A phase I study of intraperitoneal nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies

PURPOSE: This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax®) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. METHODS: Twenty-one patients with peritoneal malignancies received Nanotax® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50–275 mg/m2) of Cremophor-free Nanotax® were administered intraperitoneally for one to six cycles (every 28 days). RESULTS: Intraperitoneal (IP) administration of Nanotax® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration–time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450–2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax® IP treatment. CONCLUSIONS: Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity

Contribution of the local RAS to hematopoietic function: a novel therapeutic target

The renin angiotensin system (RAS) has long been a known endocrine system that is involved in regulation of blood pressure and fluid balance. Over the last 2 decades, evidence has accrued that shows that there are local RAS that can affect cellular activity, tissue injury and tissue regeneration. There are locally active ligand peptides, mediators, receptors and signaling pathways of the RAS in the bone marrow (BM). This system is fundamentally involved and controls the essential steps of primitive and definitive blood cell production. Hematopoiesis, erythropoiesis, myelopoiesis, thrombopoiesis, formation of monocytic and lymphocytic lineages, as well as stromal elements are regulated by the local BM RAS. The expression of a local BM RAS has been shown in very early, primitive embryonic hematopoiesis. Angiotensin-converting enzyme (ACE-1, CD143) is expressed on the surface of hemangioblasts and isolation of the CD143 positive cells allows for recovery of all hemangioblast activity, the first endothelial and hematopoietic cells, forming the marrow cavity in the embryo. CD143 expression also marks long-term blood-forming CD34+ BM cells. Expression of receptors of the RAS is modified in the BM with cellular maturation and by injury. Ligation of the receptors of the RAS has been shown to modify the status of the BM resulting in accelerated hematopoiesis after injury. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive and definitive hematopoiesis as well as modification of BM recovery by administration of exogenous ligands of the RAS. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of BM recovery after injury as well as neoplastic disorders

Clinical evaluation of endometriosis and differential response to surgical therapy with and without application of Oxiplex/AP* adhesion barrier gel.

OBJECTIVE: To correlate parameters of endometriosis obtained during routine clinical evaluation with the subsequent formation of adhesions following surgical treatment by laparoscopy. DESIGN: Randomized, controlled, double-blind, clinical trial. SETTING: Tertiary referral centers for the treatment of endometriosis. PATIENT(S): Thirty-seven patients (65 with adnexa) with stage I-III endometriosis; endometrioma-only patients were excluded. INTERVENTION: Laparoscopic surgical treatment of endometriosis, followed by randomization to Oxiplex/AP (FzioMed, Inc., San Luis Obispo, California) gel treatment (treated group) of adnexa, or surgery alone (control group); follow-up laparoscopy 6-10 weeks later. MAIN OUTCOME MEASURE(S): Adnexal Americn Fertility Society score, correlated with color and location of endometriosis, as well as stage of disease determined by masked review of videotapes. RESULT(S): Control patients with at least 50% red lesions had a greater increase in ipsilateral adnexal adhesion scores than patients with mostly black or white and/or clear lesions. Treated patients with red lesions had a greater decrease in adnexal adhesion scores than control patients. There was a correlation between baseline endometriosis stage and postoperative adhesion formation in control patients, but not treated patients. CONCLUSION(S): Patients with red endometriotic lesions had greater increases in their adhesion scores than patients with only black, white, and/or clear lesions. Oxiplex/AP gel was effective in reducing adhesions, compared to surgery alone, in all groups

Use of Temporary Implantable Biomaterials to Reduce Leg Pain and Back Pain in Patients with Sciatica and Lumbar Disc Herniation

The principle etiology of leg pain (sciatica) from lumbar disc herniation is mechanical compression of the nerve root. Sciatica is reduced by decompression of the herniated disc, i.e., removing mechanical compression of the nerve root. Decompression surgery typically reduces sciatica more than lumbar back pain (LBP). Decompression surgery reduces mechanical compression of the nerve root. However, decompression surgery does not directly reduce sensitization of the sensory nerves in the epidural space and disc. In addition, sensory nerves in the annulus fibrosus and epidural space are not protected from topical interaction with pain mediators induced by decompression surgery. The secondary etiology of sciatica from lumbar disc herniation is sensitization of the nerve root. Sensitization of the nerve root results from a) mechanical compression, b) exposure to cellular pain mediators, and/or c) exposure to biochemical pain mediators. Although decompression surgery reduces nerve root compression, sensory nerve sensitization often persists. These observations are consistent with continued exposure of tissue in the epidural space, including the nerve root, to increased cellular and biochemical pain mediators following surgery. A potential contributor to lumbar back pain (LBP) is stimulation of sensory nerves in the annulus fibrosus by a) cellular pain mediators and/or b) biochemical pain mediators that accompany annular tears or disruption. Sensory fibers located in the outer one-third of the annulus fibrosus increase in number and depth as a result of disc herniation. The nucleus pulposus is comprised of material that can produce an autoimmune stimulation of the sensory nerves located in the annulus and epidural space leading to LBP. The sensory nerves of the annulus fibrosus and epidural space may be sensitized by topical exposure to cellular and biochemical pain mediators induced by lumbar surgery. Annulotomy or annular rupture allows the nucleus pulposus topical access to sensory nerve fibers, thereby leading to LBP. Coverage of the annulus and adjacent structures in the epidural space by absorbable viscoelastic gels appears to reduce LBP following surgery by protecting sensory fibers from cellular and biochemical pain mediators

Tranilast: A Pharmaceutical Candidate for Reduction of Adhesions Using a Novel Approach

Postsurgical adhesion formation has numerous deleterious side effects in a wide variety of surgical settings. Physical barriers used together with laparoscopy were developed in hopes of reducing the tissue trauma seen with open procedures and separating tissues during the critical time of healing to reduce adhesion formation. Despite meticulous techniques by surgeons and the availability of barriers, adhesion formation remains a serious problem, with more than $1 billion spent annually on complications arising from adhesions. Our laboratories have combined a previously marketed drug, Tranilast, with a gel to provide a locally delivered medicated device that can reduce adhesion formation. This article will review the role of Tranilast in the key pathways involved in adhesion formation