3D render of a medical image with virus cells

Attacking Cancer Cells That Develop Resistance

Cancer remains one of the most intimating challenges in modern medicine, affecting millions of lives worldwide. While cancer treatment progress has been significant, resistance to therapies remains a serious challenge. Cancer cells often adapt and develop resistance to treatments that were once effective, leading to treatment failure and disease progression.

This article explores resistant cancer cells and current strategies to overcome them. Understanding resistance mechanisms and using advanced treatments can ensure successful treatment outcomes despite resistance challenges.

Understanding Cancer Cell Resistance

Cancer treatment faces a significant challenge: cancer cells become resistant to therapies that once worked. These resistance mechanisms vary from genetic mutations and epigenetic changes within cancer cells to the influence of the tumor microenvironment.

The consequences of untreated or recurrent cancer due to resistance are dire, often leading to poor outcomes and decreased quality of life for patients. Despite advancements in our understanding of these mechanisms, overcoming resistance remains a daunting task. The situation demands a collective effort to address this issue head-on.

Moreover, the economic burden of ineffective treatments adds another layer of urgency to the search for solutions. To combat this, it’s crucial to understand these mechanisms and find ways to target resistant cancer cells effectively.

Mechanisms of Resistance

  1. Genetic Mutations: Cancer cells can develop genetic mutations over time, making them less responsive to treatment. These mutations affect important cell functions, allowing cancer cells to survive and grow despite treatment.
  2. Epigenetic Changes: Changes in gene activity, called epigenetic alterations, also contribute to resistance. These changes can silence genes that control cancer growth or activate genes that promote it, making treatment less effective.
  3. Tumor Microenvironment: The environment around tumors plays a role too. Factors like low oxygen, inflammation, and nearby cells can protect cancer cells from treatment, making them harder to kill.

Importance of Finding Strategies to Attack Resistant Cancer Cells

  • Preserving Treatment Efficacy: Resistant cancer cells make treatments that used to work ineffective, lowering survival chances. Finding strategies to overcome resistance helps keep treatments working longer, improving patient outcomes.
  • Expanding Treatment Options: Overcoming resistance means more treatment options for patients. Clinicians can tailor treatment regimens to individual patients by targeting resistant cancer cells and optimizing therapeutic outcomes.
  • Enhancing Survival Rates: Effective strategies to attack resistant cancer cells prolong patient survival. By preventing or delaying disease progression, these strategies offer hope for better long-term outcomes.
  • Addressing Heterogeneity: Resistant cells within tumors vary, showing different resistance levels to specific treatments. Targeting resistant cells helps in reducing the likelihood of treatment failure and disease recurrence.

Current Strategies to Overcome Resistance

Researchers are exploring various innovative strategies to combat cancer cells that develop resistance to treatments. By understanding the underlying resistance mechanisms, these approaches aim to eliminate resilient cancer cells more effectively.

Here are some of the most promising methods being used today.

Targeting Cell-Cycle Kinase Inhibitors

Cell-cycle kinase inhibitors offer a promising solution against cancer resistance. These drugs slow or halt tumor growth by targeting cyclin-dependent kinases (CDKs). CDK inhibitors are effective, especially in hormone receptor-positive breast cancer, and reactivate natural tumor suppressors. 

Yet, cancer cells adapt, driving research into next-gen inhibitors targeting additional cell division enzymes. Consequently, early trials show potential for more effective, longer-lasting treatments, pushing researchers to innovate and outpace cancer’s adaptability for better patient outcomes.

Targeted Therapies

Targeted therapies focus on specific molecular targets linked to cancer. These treatments disrupt cancer cell growth and survival. For example, tyrosine kinase inhibitors (TKIs) block signals that make cancer cells grow. Even though resistance can occur through new mutations, targeted therapies like Imatinib for chronic myeloid leukemia (CML) and Trastuzumab for HER2-positive breast cancer have shown great success. They work best when combined with other treatments to help prevent resistance.

Combination Therapies

Combination therapies use multiple treatments to attack cancer cells from different angles, reducing the chance of resistance. This approach can include chemotherapy, targeted therapy, and immunotherapy. For example, combining BRAF and MEK inhibitors effectively treat melanoma by targeting different parts of the same pathway. This makes it harder for cancer cells to survive. Studies show that combination therapies improve response rates and extend progression-free survival, though managing side effects and interactions is important.

Immunotherapy

Immunotherapy uses the body’s immune system to fight cancer, making it a strong tool against resistant tumors. Checkpoint inhibitors like Pembrolizumab and Nivolumab block proteins that stop immune cells from attacking cancer. CAR-T cell therapy modifies a patient’s T-cells to target cancer more effectively and has been successful in certain blood cancers. Immunotherapy’s ability to adapt to cancer cells helps overcome resistance. Research is ongoing to enhance its effectiveness and manage side effects.

