From bench to bedside: review of gene and cell-based therapies and the slow advancement into phase 3 clinical trials, with a focus on Aastrom's Ixmyelocel-T.

There is a large body of preclinical research demonstrating the efficacy of gene and cellular therapy for the potential treatment of severe (limb-threatening) peripheral arterial disease (PAD), including evidence for growth and transcription factors, monocytes, and mesenchymal stem cells. While preclinical research has advanced into early phase clinical trials in patients, few late-phase clinical trials have been conducted. The reasons for the slow progression of these therapies from bench to bedside are as complicated as the fields of gene and cellular therapies.

Dose-dependent hemodynamic and metabolic effects of vasoactive medications in normotensive, anesthetized neonatal piglets.

The developmentally regulated hemodynamic effects of vasoactive medications have not been well characterized. We used traditional and near-infrared spectroscopy monitoring technologies and investigated the changes in heart rate, blood pressure, common carotid artery (CCA) blood flow (BF), cerebral, renal, intestinal, and muscle regional tissue O2 saturation, and acid-base and electrolyte status in response to escalating doses of vasoactive medications in normotensive anesthetized neonatal piglets. We used regional tissue O2 saturation and CCA BF as surrogates of organ and systemic BF, respectively, and controlled minute ventilation and oxygenation.

Near-infrared spectroscopy monitoring of cerebral oxygen during assisted ventilation.

Background: Changes in the arterial partial pressure of CO(2) (PaCO(2)) has a direct though transient effect on the cerebral vasculature and cerebral circulation. Decreased PaCO(2) levels lead to vasoconstriction and can result in dangerously low levels of cerebral perfusion that resolve in 4-6 h. It is currently believed that perfusion abnormalities contribute to intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) in the neonate.

Cerebral and somatic venous oximetry in adults and infants.

Background: The development in the last decade of noninvasive, near infrared spectroscopy (NIRS) analysis of tissue hemoglobin saturation in vivo has provided a new and dramatic tool for the management of hemodynamics, allowing early detection and correction of imbalances in oxygen delivery to the brain and vital organs.

Description: The theory and validation of NIRS and its clinical use are reviewed. Studies are cited documenting tissue penetration and response to various physiologic and pharmacologic mechanisms resulting in changes in oxygen delivery and blood flow to the organs and brain as reflected in the regional hemoglobin oxygen saturation (rSO(2)).

Estrogen protects the heart from ischemia-reperfusion injury via COX-2-derived PGI2.

There is an accumulating body of data to suggest that estrogen mediates its cardioprotective effects via cyclooxygenase activation and synthesis of prostaglandins (PG), specifically PGI2. We hypothesized that inhibition of COX-2 would prevent estrogen's cardioprotective effects after myocardial ischemia-reperfusion. Acute treatment with 17beta-estradiol (E2; 20 microg/rabbit) increased COX-2 protein expression and activity in the myocardium.

Estrogen-mediated protection in myocardial ischemia-reperfusion injury.

Before menopause, a woman has a relatively low risk for developing cardiovascular disease. After menopause, however, the risk increases nearly twofold and cardiovascular disease remains the number one cause of death among women. Observational trials and studies in animal models of cardiovascular disease suggested that females have reduced injury after myocardial ischemia and reperfusion injury.

Apolipoprotein A-IMilano/POPC complex attenuates post-ischemic ventricular dysfunction in the isolated rabbit heart.

Irreversible myocardial injury is a potential consequence of coronary artery revascularization. Reperfusion leads to the production of oxidized products that can damage myocardium. High-density lipoproteins (HDL) are effective at removing oxidized lipids.

The pathway-selective estrogen receptor ligand WAY-169916 reduces infarct size after myocardial ischemia and reperfusion by an estrogen receptor dependent mechanism.

Previous studies have shown that estrogen treatment protects the heart from reperfusion injury. The adverse effects of long-term estrogen treatment limit its clinical use and emphasize the need for the development of specific pharmacological interventions such as pathway-selective estrogen receptor (ER) ligands. Pathway-selective ER ligands are compounds that retain estrogen's anti-inflammatory ability, but they are devoid of conventional estrogenic action.

Medroxyprogesterone acetate prevents the cardioprotective and anti-inflammatory effects of 17beta-estradiol in an in vivo model of myocardial ischemia and reperfusion.

Previous studies demonstrated the protective effects of estrogen administration in models of cardiovascular disease. However, there is a discrepancy between these data and those from the recent clinical trials with hormone replacement therapy in menopausal women. One possible explanation for the divergent results is the addition of progestin to the hormone regimen in the Women's Health Initiative and the Heart and Estrogen/Progestin Replacement Study trials.

Activation of estrogen receptor-alpha protects the in vivo rabbit heart from ischemia-reperfusion injury.

The estrogen receptor (ER) mediates estrogenic activity in a variety of organs, including those in the reproductive, cardiovascular, immune, and central nervous systems. Experimental studies have demonstrated that 17beta-estradiol (E2) protects the heart from ischemia-reperfusion injury. Two estrogen receptors, ER alpha and ER beta, mediate the actions of estrogen; however, it is not certain which ER mediates the cardioprotective effects of E2.

Apolipoprotein A-IMilano and 1-palmitoyl-2-oleoyl phosphatidylcholine complex (ETC-216) protects the in vivo rabbit heart from regional ischemia-reperfusion injury.

Ex vivo studies demonstrated that a synthetic high-density lipoprotein (HDL) comprised of a complex of recombinant apolipoprotein A-IMilano and 1-palmitoyl-2-oleoyl phosphatidylcholine protects the isolated rabbit heart from reperfusion injury. Therefore, we sought to determine whether a pharmaceutical preparation of this complex, ETC-216, was cardioprotective in an in vivo model of left anterior descending artery (LAD) occlusion and reperfusion. Initially, ETC-216 (100 mg/kg) was tested in acute (one-treatment) and chronic (two-treatment) i.

Sulodexide attenuates myocardial ischemia/reperfusion injury and the deposition of C-reactive protein in areas of infarction without affecting hemostasis.

Several glycosaminoglycans (GAGs) have been demonstrated to protect the ischemic heart against reperfusion injury, in part, by modulating activation of the complement cascade. The present study assessed the cardioprotective effects of sulodexide (KRX-101), a mixture of GAGs composed of 80% low-molecular mass heparin and 20% dermatan sulfate. KRX-101 differs from other GAGs (e.

17Beta-estradiol as a receptor-mediated cardioprotective agent.

Cardiac tissue that undergoes an ischemic episode exhibits irreversible alterations that become more extensive upon reperfusion. Estrogen treatment has been reported to protect against reperfusion injury, but the mechanism remains unknown. The cardioprotective effects of 17beta-estradiol, a biologically active form of the hormone, and 17alpha-estradiol were assessed in an in vivo occlusion-reperfusion model.