Bio-reductive Activated Prodrugs (Research Paper Sample)

Bio-reductive Activated Prodrugs
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The term prodrug refers to a compound, which is a form of medication that is usually metabolized into a pharmacologically active drug after it is administered. It is converted within the body, which is what ‘metabolized’ means in this context. Doctors explain that a matching prodrug can be used to improve the manner in which a medicine is distributed, metabolized, absorbed and excreted as opposed to administering a drug directly to a patient. The importance of a prodrug comes in when a d drug is poorly absorbed into the gastrointestinal tract seeing as prodrugs are specially designed to improve bioavailability. When manufacturing prodrugs the focus is set on its ability to improve how selectively the drug interacts with the processes and the cells that are not intended to be targeted. The goal here is to get rid of the unintended and often adverse effects of a certain drug, especially when it appertains to serious treatments such as chemotherapy. In such cases, doctors have warned of undesirable side effects, which reiterate the importance of administering the drug in question properly.
Most of the herbal extracts used in the field of medicine over the years contain sugar derivatives clinically referred to as glycosides. These sugar derivatives, as Professor Michelle Hathaway of Oxford University explains, also referred to as glycosides of the active agent are hydrolyzed in the small intestines to release a chemical compound identified as bioavailable aglycone. The example given in this case is that of salicin, a β-D-glucopyranoside that releases salicylic acid when cleaved by esterase (Dispinar et al, 2012). In 1897, researcher Felix Hoffman conducted a series of experiments one of which he made Aspirin, a synthetic prodrug of acetylsalicylic acid. In 1909, Sahachiro Hata completed his experiment in Paul Ehrlich’s lab where he discovered Arsphenamine, which is identified as the first ever synthetic antimicrobial drug (Thambi et al, 2014). Unless it has been converted to an active form in the body, Arsphenamine is not toxic to bacteria. Another sulfa drug called prontosil releases sulfanilamide, an active molecule, but for this to happen it must be cleaved in the body just like arsphenamine. This drug was discovered in 1932 by Gerhard Domagk and since then numerous other examples have also been identified.
Like in every clinical experiments there have been various moral concerns regarding the invention of bioreductive prodrugs. Given these concerns, the manufacture of the first ever non-sedating antihistamine clinically known as terfenadine had to be recalled owing to the foreseeable side effects that could hurt the patient when administered (Feng et al, 2017). The parent compound, however, was discovered not to carry the same side effects with the prodrug of the active molecule fexofenadine. Following a series of clinical experiments, therefore, it was determined that the latter could be placed in the market after it became evident that fexofenadine would make a safe replacement of the original prodrug. Further research attributed anti-histaminergic effects of the parent compound to the non-sedating antihistamine loratadine (Thambi et al, 2014). In this case, however, it was discovered that that the side effects attributed to terfenadine were did not apply to the parent compound. As such it is now safe to market laratadine and desloratadine, which is its active metabolite, according to that research. The moral concerns associated with the production of this prodrug were therefore addressed to ensure that patients are getting quality medicine.
Presently an estimated 10 percent of the produced and marketed medicine are considered prodrugs. Equally, the Food and Drugs Administration (FDA) has approved approximately 30 prodrugs since 2008. Some of the prodrugs listed since then are latanoprostene bunod, which is the latest to be approved in 2017, gabapentin enacarbil (2011), dabigatran etexilate (2010), selexipag (2015), aripiprazole lauroxil (2015), tedizolid phosphate (2014), sofosbuvir (2013), and isavuconazonium approved earlier in 2015 (Feng et al, 2017).
The move towards bio-reductive activated prodrugs marks a significant milestone in medicine, especially now in the era of personalized health care. Bio-reductive prodrugs are hypoxia activated and they target low-oxygen tumor compartments to antineoplastic agents. Much of the research conducted in the prodrugs field has yielded compelling evidence that directly links hypoxia with adverse prognosis and treatment resistance (Feng et al, 2017). In spite of this compelling evidence, researchers found that selected prodrugs failed to show efficacy as seen in pivotal clinical trials. This outcome, in the contemplation of experts in the medical field, calls for a reflection on the discovery and production of these compounds. Once settled it clears the way for the introduction of more prodrugs in the market.