Nanotechnology

Nanotechnology uses nanoparticles to deliver drugs directly to cancer cells, increasing drug concentration at the tumor while reducing overall side effects. This approach can bypass resistance mechanisms like drug efflux pumps. Recent advances show that nanomedicine can improve the effectiveness of chemotherapy and targeted therapies.

Gene Editing and CRISPR

Gene editing tools like CRISPR can modify or correct genes responsible for cancer resistance. By targeting specific genes in resistance pathways, CRISPR can restore treatment sensitivity. Though still experimental, this technique shows promise for precision medicine despite ethical and technical challenges.

Emerging Experimental Treatments

New experimental treatments are being explored to fight resistant cancer cells. These include novel small molecules, antisense oligonucleotides, and adaptive therapy strategies. These innovative approaches are in various stages of research and trials, showing potential for future use in overcoming resistance.

Bottom Line

In our quest against cancer, resistant cancer cells stand as formidable opponents. Yet, with advancing knowledge and technology, we have potent weapons at our disposal. We’ve explored various strategies to combat resistance, from targeted therapies to immunotherapy and cutting-edge techniques like nanotechnology and gene editing.

Similarly, we at Globela, are open for collaboration across disciplines and borders, driven by the goal of defeating cancer. Globela’s Oncology department is committed to offering the highest quality products at affordable prices so that as many people as possible can benefit.

Whether you are a patient, a caregiver, or a healthcare professional, we are here to help you in your journey towards a cancer-free future.

19476ec9-e0b2-45c5-8e57-2119e55f6f12

Green Chemistry: A Catalyst for Transformation in Pharma Manufacturing

Green chemistry, also known as sustainable chemistry, has emerged as a hope for industries striving to minimize their environmental footprint while maximizing efficiency and innovation. Despite pharmaceutical companies’ significant economic contribution, their manufacturing processes contribute to carbon emissions. Pharmaceutical factories typically use dangerous chemicals and produce a lot of waste, but green chemistry can bring significant changes for a better environment. This article delves into how adopting green chemistry practices is necessary to revolutionize the future of pharmaceutical manufacturing.

Understanding Green Chemistry

Before exploring the implications of green chemistry for the pharmaceutical industry, it’s crucial to understand its basics. At its core, green chemistry aims to create chemical products and processes that reduce the use of hazardous substances.

Its principles include minimizing environmental impact and fostering innovation, efficiency, and safety in various industries. In pharmaceutical manufacturing, where complex chemical synthesis and rigorous quality standards are the norm, understanding green chemistry has become pivotal in a new era of sustainability and responsibility.

Consequently, green chemistry revolves around twelve guiding principles established by chemists Paul Anastas and John Warner. These principles encompass the design, synthesis, and utilization of chemical products. Also, these processes minimize environmental hazards and maximize efficiency. Some fundamental tenets included in green chemistry are waste prevention, using renewable feedstocks, energy efficiency, and designing safer chemicals and processes.

Reducing Environmental Impact

The pharmaceutical industry faces the challenge of minimizing its environmental footprint. Traditional processes use solvents, reagents, and procedures harmful to ecosystems and human health. Whereas, green chemistry provides innovative solutions without compromising product integrity. Some of these innovative solutions are: 

  1. Minimizing Waste Generation: Adopting continuous flow technologies and processes reduces waste volume, enhancing efficiency and mitigating pollution. 
  2. Embracing Renewable Feedstocks: Utilizing renewable biomass-derived feedstocks like plant oils and sugars minimizes reliance on finite fossil resources and lowers greenhouse gas emissions. Moreover, it promotes sustainability in pharmaceutical manufacturing.
  3. Optimizing Energy Efficiency: By reducing heat and electricity consumption, maximizing process integration, and leveraging renewable energy sources, pharmaceutical companies can save money and help the environment. Also, it makes their processes work together better, and using renewable energy sources.

Enhancing Safety and Compliance

What comes next in this is enhancing safety and compliance. Ensuring safety and compliance is paramount in pharmaceutical manufacturing. Green chemistry aligns with regulatory efforts to improve safety standards and promote sustainable practices within the pharmaceutical industry and they are: 

  1. Minimizing Exposure to Hazardous Substances: Green chemistry aims to replace toxic substances with safer alternatives, reducing workplace risks and fostering responsible chemical management.
  2. Meeting Regulatory Requirements: Adopting green chemistry ensures compliance with regulations like REACH and TSCA, demonstrating a commitment to sustainability and responsible stewardship.
  3. Embracing Sustainable Development Goals: Green chemistry aligns with SDGs, integrating environmental, social, and economic considerations to combat climate change and promote equitable healthcare.

