Category Archives: Pharma

DNA Drug Design for Cancer Therapy

6A direct genetic approach for cancer treatment is represented through DNA (antisense and other oligonucleotides (ODN’s)) drug design. This approach follows the mechanisms that activate genes known to confer a growth advantage to neoplastic cells. They have the ability to block the expression of these genes which allows exploration of normal growth regulation. As the Progress in DNA drug technology has been rapid, the traditional antisense inhibition of gene expression is now viewed on a genomic scale. Several antisense oligonucleotides are in clinical trials. These antisense oligonucleotides are well tolerated, and are potentially, therapeutically active. These drugs are promising molecular medicines for the treatment of human cancer in the near future.

Antisense or decoy DNA drugs can specifically inhibit gene expression and, as indicated in this review, can ultimately affect abnormal cell proliferation. Downregulation of genes that contribute to cancer progression has been the goal of antisense research, with the expectation that such an approach may lead to a selective or preferential inhibition of tumor growth without harming normal cell growth. Such targets include oncogenes, growth factors, cytokines, protein kinases, phosphoprotein phosphatases, and other positive intracellular regulators of cell growth and cell survival. Although a number of studies have demonstrated in vitro the efficacy of these ODNs against tumor growth, an examination of their long-term effects and pharmacological properties is warranted.

Recent advances in high-throughput screening of gene expression by microarray analysis would permit these studies. Results from these studies will not only provide critical information on ODN pharmacokinetics and toxicity, they will also provide insight into the mechanism of action of these molecules on their own targets and on total cellular gene expression. Such studies will thus narrow the number of selected target genes and the discovery of new target genes for antisense therapeutics.

Revisiting antisense-targeted gene expression on a genome-wide scale will facilitate the discovery of clinically appropriate antisense drugs and provide a unique perspective on the development of new chemotherapeutic combinations based on the molecular actions of these drugs.

Unlike conventional chemotherapy regimens, which depend on the maximum tolerated dose of a given drug to achieve optimal tumor-cell kill, treatment regimens involving antisense ODNs may rely more on the concept of an optimal biological dose. The ultimate goal of therapeutic ODNs is their use as long-term biological gene modulators with minimal or no toxicity. In that case, antisense ODNs represent cytostatic rather than cytotoxic drugs. As such, ODNs can induce tumor cells to differentiate or revert, eventually leading to apoptosis, and reduce or eliminate the chance of relapse in cancer patients following initial treatment. For utmost therapeutic effect, these biological target based antisense DNA drugs can be used at nontoxic minimum doses in combination with low doses of conventional cytotoxic drugs or radiation therapy for cancer.

New Antibody Conjugates in Cancer Therapy

drug_conjugateTargeting of drugs, radiation and protein toxins to cancer selectively with monoclonal antibodies (MAbs) has been considerable as a topic of interest and an area of continued development. Radioimmunotherapy of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled 90Y-epratuzumab ,anti-CD22 MAb. The advantage of pre targeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of solid tumors and lymphoma. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and pre clinically. The area of drug-conjugated antibodies is progressing with encouraging data for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The technology of Dock-and-Lock platform has contributed to the design and the evaluation of antibody-toxin conjugates and complex antibody-cytokine.

RADIOIMMUNOCONJUGATES

Radioimmunotherapy (RAIT) involves in the application of radiolabeled MAbs for targeted radiotherapy (RT). Both directly radiolabeled MAbs and in vivo radiolabelings of tumor-targeted MAbs by complexation with radiolabeled haptens have been developed.

Radionuclides Used for RAIT

Tumoricidal effects produced by continuous low-dose irradiation from a tumor-targeted radiolabeled MAb. For therapy, α- and β-particle emitters are of practical relevance. There have been numerous investigations with a number of these radionuclides, but for use with whole antibodies, the most promising radionuclides are the β-emitters 131I, 90Y, and 177Lu. 90Y is a max-energy β-emitter (Emax: 2,280 keV; max range: 12 mm) with a 64-h half-life, while 131I has a higher half-life of 8.1 days with low-intermediate energy (610 keV, range: 2.0 mm). 131I is quickly removed from tumor cells after intracellular antibody catabolism so it is not suitable for use with internalizing MAbs. The forms of intracellularly trapped 131I have been designed by us and others for use with internalizing MAbs. A recent study of IMP-R4 template utilized for incorporating residualizing radioiodine for immuno-PET quantitation of de2-7 EGFR expression in glioma in a xenograft model using 124I-IMP-R4–labeled anti-EGFR antibody, ch806. Residualizing use of radioiodine method for clinical RAIT may be supplanted by the availability of the metallic radionuclide 177Lu, which has radiophysical properties similar to those of 131I and radiolabeling chemistry similar to that of 90Y.

