Trauma can be employed from a variety of situations. It has dissimilar impacts on different people. It changes how a person thinks, how they react to certain events, and eventually changes their behavior. This research paper will cover how traumatic events can influence one’s growth and response.
Introduction
Individual trauma is precipitated by an event, series of events, or set of circumstances that an individual perceives as physically or emotionally harmful or threatening, and that can have long-term negative effects on the individual’s functioning and physical, social, and emotional well-being. (1). Trauma can manifest itself in a variety of contexts. Home life, school, the workplace, etc. “Whether an event is deemed traumatic is defined by the ‘subjective experience’ of it rather than the event itself.” (2) Trauma is classified into 2 types: Type 1 and Type 2, and three subcategories: acute, chronic, and complex.
Types of Trauma
Type 1:
According to The Trauma Practice, traumas of Type 1 are those that occur in a single episode and are unanticipated and unplanned. Acute trauma, shock, or big T trauma are some names for them. Post Traumatic Stress Disorder is a disorder associated with big T trauma or Type 1 trauma. Type 1 trauma examples could include:
severe damage or illness
violent assault
Sexual abuse
heartbreaking loss
Robbery or muggery
having experienced or witnessed violence
experiencing a terrorist assault
being present during a natural calamity
road incident
military conflict event
Hospitalisation
Psychiatric inpatient care
Childbirth
medical injury
trauma after a suicide attempt
life-threatening condition or finding
Type 2:
Complex trauma refers to trauma that may have occurred during infancy or the early stages of development. Repetitive trauma is trauma that has occurred repeatedly over time and is frequently connected to interpersonal relationships, where a person may feel physically or emotionally confined. They can also think they were forced to suffer the trauma or that they had no control over it. Complex Post Traumatic Stress Disorder is a condition associated with type 2 trauma. Type 2 trauma examples include:
family violence
emotional maltreatment in childhood
Domestic abuse
Neglect of the emotions and attachment damage
Abandonment
abusive language
Coercion
Physical abuse in the home
long-term failure to diagnose a health issue
bullying that occurs at home, at school, or at work
Sexual assault
psychological abuse
physical abuse
Subcategories:
The effect of a single event is acute trauma.
Trauma that is chronic is recurring and lasts a long time, like domestic abuse or violence.
Exposure to several and numerous traumatic situations, frequently of an intrusive, interpersonal kind, is known as complex trauma.
Historical, collective, or intergenerational trauma
This trauma is distinguished by psychological or emotional difficulties that can affect various communities, cultural groups, and generations. Adaptive coping strategies can be passed down through generations. Here are some examples:
Racism
Slavery
Removal from a family or community by force
Genocide
War Trauma or Secondary Trauma
This type of trauma can occur when someone speaks to someone who has personally experienced or witnessed a trauma. The person listening may experience secondary trauma as well as symptoms similar to those described by the person explaining the trauma.
Little “t” adversiTy
Little t trauma is less visible and discussed less frequently. Little t traumas are everyday occurrences that are accepted as a normal part of life. They can, however, be extremely traumatic. Possible examples include:
The death of a loved one (not traumatic bereavement)
Relocating to a new home
Loss of employment
Brain Development
The amygdala, hippocampus, and prefrontal cortex have all been linked to the stress response. Traumatic stress has been linked to long-term changes in these brain areas. Following traumatic stress, there is an increase in cortisol and norepinephrine responses to subsequent stressors. Antidepressants have hippocampus-protective effects that offset the effects of stress. Animal studies revealed smaller hippocampal and anterior cingulate volumes, increased amygdala function, and decreased medial prefrontal/anterior cingulate function in patients with post-traumatic stress disorder (PTSD). Furthermore, patients with PTSD have elevated cortisol and norepinephrine responses to stress. The long-term activation of the stress response system and the subsequent overexposure to cortisol and other stress hormones can affect nearly all of your body’s systems. These heightened cortisol and norepinephrine responses to stress can be noticed. Norepinephrine functions as a neurotransmitter in your brain and spinal cord to: Boost alertness, arousal, and attention. Constricts blood vessels, which helps maintain blood pressure in times of stress. Treatments that are effective for PTSD promote neurogenesis in animal studies, as well as memory enhancement and increased hippocampal volume in PTSD.(3). According to NIH: Traumatic stress: effects on the brain, they explain how traumatic stressors, such as early trauma, can result in posttraumatic stress disorder (PTSD), which affects approximately 8% of Americans at some point in their lives.
Children are especially vulnerable to trauma due to their rapidly developing brains, according to research. A child’s brain is stressed during traumatic experiences, and fear-related hormones are activated. Although stress is a normal part of life, when a child is subjected to chronic trauma, such as abuse or neglect, his or her brain remains in this heightened pattern. In order to maintain and promote survival, the child’s emotional, behavioral, and cognitive functioning may change while in this heightened state. These traumatic experiences can have a long-term effect on a child’s behavior, emotional development, mental and physical health. (2).
The Adverse Childhood Experiences Study (ACEs) highlights the long-term effects of trauma on physical and mental health. The study employs that to assess the total amount of stress during childhood, the ACE score, which is a total count of the number of adverse childhood experiences reported by respondents. The greater the number of ACEs, the greater the risk of developing problems such as alcoholism, depression, multiple sexual partners, suicide attempts, smoking, and liver disease later in life, among other negative health issues.
Pregnant women are told to not do multiple things, they are restricted from a lot of actions. Why is that, some may question? When with a baby, everything that goes into your body has the same effect on your fetus, or your unborn baby. The adage “You are what you eat” has probably been said to you before. The same idea, however, may be extended to expectant mothers because it is their unborn children who are influenced by what is consumed. Every single thing a pregnant woman consumes, drinks, or uses is somehow passed on to her unborn child. Alcohol and hard drugs are not an exception. These drugs may cross the placenta, enter a mother’s circulation, and then reach her developing child. These toxins can also be transferred to a newborn through breast milk if a mother is nursing.
What is a Placenta?
The placenta is an organ that grows in the uterus during pregnancy. A developing newborn receives oxygen and nutrients from this structure. It also cleans the baby’s blood of waste materials. The baby’s umbilical cord grows from the placenta, which is attached to the uterus’ wall throughout pregnancy. Typically, the organ is affixed to the uterus’s front, rear, side, or top. Rarely, the placenta may connect in the uterine cavity below. This situation is known as a low-lying placenta (placenta previa).
What are Some of the Effects the Unborn Baby Goes Through?
According to recent studies, consuming illegal drugs, prescription painkillers, tobacco or marijuana during pregnancy increases the risk of stillbirth (the death or loss of a baby before or during delivery) by a factor of two to three. About 5% of pregnant women, according to estimates, use one or more addictive substances. Neonatal Abstinence Syndrome (NAS), in which the newborn experiences withdrawal, can be brought on by the regular use of particular medicines. Opioid impacts have been the subject of the majority of this field’s research (prescription pain relievers or heroin). However, research has indicated that consuming coffee, alcohol, barbiturates, and benzodiazepines while pregnant may also result in withdrawal symptoms in the newborn. The drug(s) taken, the length of time and frequency of usage, the way the birth mother’s body processed the drug(s), and whether the child was born at full term or preterm all affect the type and intensity of the infant’s withdrawal symptoms.