Optimizing Efficiency and Cost-effectiveness

In pharmaceutical manufacturing, efficiency and cost-effectiveness are crucial for companies aiming to stay competitive while meeting quality and affordability demands. It can be achieved by embracing green chemistry principles, as many green technologies offer cost savings and process optimization opportunities. Several of them are: 

  1. Streamlining Manufacturing Processes: Green chemistry advocates for simpler, more streamlined processes in pharmaceutical manufacturing. It aims to optimize reaction conditions and employs innovative techniques such as continuous flow chemistry. These approaches lead to improved productivity and cost-effectiveness.
  2. Continuous Flow Chemistry: Continuous flow chemistry enables precise reaction control, reducing solvent usage and enhancing product quality and purity. It facilitates scale-up and agility in meeting market demands.
  3. Reducing Raw Material Waste: Green chemistry minimizes waste by promoting atom-efficient reactions and renewable feedstocks. Metrics like atom economy and E-factor help assess efficiency, leading to less waste and lower environmental impact.
  4. Enhancing Resource Efficiency: Efficient resource use, including energy and water, is central to green chemistry. Technologies like microwave synthesis reduce energy consumption, while bio-based materials lessen reliance on finite resources, mitigating environmental impact.

Innovating Drug Discovery and Development

Green chemistry is not limited to manufacturing; it’s also used in drug discovery and development processes. Traditionally, drug designs prioritize efficacy and potency without considering how they affect the environment. However, if we include environmental concerns when designing drugs, researchers can develop effective and environmentally friendly drugs. A few of them are: 

  1. Designing Eco-Friendly Molecules: In green drug discovery, designing molecules considers therapeutic effectiveness and environmental impact. It involves renewable feedstocks, safer solvents, and efficient synthetic routes guided by ecological profiles.
  2. Biocatalysis and Enzyme Engineering: Enzymes catalyze reactions with high precision and biodegradability, enhancing sustainability. Tailored enzymes enable efficient synthesis of complex molecules, reducing environmental impact in drug discovery.
  3. Green Synthesis Routes: Novel synthesis routes in green drug discovery minimize ecological impact and maximize efficiency. Continuous flow technologies control reactions, reducing waste and resource use for scalable, streamlined processes.
  4. Collaborative Initiatives and Knowledge Sharing: Green chemistry’s full potential in drug discovery requires collaboration. Partnerships and platforms facilitate idea exchange, accelerating innovation for the widespread adoption of sustainable pharmaceutical practices.

Challenges and Roadblocks

Green chemistry promises transformative economic and environmental benefits, reshaping the industry towards sustainability and environmental stewardship. However, the widespread adoption of green chemistry in pharmaceutical manufacturing is not without challenges.

One major obstacle is the inertia of established practices and infrastructure, making it difficult for companies to transition to greener alternatives. Additionally, there may be technical hurdles and regulatory barriers to overcome, particularly when validating new processes and ensuring product quality and consistency.

These challenges require diverse solutions, including:

  • Basic training in process excellence and renewable energy use,
  • Provide financial incentives or awards for companies embracing greener alternatives,
  • Allocate funding for research and development focused on overcoming technical challenges,
  • Work with regulatory agencies to develop clear guidelines for green chemistry practices.

Conclusion

In a nutshell, green chemistry offers a promising pathway towards transforming pharmaceutical manufacturing into a more sustainable and environmentally responsible industry. 

By prioritizing renewable feedstocks, minimizing waste generation, and enhancing safety and compliance, companies can reduce their environmental footprint and improve efficiency and cost-effectiveness. 

Despite challenges such as entrenched practices and regulatory barriers, collaborative efforts and innovative solutions can pave the way for the widespread adoption of green chemistry principles, ushering in a greener future for pharmaceutical manufacturing.

WhatsApp Image 2024-04-15 at 17.49.58

Innovations in Nephrology Care: Exploring the Latest Treatment Options

Introduction

Nephrology emerged as the leading internal medicine subspecialty post-WWI. Kidneys are vital for bodily function, filter waste, regulate fluids and minerals, control blood pressure, and produce urine and erythropoietin.

Moreover, individuals with kidney disease experience impairment in kidney function, often stemming from conditions such as hypertension and diabetes. 

The National Kidney Foundation reports that kidney disease affects roughly 37 million adults, while an additional 80 million are at risk. Additionally, racial minorities have a higher incidence of kidney disease, with African Americans being approximately four times as susceptible.

In this article, let’s learn more about the kidney, kidney diseases, and worldwide research. 

What is Nephrology

Nephrology is a vital medical branch specializing in the comprehensive study, diagnosis, and treatment of kidney-related diseases. This involves a multifaceted approach, employing clinical, laboratory, imaging, and histopathologic techniques to assess kidney function and structure.

On the other hand, Nephrologists are dedicated to preserving kidney health through tailored interventions, including dietary adjustments, medication, and kidney replacement therapy. They adeptly manage various complications such as hypertension, fluid retention, and electrolyte imbalances, ensuring holistic care for their patients. 