Medicinal Chemistry Current Approaches to Drug Discovery for Cancer and Tropical Diseases.

4The remarkable changes in technological and scientific developments in the past years have dramatically changed the pharmaceutical innovation process. Well-established strategies, such as high-throughput screening (HTS), have progressively been applied in association with novel techniques founded on genomics and proteomics, molecular and structural biology and molecular modeling. Altogether, these fields have provided outstanding advances for our comprehension of the fundamental cellular and molecular mechanisms of diseases in addition to enabling important progress in the technological arsenal used in drug discovery. Combined with novel methods in organic synthesis, such as combinatorial chemistry, the forefront approaches have built a novel paradigm in the research-based pharmaceutical industry.

Evolving paradigm, which has its roots attached to the recent advances in medicinal chemistry, molecular and structural biology, has unprecedentedly demanded the development of up-to-date computational approaches, such as bio- and chemo-informatics. These tools have been pivotal to catalyzing the ever-increasing amount of data generated by the molecular sciences, and to converting the data into insightful guidelines for use in the research pipeline. ligand- and structure-based drug design have emerged as key pathways to address the pharmaceutical industry’s striking demands for innovation. These approaches depend on a keen integration of experimental and molecular modeling methods to surmount the main challenges faced by drug candidates’ in vivo efficacy, pharmacodynamics, metabolism, pharmacokinetics and safety.

The novel scientific drug discoveries and technological advances are incorporated into the field due to the constant evolving of drug development. More efficient organic synthesis methods, chemical biology approaches and bio- and Chemoinformatics strategies have dramatically changed the process by which an initial hit is converted into a marketable drug. In part, this can be attributed to the expansion of the field towards novel therapeutic areas that are at the limits of the science and technology available today. Indeed, Present Modern strategies are strongly dependent on the high-quality interplay between the basic research originating from research institutions and academia and the Research & Development(R&D) expertise coming from industry.

In this context, multidisciplinary and integrated approaches are indispensable. Research facilities able to perform experimental and computational studies to evaluate pharmacodynamics and pharmacokinetics are greatly needed to identify molecules with a high potential to become drug candidates. This scenario demands a steady input from several areas of the chemical sciences, such as organic, medicinal chemistry, and biological chemistry, which stand at the frontier of the current drug R&D model. The integration of these disciplines in well-structured and consistent research projects is critical for developing promising drug candidates for treating critical conditions such as cancer and other topical diseases.

Current status of recombinant antibodies in cancer therapy

There are many types of cancer treatment. The types of treatment that you receive will depend on the type of cancer you have and how advanced it is. Some people with cancer will have only one treatment. But most people have a combination of treatments, such as surgery with chemotherapy and/or radiation therapy, hormone therapy, targeted therapy, immunotherapy and precision medicine.

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Antibodies have come a long way from those initial isolated by hybridoma over thirty years past to trendy engineered fragments, made by rational design. The utilization of antibodies in cancer therapy is increasing apace, with eleven antibodies approved over the past decade and quite five hundred in progress clinical trials involving monoclonal antibodies. The mixture of the antibody’s inherent characteristics with the growing pool of tumour-specific antigens has generated a large array of antibody-derived tools that area unit specifically designed to suppress and eliminate cancer cells.

Recombinant antibodies have evolved into successful therapeutics with ten approved for cancer and additional within the pipeline. Four of the highest 10 cancer therapy medicines are recombinant antibodies. Objectives: To survey the present progressive lightness the explanations for this success and looking out ahead to a subsequent generation of antibody therapy. Methods: AN analysis was dispensed to spot preclinical and clinical examples and also the underlying ideas and mechanisms that have shown a way to design higher therapies. Results greater understanding of the molecular basis of cancer has led to improved antibodies and a greater choice of targets. Fine standardisation of successful antibodies through modification of glycosylation, affinity, size and different parameters area unit paying dividends. Fc-engineering is probably going to be predominant within the close to future, however, conjugates, fragments and fusion proteins can still be developed and find their place within the arsenal of antibody therapeutics.