Risks of Stillbirth from Substance Use in Pregnancy
Tobacco use—1.8 to 2.8 times greater risk of stillbirth, with the highest risk found among the heaviest smokers
Marijuana use—2.3 times greater risk of stillbirth
Evidence of any stimulant, marijuana, or prescription pain reliever use—2.2 times greater risk of stillbirth
Passive exposure to tobacco—2.1 times greater risk of stillbirth
Source: Tobacco, drug use in pregnancy, 2013
Opioids and pregnancy
Opioids are a group of medications that are used to treat pain, but they also carry significant hazards, such as addiction. Opioids can be obtained legally or illegally. Doctors may recommend prescription opioids to treat moderate to severe pain. A prohibited opioid is heroin. An opioid with a prescription, fentanyl can be used to relieve really bad pain. But fentanyl has also been produced illegally, and it is now more widely available. Opioid use disorder is an opioid use habit that can lead to health issues, incapacity, or the inability to fulfill important obligations at work, school, or home. Buprenorphine, methadone, and naltrexone are examples of opioid drugs that may be used in medication aided therapy (MAT), in addition to counseling and behavioral therapy, to treat opioid use disorder. In the United States, opioid use disorder in pregnant women is a serious public health issue. According to a recent CDC investigation, the proportion of pregnant women with opioid use disorder at labor and delivery more than doubled between 1999 and 2014. Preterm birth, stillbirth, maternal death, and neonatal abstinence syndrome are just a few of the major unfavorable health outcomes associated with opioid use disorder during pregnancy for both pregnant women and unborn children (NAS). When pregnant women are exposed to opioids, a collection of withdrawal symptoms known as NAS is most frequently experienced in newborns.
The pills, they kill. Drugs can have a variety of affects depending on the drug, the user, and their circumstances. Learn about the short- and long-term consequences of medications as well as how your body processes them. Drug use can have an impact on not only your physical and emotional health, but also your entire life. One tablet can be fatal.
Chemicals that have an impact on the body and brain are drugs. Drugs can have a variety of impacts. Long-lasting and permanent health problems are among some of a drug’s side effects. Even after the person has stopped using the drug, they may still go on.
The three main methods of drug consumption are injection, inhalation, and ingestion. The way a medicine is administered affects your body differently. For instance, although ingesting a medicine has a delayed effect, injecting it directly into the bloodstream provides an immediate effect. However, the brain is impacted by all medicines that are overused. They cause the brain to experience a “high” by flooding it with a lot of dopamine, a neurotransmitter that helps control our emotions, motivation, and pleasure experiences. Drugs have the potential to alter how the way the brain functions can affect a person’s capacity for decision-making, resulting in strong cravings and compulsive drug usage. This conduct has the potential to develop into a drug addiction over time.
Today, one in four fatalities is related to the use of illicit drugs, and more than 7 million people suffer from an illicit drug disorder. In actuality, drug misuse is more closely linked to illnesses, disabilities, and fatalities than any other illness that can be avoided. Drug and alcohol addicts are more likely to sustain unintended injuries, be involved in accidents, and experience domestic violence.
Drugs affect your life. It’s not just your physical body and heath, they also impact your mental, social health along with how you manage your finances, relationships and sometimes can even lead to how you manage your criminal record. Depending on the drug’s kind, each one has a unique bodily effect. Some will energize you and awaken your senses. Others will make you feel at ease and at peace. Some affect how you perceive things and may result in hallucinations. Others might leave you cold. Larger doses and prolonged usage have side effects that can gravely hurt your health and even result in death. These effects include the danger of infection from sharing needles, lasting brain and organ damage, and illness risks.
So how does your body process these drugs?
The human body processes drugs in 4 unique stages:
Absorption
Drugs are absorbed into your bloodstream when you take them. The way you ingested the drug will determine how quickly this happens.
Distribution
Once a drug enters your bloodstream, it circulates throughout your body, reaching your brain and various organs. Depending on the drug type, the drug alters brain chemicals and receptors to produce a variety of effects.
Metabolism
The drug is then metabolized by your body or broken down into smaller molecules (known as metabolites) that may be excreted more quickly. These metabolites occasionally have an impact on your body as well.
Excretion
Drugs that have been metabolized pass through your digestive tract and leave your body, typically in urine or feces.
A drug’s elimination time in your body varies. It relies on a variety of elements, including the substance itself (the quantity, potency, etc.), as well as you personally (your metabolism, age, health, environment, etc).
The effects on the health
There are several short- and long-term health repercussions of substance use disorders. They can differ based on the kind of medication, how much and how frequently it is used, and the patient’s overall condition. Overall, substance misuse and dependency can have significant negative impacts. They have the potential to affect practically all bodily organs. Death is one of the most serious effects of drug misuse on health. The greatest increase in deaths has been associated with heroin and synthetic opioids. 212,000 adults and children 12 and older consumed heroin for the initial time in the previous 12 months. Over 90 Americans lose their lives each day as a result of an opioid overdose.
Aaumuktha Yalamanchili, Youth Medical Journal 2023
Stem Cells constitute an intriguing and promising field of medicine because of their ability to regenerate and heal damaged tissue. This article covers the biology of stem cells, the pros and cons, and their promising abilities to further our study of medicine.
Introduction
Stem cells are the raw materials of the body, the cells that give rise to all other cells with specialized roles. Under the appropriate conditions, these unique human cells can develop into a variety of cell types by dividing themselves to generate new cells known as daughter cells in the body or in a laboratory. This can include everything from muscle cells to brain cells. In some situations, they can also repair damaged tissues. These daughter cells can either continue to differentiate into new stem cells or can become specialized cells with a more narrowly defined function, such as bone, brain, heart, or blood cells. No other cell in the body has the capacity to naturally produce different cell types. Because of these distinguishing traits, stem cells have historically been assumed to be everlasting and ageless.
Types of Stem Cells
Every organ and tissue in your body is built on stem cells. There are numerous types of stem cells that originate in various parts of the body or form at various stages throughout our lifetimes. These include embryonic stem cells, which exist only during the early stages of development, as well as other types of tissue-specific (or adult) stem cells, which appear during fetal development and remain in our bodies throughout our lives. All stem cells have the ability to self-renew (produce copies of themselves) and differentiate (develop into more specialized cells). Aside from these two fundamental capacities, stem cells differ greatly in what they can and cannot do, as well as the conditions under which they can and cannot do specific things. To begin with, there are three fundamental types of stem cells: Embryonic Stem Cells, Adult Stem Cells, and Induced Pluripotent Stem Cells.
