Blood substitutes clinical trials

Fig. 17.4 The comparison of the costs of several blood substitutes companies to develop an oxygen carrying molecule vs. the Alios Therapeutics Inc. allosteric effector RSR 13 to an IND and phase one clinical trial.

Although most clinicians support chelation for symptomatic patients with elevated blood lead concentrations, the decision to chelate asymptomatic subjects is more controversial. Since 1991, the Centers for Disease Control and Prevention (CDC) has recommended chelation for all children with blood lead concentrations of 45 mcg/dL or greater. However, a recent randomized, double-blind, placebo-controlled clinical trial of succimer in children with blood lead concentrations between 25 mcg/dL and 44 mcg/dL found no benefit on neurocognitive function or long-term blood lead reduction. Prophylactic use of chelating agents in the workplace should never be a substitute for reduction or prevention of excessive exposure. 

This entry will first survey the reasons for developing blood substitutes and outline the principles of oxygen delivery by PFC emulsions. It will then focus on the main challenges encountered in the development of such emulsions, namely the selection of an appropriate excretable PFC and the preparation of a stable, biocompatible emulsion. It will also allude to questions related to raw material procurement, product manufacture, and cost. Further sections will concern the pharmacokinetics, efficacy, and side effects of these oxygen carriers. Finally, the potential applications of these products will be outlined, including the status of their clinical trials, and some forward looking comments will be made. 

Preliminary data concerning clinical trials in which a tHb has been infused in resuscitation from hemorrhagic shock or as a substitute for blood have shown widely disparate findings. The available data are likely too sparse to draw conclusions as to whether the pressor activity of a tHb or its absence is a meaningful factor in the therapeutic utility of a tHb. 

Alayash, A.I. Ryan, B.A.B. McLeod, L.L. Goldman, D.W. Cashon, R.E. Cell-free hemoglobin and tissue oxidants probing the mechanisms of hemoglobin cytotoxicity. In Blood Substitutes Principles, Methods, Products and Clinical Trials Chang, T.M.S., Ed. Karger Landes Systems Basel, 1998 157-177. 

Chang, T. M. S., ed. 1997. Blood substitutes Principles, methods, products and clinical trials, vols. 1 and 2. Basel, Switzerland Karger AB. 

Hemoperfusion for acute poisoning—routine treatment in patients Hemoperfusion for aluminium and iron overload— routine treatment in patients Supplement to hemodialysis in end-stage renal failure—routine treatment in patients Artificial liver support hemoperfusion and hybrid systems—experimental Red blood cell substitutes for transfusion—Phase I and Phase 11 clinical trials Blood group antibodies removal (immunosorbents)—clinical trial Hereditary enzyme deficiency—clinical trial Clinical laboratory analysis—clinical application Production of monoclonal antibodies—development... 

For the bent metallocene dihalides, structure-activity relationships were established for the halides and substitution of the Gp rings. Also, hydrolysis reactions were studied in detail with a view on aqueous stability. Model studies with amino acids, nucleic acids, proteins, and blood plasma provided more insight into the mechanism of action. Titanium compounds were most active, and titanocene dichloride has entered clinical trials. Although very promising... 

Two diethylpropion analogues (VIII) and (IX) have been described. The thiophene derivative (VIIl) and related amino modifications were claimed to have anorexigenic activity comparable to amphetamine with much less CNS stimulation. A chloro-substituted derivative (IX) [SKF-709h8, FWH-h9h) was reported to be one-fifth as potent as diethyl-propion in decreasing food intake in dogs it produced less motor stimulation in the mouse than d-amphetamine, reversed and prevented reserpine induced depression. In the anesthetized cat, a biphasic blood pressure response was observed.22 A clinical trial of (IX), at daily doses of 75-150 mg, revealed effects similar to those obtained with diethylpropion.23 A clinical study designed to demonstrate the effect of continuous versus intermittent administration of diethyl-prop ion was shown to favor continuous administration.2A A related... 

Blood substitutes were critically reviewed by Chen et al. [23] who reached the conclusion Published animal studies and clinical trials carried out in a perioperative setting have demonstrated that these products successfully transport and deliver oxygen, but all may induce hypertension and lead to unexpectedly low cardiac outputs. Overall, these studies suggest that HBOCs resulted in only modest blood saving during and after surgery, no improvement in mortality and an increased incidence of adverse reactions (p. 803). This assertion is supported by findings of the meta-analysis of Natanson et al. [57] who found that clinical trials associated with blood substitutes increased the risk of mortality by 30% and myocardial infarction 2.7-fold. 

Chen, J.Y., Scerbo, M., and Kramer, G. A review of blood substitutes Examining the history, clinical trial results and ethics of hemoglobin-based oxygen carriers. Clinics (Sao Paulo) 64 803-813, 2009. 

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