Moreover, Nephrologists play a crucial role in addressing chronic conditions like diabetes and hypertension, which significantly impact kidney function, alongside managing acute renal failure cases. Collaborating seamlessly with transplant teams, they extend their expertise to oversee the care of kidney transplant recipients, ultimately striving to enhance patient quality of life and prevent complications.

Areas of Focus in Nephrology

Nephrologists may focus on diagnosing and treating various kidney disorders, catering to specific patient groups, or conducting specialised procedures. Specialised areas within nephrology encompass:

  1. Critical care nephrology
  2. Diabetic kidney disease management
  3. Dialysis oversight
  4. Geriatric nephrology (for age 65+)
  5. Interventional nephrology (including dialysis access and arteriovenous fistula surgery)
  6. Renal oncology (kidney cancer)
  7. Kidney stones treatment
  8. Kidney transplant care
  9. Paediatric nephrology (infants to adolescents)

Latest Treatment Options in Nephrology Care

Research and innovative developments shape treatment paradigms for kidney-related conditions in nephrology care. Some of these innovations are:

Kidney Fibrosis Treatment:

Researchers found increased histone lysine crotonylation (Kcr) in fibrotic kidneys, driven by the ACSS2 enzyme. Histone lysine crotonylation (Kcr) is a new acylation modification discovered in 2011 having important biological significance for gene expression, cell development, and disease treatment. 

TGF-β for Improved CKD Treatment:

In Chronic Kidney Disease (CKD), TGF-β, a transforming growth factor affects kidney cell mitochondria, worsening the disease. However, in diseased conditions, TGF-β loses its anti-proliferative response and becomes an oncogenic factor. 

Moreover, recent research shows blocking TGF-β in mice’s proximal tubules increases mitochondrial damage and inflammation. Similar issues were found in CKD patients’ kidney samples. Hence, this new insight may lead to new CKD treatment approaches targeting TGF-β pathways.

Denosumab in Osteoporosis Patients with Kidney Disease

In a recent innovation, Denosumab, commonly used for osteoporosis in advanced kidney disease patients, raises concerns about severe hypocalcemia. A study of 2804 older females on dialysis reveals a higher risk compared to oral bisphosphonates. Prolia now carries a boxed warning, emphasising intensified monitoring during treatment.

Genetic Solution to Mitigate CKD

New research reveals that certain APOL1 gene variations increase chronic kidney disease (CKD) risk in people of West African descent. However, another mutation, p.N264k, counters this risk. In vitro studies show that p.N264k reduces the harmful effects of high-risk APOL1 variations. This suggests potential drug targets for CKD prevention.

Enhanced Advance Care Planning for Dialysis Patients

A study in 42 dialysis clinics with 430 patients and their decision-makers showed improved patient-surrogate communication through 45-60 minute discussions led by clinic healthcare workers. This approach reduces end-of-life decisional conflicts and increases adherence to care goals among dialysis patients, enhancing their overall care experience.

Medicinal Options in Nephrology Care

Medicinal Options in Nephrology Care delves into the diverse pharmacological interventions available for managing kidney-related conditions.

Renaglob

Renagold Tablet is frequently prescribed as a nutritional supplement for individuals suffering from chronic kidney failure and uremia. Its primary function is to inhibit the elevation of urea levels in the bloodstream from consuming non-essential amino acids among kidney failure patients.

Uriglob/Uriglob D

Uriglob Tablet effectively relaxes muscles in the bladder and prostate to alleviate symptoms associated with an enlarged prostate. This relaxation enables easier urination, providing rapid relief from urinary difficulties.

Trientine HCL Capsules

Trientine Hydrochloride is prescribed for Wilson’s disease, functioning as a copper-chelating agent. Its mechanism involves binding surplus copper in the body’s tissues and facilitating its elimination through the kidneys in the urine.

Selaglob

Trientine Hydrochloride reduces high blood phosphorus levels in dialysis patients. Selaglob Tablets stop phosphate absorption in the intestine, reducing blood phosphate levels.

Kalara

Calcium Polystyrene Sulfonate reduces high blood potassium levels, particularly in kidney conditions such as anuria, severe oliguria, and chronic kidney disease. It’s also utilised to lower potassium levels in patients undergoing regular dialysis.

Febuglob

Febuglob Tablet treats gout by lowering uric acid levels. It’s for patients unresponsive to allopurinol. Also used for hyperuricemia in adults with hematologic malignancies at medium to high TLS risk during chemotherapy.

Deferglob

Deferglob Tablet is prescribed for managing chronic iron overload resulting from recurrent blood transfusions. Its function involves eliminating surplus iron from the body and lowering the likelihood of organ damage induced by iron accumulation.

Conclusion

Innovations in nephrology care are revolutionising treatment approaches for kidney-related conditions, addressing diverse challenges with promising solutions.