How to dose cytotoxic chemotherapeutic drugs

Cytotoxic drugs or Cytostatics

Cytotoxic medications or cytostatics are drugs used to pulverize tumor cells. Cytotoxic drugs inhibit cell division and in this way cause cancer cells to die. Cytotoxic medications are transported in the circulatory system all through the body. Cytotoxic medications can be utilized to crush tumors, help the results of medical procedure or radiotherapy, decrease metastases and reduce malignancy indications. Cytostatics can destroy small tumours that have not been detected in tests. Cytotoxic drugs affect all healthy tissue, including those of dividing cells. But since disease cells regularly isolate notably quicker than ordinary cells, they are especially delicate to cytostatics. The consequences for ordinary cells are less pronounced and healthy cells also recover faster.

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Cytotoxic chemotherapeutic specialists have vast individual fluctuation and narrow therapeutic windows in pharmacokinetics/pharmacodynamics, dosing of these operators requires exact change. In spite of the fact that the body-surface area (BSA) has for quite some time been utilized for this reason, its adequacy for limiting interpatient fluctuation in pharmacokinetics has been addressed. The components that conceivably add to between singular changeability in medicate reaction are looked into, with an extraordinary spotlight on cytotoxic chemotherapeutic medications, for example, platinum-containing operators, taxanes, irinotecan, and antimetabolites. That the utilization of BSA neglects to limit between tolerant inconstancies in sedate reaction, causes bother in reconstituting singular dosages, and can result in human mistake, introductory level dosing with consequent restorative medication checking may be a sensible alternative.

Side effects of cytotoxic drugs

Cytotoxic medications achieve all cells in the body and they kill healthy cells as well as cancer cells. This is the reason chemotherapy has antagonistic symptoms. Treatment as a rule causes sickness, male pattern baldness and exhaustion. The reactions change starting with one individual then onto the next. A portion of the reactions vanish following a couple of days, however it for the most part takes a couple of months for you to make a general recuperation from chemotherapy. Since cytostatics influence separating cells, a considerable lot of the reactions are focused on inexhaustible tissue, for example, hair, bone marrow and mucous layers. The sort and seriousness of the symptoms rely upon the medications utilized, measurements, your general condition and how our body reacts to the medications. The most well-known reactions would nowadays be able to be viably averted and treated.

Food Toxicology

The Toxicology is the branch of science that deals with the adverse effects of chemicals on living organisms and leads to fatal condition in living organism.

Toxicology is interface of chemistry and biology.
Pharmacology: therapeutic effect
Toxicology: toxicosis or disease effect
Food toxicology deals with physical, chemical and biological properties of food particles and detection of toxic substances in food, and their diseases and infections.

Some food items are poisonous and some are medicinal, stimulatory, hallucinatory, or narcotic effects.

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Toxicology in two categories: basic and Fundamental. Fundamental work on the molecular and biological processes of toxic substances is called Basic toxicology. Applying scientific knowledge to practical problems is called Applied Toxicology.

Toxicology vs. Risk analysis: In majority of Risk analysis only the applied toxicology is used to examine whether there is the presence of chemical, natural and anthropogenic is used. Risk analysis is broadly classified to include Risk assessment, Risk characterization, Risk communication, Risk management.2

Human health risk assessment: Predictive modelling of the toxicology to human health posed by the exposure to toxicants. • For constituents that are systemic toxicants, the threat can be expressed in terms of a hazard quotient. • Hazard Quotient = Dose ÷ Toxicity Factor. Systemic toxicity is a threshold phenomenon. – Increasing exposure (dose) of a chemical will cross a threshold when biological effects will start to occur. – The dose is the total dose attributable all routes of exposure. Dose is modeled with the following general equation (unit conversion factors are used as needed): Dose = CC × CR × EF ÷ (BW × UCF) • CC — constituent • CR — contact rate • EF — exposure frequency. • BW — body weight . • UCF — unit conversion factor.

