Omer Iqbal, MD Associate Professor Department of Pathology Hemostasis and Thrombosis Research Program (708) 216-6807 OIQBAL@lumc.edu

Antiplatelet Drugs

Platelet deposition, activation, and aggregation are the crucial initial responses to arterial injury. It has been demonstrated by placebo-controlled clinical trials that aspirin reduces the risk of ischemic events by up to 30-40% among the atherosclerotic diseases of the arterial tree. Clinical efficacy may be substantially enhanced if more than one mechanism of platelet activation is inhibited. The United States FDA has recently approved the use of aspirin and dipyridamol in the management of ischemic stroke. Aspirin, through its irreversible inactivation of platelet cyclooxygenase, inhibits the thromboxane-mediated mechanisms of platelet activation.

The thienopyridine drugs, such as ticlopidine and clopidogrel, prevent platelet activation via inhibition of the adenosine diphosphate receptor. Recently clopidogrel in large-scale clinical trials demonstrated modest benefit over aspirin in reducing the long-term risk of ischemic events among patients with cardiovascular, cerebrovascular, or peripheral vascular atherosclerosis.

We are currently studying the interaction of UFH, LMWH, r-hirudin, PEG hirudin, and Factor Xa inhibitors like DX 9065a with GPIIb/IIIa inhibitors and eventual outcome if there is onboard aspirin. The current NICE-1 study (in which enoxaparine was given at a dose of 1mg/kg S.C.) and the NICE-4 study (in which enoxaparine was given at a dose of 0.75mg/kg s.c. followed by abciximab at a dose of 0.25 mg/kg followed by an infusion of 0.125 microgram/kg/min to a maximum of 10 micrograms in acute coronary syndrome) will show whether or not there is a need of abciximab in therapeutic regimens for acute coronary syndromes.

The select GPIIb/IIIa inhibitors are abciximab (reoPro), tirofiban (Aggrastat), eptifibatide (Integrelin), lamifiban (Roche's RO44-9883), non-peptide RGD mimetics fradafiban (BIBU 52) and lefradafiban (BIBU 104), xemilofiban (SC-54684A), an ethyl carbonic acid ester prodrug of the GPIIb/IIIa antagonist SC-54701A. Fradafiban and lefradafiban inhibit ADP-induced platelet aggregation.

Thrombolytic Drugs

Thrombolytic drugs, when given early (within 1-2 hours), improve survival by as much as 50% and when given within 6 hours of symptom onset by as much as 30%. Complete and timely recovery of coronary blood flow is crucial in the outcomes of acute myocardial infarction. The current therapeutic regimens do not achieve TIMI grade 3 flow at minutes in almost 50% of the cases, and 4-6% of patients develop early reinfarction despite successful reperfusion. PTCA is effective in only 75% of cases that achieve TIMI grade 3 flow and perhaps less in complicated cases. Besides, there is a 10-13% risk of reocclusion with PTCA. It is desirable that early and complete reperfusion would bring better outcomes in patients with AMI. Very little is being done in the area of destabilizing the stabilized clot by inhibiting the Laki-Lorand Factor (factor XIII) so as to make the clot vulnerable to thrombolysis. If this concept works, then no matter how many hours elapsed after the thrombolytic episode, destabilase, an enzyme, could be given to make the clot susceptible to clot lysis. Several ways of destabilizing the factor XIII will be useful in the management of acute coronary syndromes and other cerebrovascular thrombotic and ischemic disorders.

Point-of-care monitoring of antithrombin drugs using dry chemistry technology. Ideas to put ecarin in the card system developed by Cardiovascular Diagnostics, Inc., Raleigh, NC, led to the development of ecarin clotting time test cards.

• new thrombolytic drugs
• new anticoagulant drugs
• new markers of coagulation activation
• GPIIb/IIIA inhibitors
• cytokines
• cytotoxic drugs

Developed a dedicated program on the point-of-care testing (POCT) of new anticoagulant drugs such as hirudin, hirulog, argatroban, and the GPIIb/IIIa inhibitors. In particular, I have worked with interventional cardiologists and interventional radiologists to optimize the dosing of these drugs. This POCT program is a result of the SBIR/NIH grant which we received with Cardiovascular Diagnostics, Inc., during 1997-1999. I am in the process of developing additional tests for the monitoring of anti-TF, TFPI, and ADP-receptor inhibitors. Drug interactions play a very important role in the efficacy of antithrombotic drugs.

Developed specific programs to determine the relative efficacy and bleeding indices of newer anticoagulant drugs. Utilizing experimental animal models of bleeding, we are capable of predicting the bleeding effects of different drug classes. This is helpful in optimizing the safer dosages for different indications. In addition, several surrogate markers in blood samples can be measured to predict the relative therapeutic indices. Such parameters as TFPI, TAFI, and the release of other biologically active substances are correlated with hemorrhagic manifestations. Combination therapy including 2 or 3 different drugs is also investigated in these models. Most of these studies are directed to demonstrate the platelet/vascular dysfunction. Once the surrogate markers of vascular/platelet dysfunction are determined, then we can apply molecular genomics and proteomics to our studies. In this regard I am in the process of developing certain profiling of mediators.

Sabbatical Training in Molecular Biology under Professor J. Alejandro Madrigal, Director of the Anthony Nolan Bone Marrow Trust and Professor of Hematology at Royal Free Hospital, London, England. This training provided the opportunity to observe and learn:

• extraction of DNA using QIAamp spin blood kit
• HLA-A locus amplification for sequence specific oligotyping (SSO) procedure
• preparation of membranes for HLA-A and B Class I SSOP procedure
• tissue typing using dynal sequence-specific primers
• Class I SSO gel electrophoresis
• automated lifecodes HLA-A locus amplification
• HLA typing reference strand-mediated conformation analysis (RSCA)

Reference Strand-Mediated Conformation Analysis (RSCA)

This is a novel method developed at Anthony Nolan Bone Marrow Research Institute, Royal Free Hospital in London, England, by Drs. J. R. Arguello and J. A. Madrigal. This technique provides high resolution and high sample throughput for typing the HLA Class I and Class II genes. This technique utilizes a flourescent-labelled locus-specific reference DNA to selectively modify the molecular conformation of the tested DNA, and the HLA type is assigned on the basis of accurate measurement of conformation-dependent DNA mobility in polyacylamide gel electrophoresis (PAGE). This method allows the discrimination of HLA alleles, which differ by one nucleotide in a DNA fragment nearly as large as a kilobase, by using internal DNA markers for correction and gel variability and utilizing the laser-based instrumentation and computer software. Drs. Arguello and Madrigal have successfully used this method in blinded studies of HLA typing and have demonstrated its reproducible results and its ability to identify new alleles and to resolve ambiguous heterozygous combinations.

Publications:
 
 View a partial list of Dr. Iqbal's publications through the National Library of Medicine's PubMed online database.