Embryonic Stem Cells
Embryonic stem cells are extracted from the blastocyst, a mostly hollow ball of cells that forms three to five days after an egg cell is fertilized by a sperm in humans. The size of a human blastocyst is around the size of the dot above this “i.” During normal development, the cells within the inner cell mass give rise to the more specialized cells that give rise to the complete body—all of our tissues and organs. When scientists extract the inner cell mass and cultivate it in a particular laboratory environment, the cells retain the qualities of embryonic stem cells. Embryonic stem cells are pluripotent, which means they can give rise to every cell type in the fully developed body save the placenta and umbilical cord. These cells are extremely significant because they provide a sustainable supply for researching normal development and disease, as well as evaluating medicines and other therapies. Human embryonic stem cells were predominantly produced from blastocysts developed by in vitro fertilization (IVF) that were no longer required for assisted reproduction. (3) Scientists seek to learn more about how these cells differentiate as they develop. As we learn more about these developmental processes, we may be able to apply them to stem cells produced in a lab and maybe regenerate tissues like the liver, intestines, nerves, and skin for transplantation. (4).
Figure 1: The Journal Of Clinical Investigation
Adult Stem Cells
Adult stem cells, also known as somatic stem cells, are undifferentiated cells found in nearly all creatures’ bodies, including humans, in a variety of organs. Adult stem cells, which have been found in a variety of tissues including skin, heart, brain, liver, and bone marrow, are normally restricted to becoming any type of cell in the tissue or organ in which they dwell, as opposed to embryonic stem cells, which can become any cell in the body. Adult stem cells are believed to be multipotent, meaning they can differentiate into certain types of body cells exclusively, not into any type of cell. (6). These adult stem cells, which can live in tissue for decades, replace cells that are lost in the tissue as needed, such as the daily generation of new skin in humans. (5). Most adult tissues, including bone marrow and fat, contain a tiny amount of these stem cells. Adult stem cells, in comparison to embryonic stem cells, have a more limited potential to give rise to various bodily cells. Adult stem cells were thought to only be capable of producing comparable types of cells until recently. For example, researchers previously believed that stem cells found in bone marrow could only give rise to blood cells. However, new research reveals that adult stem cells can generate a variety of cell types. For instance, bone marrow stem cells might be able to develop into heart or bone cells. This research has resulted in early-stage clinical trials to assess the usefulness and safety of the product in humans. (1)
Using genetic reprogramming, scientists successfully turned ordinary adult cells into stem cells. Researchers can reprogram adult cells to behave like embryonic stem cells by modifying their DNA. This new technology may allow for the use of reprogrammed cells rather than embryonic stem cells, as well as the prevention of immune system rejection of the new stem cells. However, scientists are unsure whether employing changed adult cells will have a negative impact on humans. Researchers were able to transform ordinary connective tissue cells to become functioning heart cells. In experiments, animals with heart failure who were injected with fresh heart cells had better heart function and survival time.(1)
Types of Adult Stem Cells
Hematopoietic Stem Cells (Blood Stem Cells)
Mesenchymal Stem Cells
Neural Stem Cells
Epithelial Stem Cells
Skin Stem Cells
Figure 2: Sciencedirect
Induced Pluripotent Stem Cells
Induced pluripotent stem (iPS) cells are lab-engineered cells that have been transformed from tissue-specific cells, such as skin cells, into cells that act like embryonic stem cells. They are a happy medium between adult stem cells and embryonic stem cells. iPSCs are generated by inserting embryonic genes into a somatic cell (such as a skin cell) and causing it to return to a “stem cell like” state. IPS cells are important tools for scientists to understand more about normal development, illness start and progression, and for creating and testing new medications and therapies. While iPS cells share many of the same properties as embryonic stem cells, such as the potential to give rise to all cell types in the body, they are not identical. Scientists are trying to figure out what these distinctions are and what they represent. For starters, the first iPS cells were created by inserting extra copies of genes into tissue-specific cells using viruses. Researchers are exploring a variety of methods for creating iPS cells, with the goal of eventually using them as a source of cells or tissues for medical therapies. One example is that the first iPS cells were created by inserting extra copies of genes into tissue-specific cells using viruses. (3). These cells, like ESCs, are thought to be pluripotent. This method of genetic reprogramming to make embryonic-like cells, discovered in 2007, is unique and requires several more years of research before it can be used in clinical therapy. (4).
The Importance Of Stem Cells
Stem cells may benefit your health in a variety of ways and through a variety of novel treatments in the future. Stem cells, according to researchers, will be used to help build new tissue. For example, healthcare providers may one day be able to treat patients with persistent heart disease. They can accomplish this by cultivating healthy heart muscle cells in the lab and transferring them into damaged hearts. Other medicines could target type 1 diabetes, spinal cord injury, Alzheimer’s disease, and rheumatoid arthritis. New treatments could potentially be evaluated on pluripotent stem cell-derived cells.
Stem cells, with their unique regeneration powers, hold fresh promise for treating diseases such as diabetes and heart disease. However, substantial work in the laboratory and clinic remains to be done to understand how to employ these cells for cell-based therapies to cure disease, often known as regenerative or reparative medicine. Laboratory studies of stem cells allow scientists to understand about the cells’ basic features and what distinguishes them from other types of cells. Scientists are already employing stem cells in the lab to test novel medications and create model systems for studying normal growth and determining the reasons of birth abnormalities. Stem cell research continues to enhance understanding of how an organism grows from a single cell and how healthy cells replace damaged cells in mature creatures. Stem cell research is one of the most exciting areas of modern biology, yet, like with many burgeoning domains of scientific endeavor, it raises scientific concerns as quickly as it generates new discoveries. (4)
Although adult stem cell research is encouraging, adult stem cells might not be as adaptable and resilient as embryonic stem cells. The potential for using adult stem cells to cure diseases is constrained by the fact that not all cell types can be produced from adult stem cells. Adult stem cells are also more likely to have abnormalities because of chemicals or other environmental dangers, or because the cells made mistakes during replication. Adult stem cells, on the other hand, have been discovered to be more versatile than previously imagined. (1).
Stem Cell Line
A stem cell line is a collection of in vitro-grown cells that all descended from a single initial stem cell. A stem cell line’s cells continue to multiply without differentiating into other types of cells. Ideally, they continue to produce more stem cells and are genetically flawless. From a stem cell line, groups of cells can be extracted and shared with other researchers or frozen for future use.
Potential Therapies using Stem Cells
Regenerative medicine, often known as stem cell therapy, uses stem cells or their metabolites to stimulate the body’s natural healing process in diseased, dysfunctional, or injured tissue. It is the next step in organ transplantation and employs cells rather than donor organs, which are in short supply. In a lab, researchers cultivate stem cells. Through manipulation, these stem cells can be made to specialize into particular cell types, such as heart muscle cells, blood cells, or nerve cells. The specialised cells can then be injected into the patient. If the patient has cardiac issues, the cells might be injected into the heart muscle, for example. The transplanted, healthy heart muscle cells could then help the injured heart muscle repair.
