Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 10, Issue 1, 2012

Welcome to the first issue of 2012 of Cardiovascular & Hematological Agents in Medicinal Chemistry. I hope everyone has had a wonderful holiday season and I want to wish everyone a wonderful New Year. As you are aware, our journal aims to cover the latest and outstanding developments in medicinal chemistry, rational drug design for the discovery of novel cardiovascular and hematological agents and discusses such therapies in clinical practice. Each issue contains a series of timely in-depth reviews, original research articles and drug clinical trial studies written by leaders in the field covering a range of current topics in cardiovascular and hematological sciences. I feel that Cardiovascular & Hematological Agents in Medicinal Chemistry is an essential journal for every medicinal chemist, clinician and healthcare provider who wishes to be kept informed and up-to-date with the latest and most important developments in cardiovascular and hematological drug discovery and their clinical uses. In the coming issues of the journal, we will discuss several important topics pertinent to medicinal chemists and clinicians in the cardiovascular and hematology field such as evidence for the use of adrenaline in the treatment of neonatal hypotension, use of selective Inhibitors of plasma kallikrein, potential cardiotoxic effect of clozapine, novel antiplatelets agents in cardiovascular medicine among others. Cardiovascular medicine and hematology are both very dynamic fields with rapid advances and we will continue to strive to keep you up to date on new advances and therapies. I would also take this opportunity to invite our readers and experts to contribute hot topics and general articles in their respective fields to our journal. The journal is in its tenth successful year of publication, and is indexed by all major indexing media including Chemical Abstracts, EMBASE/Excerpta Medica, Index Medicus/MEDLINE, BIOSIS Previews, BIOSIS Reviews Reports and Meetings, Google, Google Scholar, Genamics JournalSeek, MediaFinder®-Standard Periodical Directory and Scopus and remains a valuable resource for chemists and clinicians.

Hemoglobin disorders, including thalassemia and sickle cell disease, are prevalent in populations that evolved in moderate and humid climates where malaria was endemic. Thalassemia is an inherited, autosomal recessive disease that involves a reduced rate of synthesis of a globin chain that is essential for hemoglobin synthesis. This reduced synthesis can cause abnormal hemoglobin molecules to form, leading to anemia in humans. Thalassemia and sickle cell disease affect all ethnic populations. Extensive literature on these disorders suggests that α-thalassemia and sickle cell trait that are known to protect against malaria. β-thalassemia is associated with people of Mediterranean origin and the Indian subcontinent, particularly Northern India and Pakistan. Sickle cell disease is prevalent on the African continent and, to a greater extent, in tribal areas of central and southern of India. In the last 3 decades, tremendous progress has been made in understanding of hemoglobin disorders, including the nature and types of hemoglobin diseases, animal models that can be used to advance our understanding of these diseases, possible early diagnosis of β-thalassemia that can be treated with blood transfusions, and finally the risks of repeated blood transfusions for patients with β-thalassaemia and sickle cell disease. The purpose of this special topic was to assess the current understanding of thalassemias and sickle cell disease and to review advancements in diagnosing and treating them, including a review of risks associated with blood transfusion, including iron chelating agents - as emerging treatments for these diseases. It is my hope that this issue provides timely resource for all those who are interested in thalassaemias and sickle cell disease. I am most grateful to all the contributors and outstanding reviewers for their efforts in making this special issue a reality. Sincere thanks also to the Editor, Dr. Debabrata Mukherjee, the Editorial manager, Mr. Rao G. Hussain and the production team of Cardiovascular & Hematological Agents in Medicinal Chemistry for their professional support and the opportunity to assemble this special issue.

Malaria is globally endemic in tropical and subtropical regions and so is the hemoglobinopathies, thalassemias and glucose-6-phosphate dehydrogenase (G6PD) deficiency. This biological dogma of hyper-endemic all over the tribal land in India leads to high morbidity and mortality. The directed genetic abnormalities of human erythrocytes have found to decrease the susceptibility towards malaria parasites and the heterozygotes of abnormalities probably confer protection against the Plasmodium falciparum infection. A fascinating trend for an inverse relationship between sickle cell disorders and G6PD deficiency in scheduled caste and tribal communities of Central-Eastern India has been observed. When the frequency of sickle cell allele decreases in malaria endemic cross-section of the tribal population, the frequency of G6PD deficiency allele increases and vice versa. This medical aspect is important from an evolutionary biological background and could be an excellent point for molecular analyses to determine the signature of selection in the genomic regions of β- globin and G6PD genes. Since the selection favors the mutation with least cost to the population [as the clinical manifestations of G6PD deficiency are mild and do not result in a complete loss of enzyme activity against the sickle cell disease with high morbidity and mortality in the region] and the predominant frequency of G6PD deficiency over the sickle cell disorders in some tribal communities, it seems that the replacement of sickle cell allele for G6PD deficiency is occurring in the scheduled castes/tribes of Chhattisgarh, Madhya Pradesh, Maharashtra and Odisha states in Central India. These findings are consistent with our previous studies carried out in Central-Eastern India.