APPROACHES IN PHARMACOVIGILANCE

1The importance of pharmacovigilance the ongoing assessment of the safety of a marketed medicine has been increasingly appreciated in recent years, owing in part to high-profile safety issues with widely used drugs. In response, strategies to improve the collection, integration and analysis of data related to post-marketing drug safety are being initiated or enhanced. The key tools that are available for pharmacovigilance are appropriate to use in different situations and consider the future directions of the field.

Study designs used in pharmacovigilance

Case reports and case series:  Case reports are concerned with single patients who have been exposed to a drug and experienced an adverse reaction. Case series can refer to a collection of patients who have been exposed to the same drug and whose clinical outcomes are then evaluated and described. Alternatively, a case series can be a collection of patients with a single outcome, whose history is then checked to ascertain previous drug exposure.

Case-control studies:  Case-control studies are retrospective studies where a group of patients with a particular disease (or ADR) are compared with a group of patients who do not have the disease, and their histories of previous exposure to a “risk factor” are compared. They can be used to study multiple drug exposures, uncommon diseases. They are relatively easy, fast and cheap in terms of data collection. However, case control studies also have their weaknesses i.e. Finding appropriate matched controls may be difficult.

Cohort studies: Cohort studies compare a group of individuals with a drug exposure to a group without the same exposure in terms of adverse outcomes. The study can be either prospective or retrospective. They allow calculation of incidence rates and precise risks and can be used to study multiple outcomes providing unbiased drug exposure data with selection bias less than in case-control studies. Their weaknesses are that they are relatively more expensive, especially the ad hoc studies.

Meta-analyses: In this era of evidence-based medicine, meta-analyses allow investigators to review clinical trial data systematically. Although most investigators are interested in the efficacy of treatments, it is also possible to investigate adverse outcomes systematically. A systematic review of randomized controlled trials involving administration of human albumin in critically ill patients has been undertaken.

Until recently, pharmacovigilance was mainly based on spontaneous reports, which provide low evidence of risks associated with medicines. Today, the importance of the full spectrum of the evidence hierarchy is recognized. This article reviews new approaches and data sources used in pharmacovigilance and shows that individual case safety reports, observational data, clinical trials and meta-analyses have unique characteristics that complement each other for the overall benefit–risk evaluation of medicines

In the past two decades, pharmacovigilance scientists have increasingly adopted the fundamentals of epidemiological research and applied them to the study of drugs. These techniques give us better understanding of the beneficial and adverse outcomes of medicines use. No doubt they will continue to play important roles in pharmacovigilance.

Test drug trains in on malignancies related with Epstein-Barr infection

Epstein-Barr Virus (EBV) doesn’t straightforwardly cause malignancy, yet disease with this normal herpes infection brings an expanded danger of a few cancers, including quickly developing lymphomas. This week in mSphere, analysts write about another medication that works by focusing on EBV-positive tumors. In investigates mice, the medication restrained tumor advancement and metastases for EBV-related lymphomas. The discoveries propose the medication might be helpful in treating malignancies in EBV-positive patients and have prompted a stage I trial in that patient populace.1

The Epstein-Barr infection is common to the point that nearly everybody has been contaminated when they achieve their twenties. A contamination can cause mononucleosis (the “kissing sickness”), however numerous individuals stay asymptomatic their whole lives. An expanded danger of different sorts of tumor, including nasopharyngeal and stomach malignancies, has been related with EBV diseases.

Diseases by EBV are thought to advance the development of B lymphocytes, bringing about lymphomas. Significantly, EBV encodes a protein called LMP2A (Latent Membrane Protein 2A) that can seize the phone flagging component of the B cells it taints. Researcher has discovered that LMP2A can both anticipate apoptosis, or cell passing, and drive the cell-division cycle, advancing disease in murine models. For the new investigation, researchers considered mice that had been hereditary changed to express LMP2A protein in B cells that advanced lymphoma improvement. In treated mice, the medication, a tyrosine kinase inhibitor called TAK-659, neutralized the malignancy advancing systems of the LMP2A protein. The medication slaughtered tumor cells however left host cells unaffected. It likewise advanced apoptosis in tumor cells and halted the spread of tumor cells into close-by bone marrow. 2

In view of past clinical research, the organization propelled three stage I clinical preliminaries to test the wellbeing of the medication in patients with a few lymphomas, intense myelogenous leukemia, and some strong tumors. Those investigations are enrolling. In light of the discoveries distributed for the current week in mSphere, which approved the medication’s viability in EBV-positive lymphomas, the organization included a partner of EBV-positive patients to one of those preliminaries.