Embryonic Stem Cell (ESC) Therapies
ESCs have the potential to treat some diseases in the future. Scientists are still learning how ESCs differentiate, and once this process is more understood, the objective is to apply what they’ve learned to get ESCs to develop into the cell of choice that is required for patient therapy. Diabetes, spinal cord injury, muscular dystrophy, heart illness, and vision/hearing loss are among the diseases being treated by ESC therapy. (4)
Adult Stem Cell Therapies
For more than 40 years, bone marrow and peripheral blood stem cell transplants have been used to treat blood illnesses such as leukemia and lymphoma, among others. Scientists have also discovered that stem cells may be found in nearly all parts of the body, and research is ongoing to learn how to identify, remove, and multiply these cells for future application in therapy. Scientists want to develop treatments for ailments such as type 1 diabetes and cardiac muscle restoration after a heart attack. Scientists have also demonstrated the potential for reprogramming ASCs to cause them to transdifferentiate (revert to a cell type other from the one it was replenishing in the local tissue). (4)
Induced Pluripotent Stem Cell Therapies
Therapies based on iPSCs are intriguing because recipient somatic cells can be reprogrammed to a “ESC like” state. The necessary cells could then be produced by using processes to differentiate these cells. This appeals to physicians because it avoids the issue of histocompatibility and lifelong immunosuppression, which is required when donor stem cells are used in transplants. iPS cells are pluripotent cells that mirror most ESC traits, but they do not currently carry the ethical baggage of ESC study and use because iPS cells have not been induced to grow the outer layer of an embryonic cell essential for the cell’s growth into a human individual. (4)
Pros and Cons of Stem Cells
Figure 2: University of Nebraska Medical Center: Types of Stem Cells
Potential Problems in using Stem Cells
Stem cells require considerably more research before their use may be increased. Scientists must first discover more about how embryonic stem cells develop. They will learn how to manage the kind of cells that are produced from them thanks to this. Using adult pluripotent stem cells presents difficulties for scientists as well. Researchers are trying to find a better approach to cultivate these cells because they are challenging to do so in a lab. The body also contains trace amounts of these cells. There is a bigger possibility that they will have DNA issues.
Another issue is that the embryonic stem cells that are now available are likely to be rejected by the body. Additionally, some people believe that using stem cells derived from embryos violates moral principles. For embryonic stem cells to be effective, researchers must be confident that they will develop into the required cell types. Researchers have identified ways to control stem cells to become specific types of cells, such as directing embryonic stem cells to become heart cells. In this field, research is underway. Additionally, embryonic stem cells have the capacity to develop erratically or innately specialize in certain cell types. Researchers are investigating how to control the proliferation and differentiation of embryonic stem cells. Embryonic stem cells could possibly set off an immunological reaction in which the body of the receiver assaults the stem cells as foreign invaders, or they could simply stop working as they should, with unknown repercussions. Researchers are still investigating how to prevent these potential complications. (1).
At present, due to a worldwide shortage, 17 people die every day while waiting for an organ transplant—nearly a third of the people on a waiting list. Xenotransplantation (transplantation of animal organs into humans) could greatly reduce this shortage if fully actualised—with a significantly in-demand and crucial donor organ being the heart.
Studies suggest the animal organ donor would likely be a pig. Baboons have been considered, but are more impractical as potential donors given their smaller body size, experience infrequent occurrence of blood group O (the universal donor), their long gestation period and small number of offspring. This affects their overall availability. Pigs, on the other hand, have a decreased risk of cross-species disease transmission due to their phylogenetic distance from humans and are more readily available. Even still, with the advent of CRISPR-Cas9 genome editing, replacement hearts can be genetically edited with human genes to deceive the patient’s immune system into accepting it.
Heart xenotransplants have been attempted many times before with little success. However, recent novel advancements have led to an overview of its scope and potential, as well as what hurdles still remain. If heart xenotransplantation truly is an option, they are a potentially more effective and readily available alternative to allotransplants, that could become safe, accessible and truly life-extending.
Trials, Failures and Successes
There have been multiple attempts at animal heart-to-human transplants in the past. One of the earliest attempts was in 1984, when an America infant girl, Stephanie Fae Beuclair or “Baby Fae”, was born with hypoplastic left heart system in which the left side of the heart is severely underdeveloped and unable to support the system circulation. The procedure performed at Loma Linda University Medical Centre involved a baboon heart and was the first successful infant heart transplant ever. However, three weeks later, Baby Fae still died of heart failure due to rejection of the heart transplant. This is thought to have been caused by an unavoidable humoral response due to an ABO blood type mismatch. Type O baboons (universal donors) are very rare, and all the baboons involved were type AB. the rarity of type O baboons.
The first transplant of a non-genetically modified pig heart xenotransplantation happened in India in December 1996. The patient was Purno Saikia, a 32-year-old terminally ill man who died shortly after the operation due to multiple infections. The procedure was condemned by medical institutions due to the unethical conditions and malpractice. The instance was accepted by the scientific community because the findings were never scientifically peer-reviewed.
In more recent years, researchers have successfully transplanted pig hearts into baboons and saw them survive for 945 days. However, these transplanted hearts were not essential to the life of the recipients, and life-supported pig-to-baboon transplants have only lasted about two months. Nevertheless, researchers found that organ survival after transplantation could be improved by intermittently pumping (perfusing) a blood-based, oxygenated solution containing nutrients and hormones through the hearts at a low temperature. (Fig. 1).
(Fig. 1)
This optimised protocol was tested in five more baboons. First, they reduced the baboons blood pressure to resemble that of pigs, before giving the baboons temsirolimus (a drug that combats heart overgrowth by stifling cell proliferation). Finally, they modified the standard hormone-treatment regimen. Out of five, two baboons lived healthily for three months, another two lived for over six months before being euthanised for non-health related reasons, and one died after 51 days. The survival rate was highly impressive and a cause for hope.
Finally, in the most recent occurrence, in January 2022, doctors led by surgeon Bartley Griffith at the University of Maryland Medical Center performed a heart transplant from a genetically modified pig heart into a terminally ill patient, 57-year-old David Bennet Sr., who was ineligible for a standard allotransplant. Bennett had been on cardiac support for almost two months and could not receive a mechanical heart pump because of an irregular heartbeat. He could not receive a human transplant, because he had a history of not complying with treatment instructions. Since he otherwise faced certain death, the researchers received special permission from the FDA to carry out the procedure under compassionate use criteria.
The pig involved had undergone ten genetic modifications. The company who owned the pig, Revivicor, removed three pig genes that would produce enzymes responsible for producing sugar antigens that would lead to hyperacute organ rejection. They also added six human genes to help the body accept the organ. To modify the pig heart used in the transplant, the company removed three pig genes that trigger attacks from the human immune system, and added six human genes that help the body to accept the organ. A final modification aimed to prevent the heart from responding to growth hormones, ensuring that organs from the 400-kilogram animals remain human-sized.