Beta (β) Thalassemia is a common globin gene disorder in India. Although about 65 different mutations are known in the multiethnic populations of India, the group of 9 ‘core mutations’, i.e. IVSI,5 (G>C){HBB:c.92+5G>C}, 619 base pair deletion(bp del){NG_000007.3:g.71609_72227del619}, FS8/9 (+G){HBB:c.27_28insG}, IVSI,1 (G>T) {HBB:c.92G>T}, FS41/42 (-CTTT){HBB:c.124_127del-CTTT}, C15 (G>A){HBB:c.47G>A}, FS16 (-C){HBB:c.51delC}, C30 (G>C){HBB:c.93G>C} and C5 (-CT){HBB:c17_18delCT} cover about 96% of mutations in the carriers. We attempted a multiplex PCR to detect these mutations using ARMS method and strategized it in high risk groups of western India. The system was found reliable, cost effective, fast and most applicable for mutation screening of β Thalassemia in Indian populations.

Beta-Thalassaemia Major is a genetic blood disorder caused by the reduced synthesis of beta globin chain. The consequences of the resulting chronic anaemia are also common and include growth retardation, bone marrow expansion, extramedular hematopoiesis, splenomegaly, increased intestinal iron absorption, susceptibility to infections, and hypercoagulability. Transfusional iron overload can affect heart function by directly damaging tissue through iron deposition or via iron-mediated effects at other sites. Cardiac dysfunction is common in patients with thalassaemia and is the leading cause of mortality. The main cardiac abnormalities reported in patients with thalassaemia major (TM) and iron overload are left ventricular systolic and diastolic dysfunction, pulmonary hypertension, valvulopathies, arrhythmias and pericarditis. These cardiac abnormalities are a consequence of the general co-morbid conditions in thalassaemia but are closely related to concomitant endocrine deficiencies, hypercoagulability state and inflammatory milieu. Iron's toxicity within cells arises from its capacity to catalyse the production of reactive oxygen species that cause lipid peroxidation and organelle damage, which lead ultimately to cell death and fibrosis. With the introduction of new technologies such as cardiac magnetic resonance T2∗ , the early detection of cardiac iron overload and associated cardiac dysfunction is now possible, allowing time for reversal through iron chelation therapy.

The recent discovery of the “Stress Repair Mechanism” (SRM) enables the Unified Theory of Medicine postulated by Hans Selye. It confers cohesive theories of anesthesia, analgesia, and allostasis that enable the alteration of anesthetic technique to optimize surgical outcome. The SRM continuously maintains and repairs the vertebrate body in accord with stressful forces and stimuli. Three synergistic pathways activate the SRM: the spinal pathway, the cognitive pathway, and the tissue pathway. Emotional mechanisms modulate the cognitive pathway, which explains allostasis. Surgery simultaneously stimulates all three synergistic pathways, causing harmful SRM hyperactivity that manifests as the Surgical Stress Syndrome. Anesthesia inhibits the cognitive pathway. Analgesia inhibits the spinal pathway. Synergistic combinations of anesthesia and analgesia minimize SRM hyperactivity better than either alone. This principle improves outcome, simplifies anesthetic technique, and minimizes polypharmacy and drug toxicity. Once verified, stress theory will advance surgical safety, accelerate recovery, minimize complications, reduce costs, enhance patient comfort, and guide pharmaceutical development to discover treatments that inhibit the tissue pathway, and thereby eliminate surgical stress altogether.

Aim: The authors of this review present the current evidence of the physiology, indications and use of adrenaline in neonates, with particular focus on the treatment of hypotension. Method: A structured literature search was performed across selected electronic databases, reference lists and related articles. Abstracts arising from the search were screened for relevance according to predefined inclusion criteria. Full articles for the selected abstracts were obtained and then reviewed. Articles were analysed through a two stage process until agreement was reached between the research team on the studies for inclusion. Results: We identified 187 animal and human studies (published between 1924-2011) using various methodologies but with two main themes: the physiology of endogenous adrenaline in neonates and the therapeutic uses of this hormone in neonatal medicine. The physiological studies measured catecholamine levels in cord blood, neonatal urine and blood, some in response to interventions such as suctioning, skin massage or morphine infusion. Within the therapeutic studies there was only one randomised controlled trial (RCT): a comparison of dopamine versus adrenaline involving 60 infants of < 32 weeks gestational age. Conclusion: Despite the number of studies identified, we found few adequately-controlled studies on the therapeutic use of adrenaline in neonates. Future research should focus on RCTs comparing adrenaline to other commonly used inotropes.