The medication has guarantee both as a solitary operator and in mix with other disease treatments, including immunotherapies, it consolidates extremely well with checkpoint inhibitors, researchers said that the new discoveries exhibit the medication’s adequacy can be tried among various sorts of growth, as well as more by and large among those related with EBV.

New HIV treatment for drug-resistant patients

1In a clinical research, another HIV sedate diminished viral replication and expanded insusceptible cells in people with cutting edge, medicate safe HIV contamination. Utilized in mix with existing HIV solutions, the medication is a promising system for patients who have come up short on compelling treatment alternatives, the analysts said.

For a few people with HIV, existing medication treatments neglect to stifle the infection, prompting drug obstruction and intensifying illness. While a few HIV drugs focus on the infection viably, there has not been another class of HIV drug endorsed to battle the ailment in 10 years. A medication that objectives the essential receptor for HIV passage into insusceptible cells known as CD4 T cells. This novel system of activity keeps HIV from entering target cells.

Various destinations partook in the examination, including Yale, selecting patients with multi-sedate safe HIV. Patients got a dosage of ibalizumab, which is conveyed intravenously, notwithstanding their falling flat regimen, for multi week. After that period, they got ibalizumab in mix with advanced treatment regimens for a half year.

The exploration group found that following multi week on ibalizumab, most of the 40 patients (83%) selected in the investigation experienced lessening in viral load, which alludes to the measure of HIV identified in the blood. Following 25 weeks, about portion of patients saw viral load concealment plunge underneath the level of identification. The specialists likewise detailed an expansion in CD4 T cells, which are a marker for insusceptible quality. A solitary individual encountered an unfavorable occasion, which was felt to be ibalizumab-related and brought about withdrawal from the examination, the scientists said.2

The outcomes were outstanding for this medication safe populace of patients considered, they had greatly propelled HIV and safe infection with constrained alternatives. To see viral concealment in a huge level of these patients at a half year is gladdening. The outcome speaks to a genuinely necessary new component of activity for patients who have very safe HIV. As the primary monoclonal counter acting agent endorsed to treat HIV, ibalizumab is a promising choice for people who have attempted a few other medication treatments. As a result of its novel component, ibalizumab won’t collaborate contrarily with different meds. It is additionally conveyed intravenously at regular intervals and keeps going longer than current HIV drugs, which are taken every day by mouth.

Drug Discovery and Development

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At initial stage of Drug  Discovery, based on the single molecule disease target, scientist identifies the high specificity compound which modulates and interacts with the target. The approach used by them was “one target and one drug” approach which is the failure one. Thus, result in the intake of series of specific target drugs which reacts in ineffective way to the isolated target. The new drugs are prepared well than the previous generation to increase the life, strength, reduces the pain and suffering. The development of new drugs makes the pharma industry to take risk in cost and time. The new Drugs are discovered in the basis of cheap (to the people) and more effective. The various phase are there for drug discovery and development, at last the drug enters via New Drug Application (NDA) and then launched into the market only by satisfying FDA rules and regulations. The base for the drugs is synthetic molecules, which is directly, or indirectly a natural product or polyconstituents. In future the contemporary drugs and Ayurveda will have win –win relationship. Contemporary Drug discovery and development (DD) process is becoming longer and expensive. Establishing the right balance between efficacy and safety is the crucial part of DD process.

For more specific treatment, genetic engineering applications have been implemented, where targeted diseased gene is treated in more effective way by combination of pharmacology and genetic engineering.

Developments of new rationally designed targeted therapies:: Several recent phase-I trials of molecularly targeted agents have demonstrated remarkable progress when patients were selected based on their molecular profile and subsequently treated with an agent directed against this specific target. The shift from ‘one size fits all’ to molecularly defined subpopulations has been particularly successful in the treatment of patients.