The surgery initially succeeded and the patient was well. The heart was not immediately rejected and continued to function for over a month, surpassing a critical milestone for transplant patients. However, two months after the transplantation, the recipient died. The exact cause of death is currently unclear, but there are many limitations inherent to xenotransplantation that could be the cause.
Limitations & Setbacks
The most prevalent and reoccurring limitation of xenotransplantation is organ rejection and immune system response. Some degree of rejection is inevitable, but can be limited with drugs that suppress the immune system. ‘Xenozoonoses’ are the biggest threat to rejection, as they are xenogenetic infections which can lead to fatal infections and then rejection of the organs. There are several types of rejection organ xenografts face, including hyperacute rejections, acute vascular rejection, cellular rejection and chronic rejection.
Hyperacute rejection is rapid and violent and occurs within minutes to hours from the time of the transplant. Strategies to overcome it include interruption of the immune system response of the complement cascade by the use of cobra venom factor. However, the toxicity of cobra venom factor could be harmful and could potentially deprive the individual of a functional complement system. Transgenic organs in which the enzyme that could for immune system ‘flags’ and express human complement regulators instead are also an option. Even if this is surpassed, there is still acute vascular rejection, which can occur with 2 to 3 days and can be dreamed with immunosuppressive drugs, and cellular rejection, due to the response of the humoral immune system, are still highly likely to occur.
Furthermore, if all these stages of organ rejection have been surpassed, there is still the poorly-understood prospect of chronic rejection, which David Bennet Sr. is likely to have suffered from. Chronic rejection is slow and progressive, and scientists are still unclear on how precisely it works. It is known that XNAs and the complement system are not primarily involved. Chronic rejection leads to pathologic changes of the organ, and why transplants must often be replaced after many years. It is likely that chronic rejection will be more aggressive in xenotransplants than allotransplants.
There is one final major risk: porcine endogenous retroviruses, or PERVs. These are pig-viruses which could be transmitted to humans. While the risk of PERV-related complications are considered to be small, regulatory authorities worldwide view the possibility with caution. However, on this front, genome-editing technology such as CRISPR-Cas9 has led to researchers being able to produce live, healthy pigs in which PERVs and their related genes have been deactivated, indicating one way in which PERV-transmission can be circumvented. Regardless, there are still many hurdles before heart xenotransplantation is fully realised.
Conclusion
The journey of animal-to-human heart transplantation is a long and convoluted one, and one that is likely to continue facing challenges and setbacks. Nevertheless, promising advancements have been made in the past few years alone. Even in the most recent case of David Bennet Sr.’s unfortunate death after his pig-heart transplant, there is the consideration that he multiple pre-existing health conditions may have had just as much to play in his untimely death as the transplant itself. Researchers and doctors alike will have many things to take into account, from informed patient consent to the possibility of disease transfer from animals to humans, but consideration of risks should not stop safe research into a field with much power to help those in need.
Ishika Jha Youth Medical Journal 2022
References
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[2] Michler R. E. (1996). Xenotransplantation: risks, clinical potential, and future prospects. Emerging infectious diseases, 2(1), 64–70. https://doi.org/10.3201/eid0201.960111
[3] Sachs D. H. (2018). Transplantation tolerance through mixed chimerism: From allo to xeno. Xenotransplantation, 25(3), e12420. https://doi.org/10.1111/xen.12420
[4] Bailey LL, Nehlsen-Cannarella SL, Concepcion W, Jolley WB. Baboon-to-Human Cardiac Xenotransplantation in a Neonate. JAMA. 1985;254(23):3321–3329. doi:10.1001/jama.1985.03360230053022
[5] Cooper D. K. (2012). A brief history of cross-species organ transplantation. Proceedings (Baylor University. Medical Center), 25(1), 49–57. https://doi.org/10.1080/08998280.2012.11928783
[16] Boneva, R. S., Folks, T. M., & Chapman, L. E. (2001). Infectious disease issues in xenotransplantation. Clinical microbiology reviews, 14(1), 1–14. https://doi.org/10.1128/CMR.14.1.1-14.2001
[17] M Andacoglu, O. (2018, November 13). Xenotransplantation: Overview, Choosing the Donor Species, Immunologic Barriers to Xenotransplantation. Retrieved from Medscape.com website: https://emedicine.medscape.com/article/432418-overview
[18] D. Candinas, D.H. Adams, Xenotransplantation: postponed by a millennium?, QJM: An International Journal of Medicine, Volume 93, Issue 2, February 2000, Pages 63–66,
[19] Vanderpool H. Y. (1999). Xenotransplantation: progress and promise. Interview by Clare Thompson. BMJ (Clinical research ed.), 319(7220), 1311. https://doi.org/10.1136/bmj.319.7220.1311
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[24] Florencio, P. S., & Ramanathan, E. D. (2001). Are Xenotransplantation Safeguards Legally Viable? Berkeley Technology Law Journal, 16, 937–977. Retrieved from https://www.jstor.org/stable/24116896
As of June 2022, over 2103 cases of monkeypox have been reported in 11 countries outside of areas where it is typically endemic. Prior to 2022, the UK had only ever reported 7 cases of monkeypox, but as of this month, the country has 793 confirmed cases. The strand related to the spread has been sequenced and found to be distinct from the strand typical in West Africa, which causes milder symptoms but is more infectious.
Monkeypox is a rare viral disease spread by close contact by small airborne droplets with symptoms including a fever, rash and swollen lymph nodes. The zoonotic virus earns its name from being first detected in laboratory monkeys in 1958 and is thought to transmit from wild animals to people. With a risk of death between 0-11%, there is no known cure, though the smallpox vaccine is about 85% effective against infection in close contact.
Experts believe monkeypox is unlikely to be a repetition of the devastation on the scale caused by the COVID-19 pandemic: it does not transmit from person-to-person as readily, and due to its relation to the smallpox virus there are existing treatments that can be used to combat its spread. Therefore, despite monkeypox still being a cause for concern, it is not yet a cause for widespread panic.
However, that has not prevented the public health response and discussion about monkeypox being infected with old stigmas.
Response and Reporting
The first known case of Monkeypox in humans occurred in 1970 in the Democratic Republic of Congo. Since then, it has been primarily associated with west and central Africa, however the majority of early cases outside the region in the present outbreak occurred in gay and bisexual men.
The causes for this are currently unknown. Presently, European authorities are investigating men’s saunas and crowded Pride festivals, such as celebrations in the Canary Islands of Spain and Belgium, as partial sources for the outbreak. The composition of the outbreak is complicated and not entirely conclusive, however, this had not stopped inaccurate health reporting from taking place. Many outlets, such as the emphasised the source of the outbreak among queer people as a ‘reason’ for the outbreak, which has been highlighted by many as being unfortunately evocative of the initial reporting of pneumocystic pneumonia in clusters of gay men with AIDs forty years ago in 1981. This is despite official health authorities such as Colin Brown, director of the clinical and emerging infections at the UK Health Security Agency, has stated that monkeypox does not spread easily nor is generally considered a sexually transmitted infection, though it can be passed in “close personal contact with an infected symptomatic person”. The World Health Organisation has also confirmed monkeypox is not a sexually transmitted infection nor exclusive to queer men.