The landscape of nephrology is evolving, from groundbreaking genetic insights offering potential preventive strategies for chronic kidney disease to enhanced communication practices improving end-of-life care for dialysis patients. Furthermore, advancements in medicinal options provide tailored interventions, such as Renagold for nutritional support and Trientine HCL for Wilson’s disease.

These developments underscore nephrology’s commitment to optimising patient outcomes and enhancing the quality of life, ushering in a new era of personalised and effective kidney care.

 Globela Pharma offers high quality and affordable nephrology solutions across 50+ countries. 

WhatsApp Image 2024-02-29 at 18.43.52

Beyond the Virus- The Connection Between CVD and COVID-19 Complications

Introduction-

The world witnessed a catastrophe in the form of the COVID-19 pandemic. As per statistical data, more than 702 million active Covid positive cases are present worldwide. Moreover, the world lost around 7 million to the deadly virus. The COVID-19 is characterised by severe respiratory distress syndrome caused by novel SARS-CoV-2. 

At the beginning of COVID-19, evidence of the acute symptoms of the pandemic was pretty straightforward. However, several studies are being carried out to analyse the long-term sequelae of COVID-19. Reports of the trials suggest a strong link between COVID-19 and Cardiovascular Diseases.

According to the World Health Organization, Cardiovascular Diseases are the leading cause of mortality worldwide. Heart attack and stroke are significant CVDs that have high mortality prevalence. The data put forward by a report, COVID-19 and Cardiovascular Diseases, published in 2020, stated a high occurrence of CVDs in COVID-19-positive patients, with more than 7% of patients experiencing myocardial injury due to the virus. 

Therefore, the identification of risk factors and prevention of cardiovascular diseases in patients with a COVID-19 history is a challenge for the medical fraternity. Risk factors associated with cardiovascular diseases are well known, such as lifestyle and genetics. However, the role of these two factors in precipitating CVDs in patients affected by SARS-CoV-2 is still unknown.

COVID-19 and CVDs

One of the long-term consequences of the pandemic manifested in the form of an increased global cardiovascular burden. Recent statistical data presents a rise in mortality and morbidity related to Cardiovascular diseases owing to the direct and indirect effects of COVID-19.

Moreover, research has found an interlink between genetic factors and poor lifestyle with cardiovascular disorders in COVID-19 patients. 

The genetic association is determined using the Polygenic Risk Score. High values show a high risk of developing coronary artery disease, atrial fibrillation and venous thromboembolism in people with SARS-CoV-2 infection. Similarly, poor living habits such as smoking habit, increased alcohol consumption, and sedentary living put individuals at a higher risk for developing cardiac complications. 

Although the exact pathophysiology behind the risk of CVD in COVID-19 patients is not yet understood, researchers have attempted to explain a couple of mechanisms. Some of them are:

Direct cardiotoxicity- The SARS-CoV-2 virus directly infects the cardiac cells leading to myocarditis. 

Post-disease hyper-inflammation- Post-COVID-19 cases have shown uncontrolled release of cytokines leading to plaque formation and vascular inflammation. It ultimately precipitates Myocardial Infarction, cardiomyopathy and Heart Failure.

Systemic manifestations- COVID-19 also causes systemic complications such as Disseminated Intravascular Coagulation(DIC), sepsis etc which result in cardiovascular diseases.

Genetics and Lifestyle- Potent Risk Factors for CVD

Genetics and lifestyle influence the occurrence of cardiovascular diseases. A family history of CVD raises the chances of acquiring the disease. The proportion of risk will also be influenced by the age of the affected relative. CVDs such as congenital diseases, high cholesterol levels, and high blood pressure can be inherited. Alteration even in the single gene code can lead to heritable cardiac disorders.

Similarly, lifestyle also influences the prevalence of CVD in an individual. Poor diet, high alcohol consumption, a history of smoking, and less physical activity are culprits of cardiac diseases.

But, how do these two potential risk factors augment the chances of CVDs in people who have a history of COVID-19?

What does Research Show?

A study was conducted between March 2020 and September 2021 on 25,335 COVID-19-positive patients to evaluate the role of genes and lifestyle. The study aimed to correlate the link between PRS(Polygenic Risk Score), lifestyle factors and cardiovascular disorders in selected patients within 90 days after diagnosis of COVID-19. 

A polygenic Risk Score is an accumulation of genetic risk factors for a particular trait. It is an authentic tool to predict precision medicine and cardiovascular disease occurrence rates. In the study, the PRS was determined for cardiac diseases such as venous thromboembolism, coronary artery disease, atrial fibrillation and ischemic strokes. Moreover, the prospective cohort research also used a lifestyle index comprising 9 variables to determine its role in the precipitation of cardiovascular diseases.

