrolide and an acid