Irresponsible reporting in the name of accuracy can be harmful; when a disease or condition is associated with a marginalised group, people may not risk coming forward for fear of being associated or outed. This can be seen in the early days of HIV epidemic, when individuals who contracted the virus went underground and did not seek out medical care. However, the issue is complicated: while acknowledging that diseases of any kind are a wider threat that can affect anyone can reduce stigma and encourage people to come forward, it can also reduce specific resources for communities that still may genuinely need them the post.
The LGBT community is not the only one in which misplaced reporting on the monkeypox outbreak has caused harm: racial and global economic disparities in global healthcare have also been highlighted. WHO was recently forced to change its official monkeypox pictures, after African doctors and advisors pointed out that, despite the concern being over the global outbreak, all the pictures used were of Black people.
The Democratic Republic of Congo is the country that has been dealing with the world’s largest, most persistent and most deadly strain of monkeypox outbreak by far, with at least 1238 cases and 57 deaths this year and a fatality rate of 10%. Many of these deaths are preventable, but still occur due to underfunded hospitals and lack of horses. Some African doctors feel monkeypox has only become a high priority for the medical community now that individuals in the Global North are being affected by the outbreak. The Biden administrations has purchased 119 millions dollars worth of the smallpox vaccine, which has been licensed for use against monkeypox, after the first American case of monkeypox and European countries are strongly considering stockpiling antivirals. This is reminiscent of the COVID-19 outbreak, in which Canada bought enough vaccines to vaccinate its entire population 9 times over, but countries such as Uganda and Bangladesh still faced severe vaccine shortages, with only 17% of Africans fully vaccinated. The unequal distribution of healthcare resources is a long-standing issue and continues to be seen with the outbreak of monkeypox today.
The Way Forward
Challenges lie ahead. Despite stressing that the monkeypox outbreak does not resemble the early days of the COVID-19 pandemic because it does not transmit as easily, WHO does expect more monkeypox cases.
Reporting on monkeypox being accurate and careful is not just a matter of not perpetuating stigma, but avoiding misinformation and misleading health advice. Health officials have stressed the need to communicate very clearly to the public and the health response will likely have to look beyond vaccination and focus on quarantine, isolation and community education.
Despite comparisons to the lacking and dangerous response to the HIV/AIDS epidemic, there are important differences in the health response today and that of forty years ago. For example, UNAIDs has explicitly come out and condemned the racist reporting around the recent outbreak, with deputy executive director Matthew Kavanaugh stating, “Stigma and blame undermine trust and capacity to respond effectively during outbreaks like this one. Experience shows that stigmatising rhetoric can quickly disable evidence-based response by stoking cycles of fear, driving people away from health services, impeding efforts to identify cases, and encouraging ineffective, punitive measures.” Statements released by trusted outlets such as the BBC have also explicitly stated that monkeypox is not sexually transmitted. A related discussion most also occur in relation to the global and economic inequalities of pandemic responses and distribution of medical resources, with increased investment in deprived areas of world that may need it the most. These measures are the ones that health officials emphasises will allow for the most co-ordinated, effective and informed health response to the monkeypox outbreak.
[2] Petersen, Brett W.; Damon, Inger K. (2020). “348. Smallpox, monkeypox and other poxvirus infections”. In Goldman, Lee; Schafer, Andrew I. (eds.). Goldman-Cecil Medicine. Vol. 2 (26th ed.). Philadelphia: Elsevier. pp. 2180–2183
[15] Li, Z., Lu, J. and Lv, J. (2021). The Inefficient and Unjust Global Distribution of COVID-19 Vaccines: From a Perspective of Critical Global Justice. INQUIRY: The Journal of Health Care Organization, Provision, and Financing, 58, p.004695802110609. doi:10.1177/00469580211060992.
[17] British Broadcasting Company (2021). Covid: Vaccines running out in poorer nations, WHO says. BBC News. [online] 21 Jun. Available at: https://www.bbc.co.uk/news/world-57558401.
Remember when your mom used to yell at you for not washing your hands before you eat? Or maybe not maintaining good hygiene? Well, she isn’t wrong. So, what is this key role of personal hygiene and how do you implement it?
The Key Role of Personal Hygiene
Your chance of contracting diseases and ailments often spread by viruses and bacteria is reduced by practicing good hygiene. Every time you cough, use the toilet, pet your pet, or touch a surface that is often touched by others, like a stair railing, your hands come into contact with germs. This bacteria can grow if you don’t frequently wash your hands and body, which raises your risk of infection and other health issues. By keeping yourself clean and washing your hands frequently, you may get rid of bacteria that cause sickness and reduce your chance of getting sick.
When wounds and skin irritation are present, maintaining good hygiene is essential to preventing infection. Poor hygiene can cause dirt and other germs to enter skin wounds and remain there, whereas proper hygiene can keep these bacteria at bay to avoid infection. Maintaining good hygiene helps you avoid infecting family, friends, and coworkers with bacteria and diseases.
Here are examples of conditions that you may develop if you have poor personal hygiene:
Covid-19
Gastroenteritis
Diarrhoea
Colds and flu
Scabies
Threadworms
Being around people who don’t practice excellent hygiene can make you feel uncomfortable because of things like body odor and poor breath, and it raises your chance of being sick and infected. Your social life and connections, especially professional ones, might suffer from poor hygiene. Many businesses encourage or demand that workers maintain proper hygiene, and they frequently prefer to recruit candidates who are tidy and who appear to have acceptable hygiene practices. Employers in the food and medical industries place a premium on good cleanliness because it can prevent contamination and the spread of illness. Children who maintain excellent hygiene will be less likely to experience bullying at school, since data points to poor cleanliness as one of the main causes of bullying. Parents who stress the value of excellent hygiene to their kids help them develop healthy habits early in life and shield them from bullies.
You may feel more confident and at ease, both physically and emotionally, by keeping yourself clean and well-groomed. Feeling filthy, greasy, and unclean not only compromises your physical health but may also lead to uncomfortable, agitated, and anxious feelings. Your mood, your interactions with others, and how you feel about yourself can all be affected by poor hygiene.
Maintaining good hygiene may increase your self-worth, confidence, and make you appear more appealing to others. Maintaining good hygiene may help you succeed at work, at the gym, and in other situations when you need to be at your best.
How Can You Implement It?
Try to take a daily shower or bathe. Wash thoroughly, paying special attention to the areas surrounding your genitalia and anus. Maintaining cleanliness will eliminate microorganisms that produce body odor and stop skin irritations. Use soap, shower gel, or a hypoallergenic body wash to wash yourself. More bacteria can be removed using soap, but you might need to wash delicate body regions in plain water or salt water first. Use a fresh, moist towel or sponge to clean yourself if there isn’t any or very little tap water available.