The study used the Cox proportional hazard model to calculate the hazard ratio and confidence interval for studying the link between genes and CVD. In contrast, the multivariable Cox regression model was applied to determine the lifestyle factors.

The result of the study confirmed a linear association between gene mutations and a higher incidence of cardiovascular disorders post-COVID-19 infection. The participants with the top 20 per cent Polygenic Risk Score have a high risk of developing atrial fibrillation(3-fold increase), coronary artery disease(3.5-fold increase) and venous thromboembolism (2-fold rise). However, no apparent association is observed between ischemic strokes and genetic factors. Another interesting finding is the positive existence of risk factors even in fully vaccinated individuals.

A positive correlation exists between a healthy lifestyle and a lower incidence of CVDs in COVID-19 patients. It is also noteworthy that COVID-positive cases with unhealthy lifestyles, when switched to healthy living diminished their risk of developing CVDs. Cardiac complications such as CAD and AF also demonstrate an additive rise in patients with high scores of PRS and an unhealthy lifestyle.

The Conclusion

Although the fatal wave of the pandemic is over. The world lost more than a million lives. But, the threat persists. The long-term consequences of COVID-19 in patients with a positive history are still a medical mystery. Several research groups and pharmaceutical companies like Globela Pharma are trying to do evidence-based studies to deal with chronic complications.

R&D blog-min

Role of Research and Development in Modern Pharmaceutical Industry

Introduction

In a life cycle of a drug from its discovery till launch, a series of crucial steps are involved in order to comply with regulatory requirements as per respective local regulatory authority. These steps from discovering a new drug to its launch in the market contributes to research and development in the pharmaceutical industry. The process is time consuming and may take several years for completion.

Steps involved in research and development in the modern pharmaceutical industry are as follows, i) early drug discovery, ii) preclinical studies, iii)clinical development, iv) review and approval by applicable regulatory bodies, v) post marketing surveillance.

Identifying a potential target-

Early drug discovery involves target identification and validation, hit discovery, assay development and screening, high throughput screening, hit to lead and lead optimization. Target identification begins with identifying the function of potential therapeutic agents and its role in the disease. It can be approached by direct biochemical methods, genetic interactions or computational interface. However, a combined approach may be required to fully characterize on-target and off-target interactions in order to understand molecular action mechanisms. Main motive of hit discovery is to identify molecules with potential interactions with drug targets.

Assay development-

Different types of assays can be used for assay development and compound screening, ranging from biochemical to cell-based assays. The choice of the assay depends on the biology of the drug target protein, scale of the compound screen, the equipment infrastructure, etc. Factors required for assay development are; i) Pharmacological importance of the assay– ability to identify compounds with the desired mechanism of action, ii) Reproducibility– is readily reproducible across assay plates, screen days and the length of the drug discovery programme, iii) Quality– pharmacology of the standard compounds falls within predefined limits, iv) Effects of compounds in the assay– should not be sensitive to the concentrations of solvents used in the assay.

Screening methods-

High throughput screening, (HTS) involves screening of the entire compound library against the drug target. Knowledge-based screening is a method of selecting from the chemical library smaller subsets of molecules with potential activity at the target protein. Fragment screening is making very small molecular weight compound libraries which are screened at high concentrations. Physiological screening is a tissue-based approach with the response more in direction with the desired in vivo effect.

Lead optimization-

Drug-like molecules must go through different phases to identify the hit lead molecule and optimization with a potency of 100nM – 5mM at the drug target. The refinement process involves generating dose-response curves in primary assay for each hit. Followed by examining the surviving hits in a secondary assay. Generation of rudimentary structure-activity relationship, SAR data and identifying the essential elements in the structure linked with the activity. Lastly, in vitro assays providing significant data with regards to absorption, distribution, metabolism and excretion (ADME) properties as well as physicochemical and pharmacokinetic (PK) measurements. Overall, the aim is to achieve a lead compound optimized with desirable effects on the target that can provide therapeutic benefits within an acceptable safety window. Average time required for this step is 2-6 months.

A glance at preclinical trials-

Preclinical studies or non clinical studies, carries out testing on animals to accurately model the desired biological effect of a drug in order to predict treatment outcomes in patients determining its efficacy, and to identify all toxicities associated with the drug to predict adverse effects for safety assessment. There are two types of preclinical studies, i) in vitro, ii) in vivo, iii) ex vivo assay and iv) in silico. In compliance with good laboratory practices, GLP, in vitro studies are carried out outside of living organisms in a test tube, glass or petri dish. On the other hand, in vivo studies are those which involve living organisms, including animal studies and human clinical trials. Ex vivo assay refers to a medical procedure in which an organ, cell or tissue are taken from the living body for treatment testing such as skin biopsies or isolated samples from tumor biopsy. In silico studies refers to using computer simulations to predict the reaction of a compound with specific proteins or pathogens. 