In this respect, evidence shows that there is a clear disconnect between the pharmacology of bio-reductive prodrugs and the pathobiology of tumor hypoxia with regard to the manner in which they have been clinically developed. The activity of bio-reductive prodrugs is discovered to be dependent on the coincidence of tumor hypoxia, intrinsic sensitivity of malignant clones, and expression of specific prodrug activating reductases (Thambi et al, 2014). The hypoxia itself varies significantly in effect for individual tumors; and it does not necessarily apply to certain cancer subtypes. Ultimately, overcoming the technical setbacks of discovering and developing hypoxia-activated prodrugs and defining the predictive biomarkers is considered an essential milestone in the new era of personalized cancer care.
The existence of hypoxia in tumors preceded the discovery of cellular oncogenes and coincided with the discovery of DNA structure. Meanwhile, the compelling rationale for the introduction of clinical stage drug development programs was the prevalence of hypoxia and its association with treatment failure and its contribution to poor prognosis in multiple indications. Most of the studies in this field focus on prodrugs of antineoplastic agents activated by oxygen inhibited enzymatic reduction in the cells (Lee et al, 2013). In this effect, clinical development has been discontinued for six compounds namely banoxantrone, apaziquone, porfiromycin, PR-104, tirapazamine, and RH1. However, the clinical development of two compounds named tarloxotinib bromide/TH-4000 and evofosfamide/ TH-302 remain active (Dispinar et al, 2012). According to reports, the latter did not achieve primary survival endpoints in relation to chemotherapy. Therefore, the evident failure in the clinical development of evofosfamide and tirapazamine, two of the major prodrugs attracted the need for a review of the specific liabilities that will help with the correction of drug discovery efforts in the future. In many ways, the clinical development of hypoxia-active or bio-reductive prodrugs is yet to fully meet the scientific advancements in molecular profiling for quality treatment of various cancer subtypes and tumors in medical oncology. According to a series of studies conducted by Mateo et al (2015) Chapman et al (2011), the major setback of the clinical development of prodrug compounds is confounded by the heterogeneity of the target and complex biology of the target as well as the failure to clearly define and access clinical indications where hypoxia is treatment limiting due to its presence (Feng et al, 2017). It is to be understood here that the clinical development of these primary compounds is performed using diagnostic assays that are deemed fit for commercial drug developing by meeting certain standards set by the FDA (Dispinar et al, 2012). Treatment limiting hypoxia is especially imperative as it appertains to bio-reductive prodrugs od specific DNA-responsive cytotoxins. Given the toxicity of these cytotoxins there needs to be a significant dose reduction to boost the quality of the standard of care, especially in the new era of personalized medical care. Similar studies have revealed that the need to develop diagnostics of projecting the sensitivity of specific tumors to hypoxia-activated prodrugs is of paramount importance. The effort undertake in this respect requires a strong understanding and comprehension of the molecular pharmacology of these compounds. Working with this claim, the challenges for developing bio-reductive prodrugs are understood to be reflective of the broader trends of the clinical manufacture of precision medicine in general.
Bio-reductive activation of N-oxide-based prodrugs
An enveloping number of studies indicate that tertiary amine N-oxides qualify as bio-reductive prodrugs. The N-oxides are derivatives of DNA intercalators are relatively non-toxic prodrugs and a series of lab research studies has proven that the non-toxic N-oxide prodrugs can be activated – under hypoxic conditions - by enzymatic reductions (Thambi et al, 2014). The bio-transformation referred to here can largely increase the DNA binding affinity by introducing cationic charge. This process will provide a hypoxia proactive prodrug mechanism for activation. There are several features that N-oxides have that make them part of this class of bio-reductive prodrugs. The three intercalator N-oxides called AQ4N, DACA-NO, and NC-NO give out AQ4, DACA, and NC nitracrines respectively on reduction (Dispinar et al, 2012). The three N-oxides were found to be less toxic and they were seen to have remarkable increases in cytotoxicity under hypoxia. A series of experiments also reveal that the DACA and AQ4 nitracrines and their corresponding N-oxides were more active on cycling cells and less ...