Wash your hands thoroughly for at least 20 seconds to prevent getting ill.
Your hands should be wet.
Use enough soap to completely coat your hands.
Rub your palms together.
Clean your hands’ backs and the spaces in between your fingers.
If one is available, use a scrubbing brush to clean filthy nails.
Rinse your hands well on both sides, ideally in a sink full of fresh water.
Using a fresh towel, dry your hands.
To turn off the faucet, use the towel.
Hand sanitizer is an additional option. Be careful to apply enough of the ointment to completely cover your hands. Make careful to rub your hands’ palms, backs, and between your fingers.
Washing your hands after using the restroom is especially crucial since feces, which you may come into touch with, contain billions of bacteria. Wash your hands as well:
Before and after contacting a sick person or cleaning up vomit or bodily fluids. Before and after blowing your nose. Before and after healing cuts or wounds. Before and after touching trash, unclean surfaces, or items. Before and after handling pets or farm animals.
The Medical Field and Personal Hygiene
Due to the physical contact that healthcare workers, patients, and family members have, microbes are easily transferred throughout the industry. The risk of cross-contamination and the spread of contagious illnesses is drastically decreased by practicing basic personal hygiene.
So the next time you get yelled for not washing your hands, do it.
Type 2 diabetes mellitus can be a difficult disease to live with and can severely affect one’s quality of life. Diabetes mellitus is a chronic condition in which your body cannot regulate your blood glucose levels, the two main types being type 1 and type 2. These are due to either an inability to produce insulin (type 1) or when the insulin produced is ineffective (type 2). Type 2 diabetes, or non-insulin dependent diabetes mellitus, can occur as a result of lifestyle factors, such as diet and obesity. These lead to insulin resistance or the inability to produce enough insulin as necessary. Currently, there are 4.1 million people in the UK with diabetes, with 90% of these cases due to type 2 diabetes. It is estimated that 1 in 10 adults will develop type 2 diabetes by 2030 (Lacobucci, 2021)
One treatment for type 2 diabetes is the use of sulfonylureas – a group of oral drugs with hypoglycaemic effects (ability to lower blood glucose levels). Since their discovery in the 1940’s, medicinal chemists have changed the structure of these drugs, to make them more effective for clinical use. These modifications have led to more favourable properties in metabolism, potency, efficacy and safety, which have made the drugs a more effective, safe and convenient treatment for type 2 diabetes mellitus. These will be discussed later on in the article.
This article will explain the chemistry of sulfonylureas, the pharmacology behind them and how they have changed over time to make them more effective in the treatment of type 2 diabetes mellitus.
Type 2 Diabetes Mellitus Cause
Type 2 diabetes occurs when there is a deficiency in insulin secretion by the β-cells in the pancreas, or when cells develop a resistance to insulin action (Galicia-Garcia, et al., 2020). This is usually due to obesity and an unhealthy lifestyle, including lack of exercise, and a high fatty and sugar diet. Insulin is a peptide hormone that is secreted by β-cells in the pancreas. It is responsible for lowering blood glucose levels by stimulating the conversion of glucose in the blood into glycogen to be stored in muscle, fat, and liver cells. When there is a deficiency or resistance of insulin it leads to hyperglycaemia (high blood glucose levels), due to the reduced ability to convert glucose into glycogen. This would lead to symptoms such as vomiting, dehydration, confusion, increased thirst, and blurred vision to name a few.
Physiology Behind Insulin Secretion and Structure
To understand the pharmacology of the sulfonylurea compounds,one must first understand the physiology behind the secretion of insulin.
As stated above, insulin is a peptide hormone, so it is made from a polypeptide chain. Transcription of the insulin gene (found on chromosome 11) occurs and the resulting mRNA strands are translated to produce two peptide chains. These chains are held together in a quaternary structure by two disulfide bonds to form the hormone insulin (Brange & Langkjoer, 1993).
Insulin secretion must be tightly controlled to maintain efficient glucose homeostasis. To do so, the secretion of insulin is regulated precisely to meet its demand. The β-cells of the pancreas contain glucose transporter 2, a carrier protein that allows facilitated diffusion of glucose molecules across a cell membrane. These transporters allow glucose to be detected and enter the β-cells. Upon cytoplasmic glucose levels rising, the pancreatic β-cells respond by increasing oxidative metabolism, leading to increased ATP in the cytoplasm (Fridlyand & Philipson, 2010). The ATP in the cytoplasm of the β-cells, can bind to ATP sensitive K+ channels on the cell membrane, causing them to close. This leads to a build up of K+ ions within the cell as they are unable to leave the cell, leading to the depolarisation of the cell. The increasing positive membrane potential, leads to the opening of voltage gated Ca2+ channels, leading to an influx of Ca2+ ions. This further depolarises the cell, which triggers the release of insulin from the cell, packaged in secretory vesicles, by exocytosis (Fu, et al., 2013).
Pharmacology of Sulfonylureas
Sulfonylurea’s act inside the pancreatic β-cells. On the ATP sensitive K+ channel, there are sulfonylurea receptors to which the drug binds, causing them to close. The cascade of events that follows leads to the release of insulin by the pancreatic β-cell. This mimics the activity that occurs when glucose is taken into the cell, as mentioned earlier. (Panten, et al., 1996). (possibly delete this instead as it is repeated)
This process allows more insulin to be released, to lower blood glucose levels when insufficient insulin is produced naturally. Sulfonylureas are only effective in type 2 diabetes, since insulin production is not impaired (as in type 1 diabetes), rather the release of or resistance to insulin is affected.
Common Chemistry of all Sulfonylureas
All the sulfonylurea drugs are characterised by their common sulfonylurea group. This functional group allows this unique group of compounds to bind to SUR on ATP sensitive K+ channels, giving it its hypoglycaemic properties. The common structure of sulfonylureas is shown in figure 1 (Fvasconcellos, 2011), with the blue R groups indicating replaceable side chains, which fluctuates between each drug development over time giving slightly different properties between the drugs. Over time, scientists have improved the drugs efficacy by changing the side compounds. Additionally, scientific research has led to development of other drugs from the same pharmacological group, but with altered side chains (again, giving them different properties) which have also improved the efficacy of the drug. These changes have altered properties of the drug such as potency, metabolism, half-life, tolerance and safety, to make the drug more effective for clinical use.
Figure 1 Sulfonylurea functional group
History and development of the drugs and their chemical structure
Sulfanilamide and IPTD
In 1935, a French research term discovered the active chemical in the antibiotic prontosil, known as sulfanilamide (Sorkhy & Ghemrawi, 2020). Sulfanilamide was found to be a poor antibiotic and so derivatives of it were synthesised and tested. These compounds, such as such as p-amino-sulfonamide-isopropylthiodiazole (IPTD), which was used as an antibiotic for the treatment of typhoid in 1942, revealed unexpected hypoglycaemic side effects. These were discovered by French physician, Marcel Janbon (Quianzon & Cheikh, 2012). However, scientists could not identify how these side effects were caused.