Goal of preclinical studies involve determination of pharmacokinetics, proof of concept, formulation, optimization & bioavailability, establishing safe dose, therapeutic dose, lethal dose and maximum tolerated dose. The compound from drug discovery is modified through preclinical studies and becomes Investigational New Drug, IND. IND application is filed for review and approval as per guidelines and standards of local and national regulatory authority. On an average the time required for this phase is approximately ranging from 1-6 years.

A complete overview of Clinical trials-

Clinical development of drug discovery begins after approval of IND for further testing. Clinical trials are conducted for testing of the new drug classified into several phases.

Phase 0 and Phase I-  Phase 0 is known as human micro dosing studies, which involves 10-15 individuals who are administered with small amounts of sub therapeutic dose mainly to determine pharmacokinetics, oral bioavailability and half-life of the drug. Phase 0 trials are often skipped to direct Phase I trials unless some of the data is inconsistent from previously conducted preclinical studies. Phase I studies are conducted amongst healthy volunteers to test the safety, tolerability, pharmacokinetics & pharmacodynamics, side effects & adverse effects, optimum dose, half-life and formulation method for the drug. In circumstances when testing for diseases like cancer or HIV, the treatment for which is likely to make healthy individuals ill, clinical patients are selected as an exception. Phase I trials are not randomized and hence are vulnerable to selection bias. This phase involves 20-100 individuals. Phase I trials can be further divided into, i) Single ascending dose, Phase I (a) in which a small number of participants are entered sequentially at a particular dose while monitoring them for a period of time to confirm safety. If no adverse effects are noted, then dose is escalated for newer groups. It is continued until pre-calculated pharmacokinetic safety levels are achieved or intolerable side effects are noted, it is the point where drug reaches at maximum tolerated dose, MTD; ii) Multiple ascending dose, Phase I (b) in which group of participants receives multiple low doses of the drug, which is subsequently escalated for further group of participants up to a predetermined level. It helps in determining pharmacokinetics and pharmacodynamics of multiple doses of the drug along with its safety and tolerability.

Phase II- Phase II trials are performed on larger groups (50–300) and are designed to assess biological activity and effect of the drug. Trial design of Phase II trials are either as case series, which demonstrates safety and efficacy in a selected group of participants, or as randomized controlled trials ,RCT, where some participants receive the drug/device and others receive placebo/standard treatment. Phase II studies are divided into Phase II (a) and Phase II (b). Phase II (a) studies are pilot studies designed to demonstrate clinical efficacy or biological activity of the drug. Phase II (b) studies determine the optimal dose at which the drug shows biological activity with minimal side-effects. It is also known as maximum effective dose, MaxED.

Phase III- Phase III trials are conducted in a large patient population of 300-3000 individuals determining the efficacy of the new drug in comparison to existing standard treatment. They are time consuming and expensive with complicated trial designs such as Randomized controlled multicentre trials with single, double or triple blinded factors in order to avoid bias and clean results. Phase III (a) studies are trial designed and executed to obtain statistically significant data for new drug approval by regulatory authority. Phase III trials that continue while awaiting regulatory approval in order to provide life-saving drugs to patients until the drugs are available in the market are categorized as Phase III (b) studies. Label expansion studies by the sponsor also fall under this category.

Phase IV- If the new drug successfully passes through Phase I, II, and III, with desirable outcomes, the manufacturing, preclinical and clinical data is then submitted as a new drug application, NDA, for review and marketing approval by national applicable regulatory authority. Post approval the new drug is marketed and Phase IV trials begin, which is post marketing surveillance of the new drug and lasts for up to 5 years. The entire process from developing a drug from preclinical research till marketing can take approximately 12-18 years. A Phase IV trial is a drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test. These trials involve the safety surveillance, i.e, pharmacovigilance and ongoing technical support of a drug after it receives regulatory approval to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive reasons, such as finding a new market for the drug, or other reasons, for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials. The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).

Conclusion

Thus Research & Development is essential when it comes to the pharmaceutical industry, since R&D services not only generate income for the companies involved in the research but it often saves lives. Reliable Pharmaceutical R&D services allow for companies to have technical and manufacturing procedures, quality control measures and production scope aspects as per required standards.

Test-min

The science behind developing a new medicine

Introduction

The need for new medicine arises with time as older available medicines lose desirable effect due to tolerance or origination of newer diseases that require advance cure through new medicines. In order to treat a particular disease, it is important to understand the cause behind it. Attributes of disease such as acquiring, transmission and progression needs to be studied. Type of cells that are affected, alteration in genetic factors of diseased cells and the presence or absence of proteins in the affected cells should also be taken into account. In the case of infectious diseases, the characteristics of microorganisms and its replication in the human body requires thorough knowledge and understanding.

In modern day laboratory set ups, sophisticated tools are used for shedding light on above concerns. The tools are designed to discover the molecular roots of disease and pinpoint critical differences between healthy cells and diseased cells. By determining the molecular defects behind a particular disease, scientists can identify the best targets for new medicines. In some cases, the best target for the disease may already be addressed by an existing medicine, and the aim would be to develop a new drug that offers other advantages. Although, drug discovery aims to provide an entirely new type of therapy by pursuing a novel target.

Gathering data on disease progression-

Amongst different models of studying a disease, cell cultures help studying diseased and healthy cells and differences in cellular processes and protein expression. Cross species studies are done in which genes and proteins that are found commonly between humans and other species. Function of these human genes are revealed to be parallel with other organisms. Bioinformatics is a field of biotechnology that is associated with biology and information technology.  It aids in better assessment of disease. Biomarkers are protein substances used for measuring biological function, identifying disease processes or determining response to a therapy. They also have diagnostic applications. Proteomics is the study of protein activity within a given cell, tissue or organism. A change in protein activity can provide information on the disease process and the impact of medicines under study.

Drug discovery

  After crucial analysis of the disease in question, a target is selected or identified, which is supposed to have an effect by a novel intervention. For instance, cholesterol lowering drugs target enzymes that are involved in production of cholesterol. Antibiotics are designed to target specific proteins that are critical for survival of bacteria. Scientists and researchers estimate there are about 8,000 potential therapeutic targets that might provide a basis for developing new medicines. Most of them are proteins of various types, including enzymes, growth factors, cell receptors, and cell-signalling molecules. Some targets are present in excess during disease, so the goal is to block their activity which is achieved by developing a medicine that binds to the target and prevents it from interacting with other molecules in the body. On the other hand, the target protein is deficient or missing, and the goal is to enhance or replace it in order to restore healthy function. Advancements in the field of biotechnology have made it promising, to create therapies that are similar or identical to the complex molecules the body depends on to remain healthy. It is essential for researchers to prove the validity of a particular target through establishing its role in disease progression. The key is to demonstrate that the activity of the target is running the course of the disease.

Drug development

Once the target has been selected, the next step is to identify a drug that impacts the target in the desired way. Multiple chemical compounds can be studied simultaneously with a technology called drug screening. With automated systems, scientists can rapidly test thousands of compounds to observe the ones that interfere with the target’s activity. Potential compounds can be put through added tests to find a lead compound with the best potential to become a drug.

Collecting preclinical data

 Once a promising test drug has been identified, it must go through extensive testing before it can be studied in humans. This testing for analysing safety of a drug constitutes preclinical studies. Many drug safety studies are performed using cell lines engineered to express the genes that are often responsible for side effects. Cell line models have decreased the number of animals needed for testing and have helped accelerate the drug development process. Some animal tests are still required to ensure that the drug doesn’t interfere with the complex biological functions that are found in humans.

Clinical phases of drug testing

If a test drug has no serious safety issues in preclinical studies, researchers can seek permission from regulatory authority to perform clinical trials in humans. There are three phases of clinical studies which are executed in the form of clinical trials, and the new drug is required to meet certain criteria before moving on to the next phase.

Phase 1: Tests in 20 to 100 healthy volunteers and under special circumstances, patients. The main goals are to assess safety and tolerability and explore the behaviour of the drug in the body. Half-life of the drug is estimated.

Phase 2: Studies in about 100 to 300 patients. The goals are to evaluate the efficacy of the drug, calculate dosage based on data from preclinical studies and to explore the safety index of the drug.

Phase 3: Large studies involving 500 to 5,000 or more patients, depending on the disease and the study design. Large scale trials are often needed to determine if a drug can prevent negative outcomes on a patient’s health. The goal is to compare the effectiveness, safety, and tolerability of the test drug with standard drug or a placebo.

If the test drug shows clear benefits and acceptable risks in phase 3, the company can file an application requesting regulatory approval to market the drug. In India, the Central Drugs Standard Control Organisation, CDSCO, is governed by the Directorate General of Health Services, Ministry of Health & Family Welfare, MoHFW. Regulators review data from all studies conducted and make a decision whether the benefits of the medicine outweighs the risks it may have. 

New drug launch in the market

Post approval for marketing of the new drug, routine monitoring is required up till 5 years which is called Pharmacovigilance or Post marketing surveillance. It is Phase 4 of clinical studies. A pharmaceutical company can also continue its clinical trials on an approved drug to spot its effects under other specific conditions (alternative use) or in other groups of patients, and additional trials may also be required by regulatory agencies.

Conclusion

The whole drug development process from drug discovery till marketing approval takes 10 to 18 years to complete on average with high expenses going up to 1.3 billion USD. Only a limited number of drugs are able to achieve success through each phase. Hence, developing a new drug is an extensive process and the time, money and effort that goes behind it stands high for superior quality drugs becoming available in the market.