In 1946, Auguste Loubatières, investigated the effect of IPTD on dogs. He administrated the drug to fully pancreatectomized and partially pancreatectomized dogs and found that the drug was ineffective in the fully pancreatectomized ones but effective in the partially pancreatectomized ones. This later lead to his conclusion that the drugs’ hypoglycaemic property was due to its ability to stimulate insulin secretion directly in the pancreatic β-cells (Loubatières-Mariani, 2007).
Carbutamide
The first sulfonylurea to be marketed as a drug for diabetes was Carbutamide. It was synthesised in East Germany by Ernst Carstens and in the early 1950’s, clinical trials for this sulfanilamide derivative Carbutamide were carried out, by Hellmuth Kleinsorge, for the treatment of urinary tract infections. However, during treatment, side effects of hypoglycaemia were also noted (Kleinsorge, 1998) – similar to those experienced by patients treated with IPTD for typhoid in 1942.
These findings were presented to Erich Haak, of the East German Ministry of Health, in 1952, which ultimately culminated in the ban of the drug. Haak later moved to West Germany where he patented the drug to be tested for antibacterial use, without disclosing the side effects of hypoglycaemia. Karl Joachim Fuchs, a doctor who was part of this drug testing, noticed symptoms of ravenous hunger and euphoria upon taking the drug himself, which were found to be due to hypoglycaemia. Following this, studies were undertaken, and a general conclusion was that Carbutamide was most effective in people over 45 years of age, who had had diabetes for less than 5–10 years and had not used insulin for more than 1–2 years (Tattersall, 2008). The use of Carbutamide was short lived as it was found to have fatal side effects in a small number of people, including toxic effects on bone marrow (National Center for Biotechnology, 2005).
The structure of Carbutamide is shown in figure 2 (Anon., 2021). It can be seen, attached to the benzene ring on the left-hand side of the sulfonylurea functional group, can be seen an amine group. Attached to a second amine group on the right side of the functional group is a four-carbon chain. As mentioned previously, it is the sulfonylurea functional group that gives rise to the drugs hypoglycaemic effects. This is the first drug to contain the sulfonylurea functional group (seen in figure 1) and the beginning of many discoveries into the treatment of non-insulin dependent diabetes mellitus.
Figure 2 Structure of Carbutamide
Tolbutamide
After the discovery of the fatal side effects of Carbutamide, the next sulfonylurea drug to be synthesised was Tolbutamide; it was one of the first sulfonylureas to be marketed for controlling of type 2 diabetes, in 1956 in Germany (Quianzon & Cheikh, 2012). There were minimal changes to the chemical structure in this next development of the sulfonylureas. The amine group on the left hand side of Carbutamide was swapped for a methyl group to give Tolbutamide, shown in figure 3 (Anon., 2021), which helped reduce the toxicity of the drug. However, as a result tolbutamide was subsequently being metabolised too quickly (Monash University, 2021), which led to low levels of the (active) drug in the blood. The drugs efficacy was therefore lower than expected, resulting in it having to be administered twice a day, which was an inconvenience for patients.
Figure 3 Structure of Tolbutamide
Chlorpropamide
It was soon discovered that the methyl group attached to the benzene ring in Tolbutamide was the site of its metabolism (Monash University, 2021) and so it was replaced by medicinal chemists with a chlorine atom in the next drug, Chlorpropamide (see figure 4 ), (Anon., 2021). This helped reduce metabolism, giving the drug a longer half-life, so it was not cleared as quickly from the body. Indeed, a University of Michigan study found that chlorpropamide serum concentration declined from about 21 mg/100ml at 15 min to about 18 mg/100ml at 6 hours, whereas the tolbutamide serum concentration fell more rapidly from about 20 mg mg/100ml at 15 min to about 8 mg/100ml at 6 hours. Therefore, it could be seen that under experimental conditions, tolbutamide disappeared from the blood approximately 8 times faster than chlorpropamide (Knauff, et al., 1959). This would mean less frequent dosing with chlorpropamide, which would make the drug much more convenient for patients to treat type 2 diabetes. However, further research subsequently revealed that, due to the longer half-life of chlorpropamide, the hypoglycaemic effects were compounded and lasted longer than previously expected (Sola, et al., 2015). This meant that Chlorpropamide could not be administered for the safe treatment of type 2 diabetes.
Figure 4 Structure of Chlorpropamide
Glibenclamide
Glibenclamide is the first of what is known as the second-generation sulfonylureas. Introduced for use in 1984, these mainly replaced the first-generation drugs (Carbutamide, Tolbutamide, Chlorpropamide etc) in routine use to treat type 2 diabetes. Due to their increased potency and shorter half-lives, lower doses of these drugs could be administered and only had to be taken once a day (Tran, 2020). These second-generation sulfonylureas have a more hydrophobic right-hand side, which results in an increase in their hypoglycaemic potency (Skillman & Feldman, 1981). In Glibenclamide, the left-hand side of the drug changed drastically from chlorpropamide, as seen in figure 5 (Anon., 2021). This suggested to medicinal chemists, an innumerable number of possible changes that could be made to the drug, simply by changing the left and right-hand sides, resulting in better potency, safety, efficacy and convenience (Monash University, 2021). Consequently, the metabolism of the drug varied between patients, and this in addition to increased hypoglycaemia and increased incidence of Cardiovascular events (Scheen, 2021), meant that the drug is not a first choice in recommendation to treat type 2 diabetes.
Figure 5 Structure of Glibenclamide
Glipizide
Glipizide, figure 6 (Anon., 2021), shares the same hydrophobic structure on the right-hand side as Glibenclamide, however a few changes have been made to the left-hand group, resulting in faster metabolism. Although it has similar potency to that of Glibenclamide; however, the duration of its effects was found to be much shorter (Brogden, et al., 1979). Glipizide has the lowest elimination half-life of all the sulfonylureas, reducing the risk of the long-lasting hypoglycaemic side effects found in previous developments (Anon., 2022).
Figure 6 Structure of Glipizide
Gliclazide
Gliclazide is the most common sulfonylurea used in current medicine for the treatment of non-insulin dependent diabetes mellitus; it is part of the World Health Organisation’s most recent list of essential medicines (World Health Organisation, 2021). The chemical structure of Gliclazide can be seen in figure 7 (Anon., 2021). Fascinatingly, medicinal chemists returned to the use of a methyl group on the left-hand side of the drug, which was last seen in Tolbutamide. As mentioned before, the left-hand group on the drug, attached to the benzene ring, is responsible for the metabolism of the compound. Returning to the use of a methyl group, allows for a faster metabolism of the drug, which helped to remove the unwanted longer hypoglycaemic side effects, especially for use with elderly patients (Monash University, 2021). The right-hand group of gliclazide is comprised of two hydrophobic rings which, as mentioned previously, are responsible for its increased potency. Gliclazide has also been shown to be one of the most effective sulfonylureas. According to Harrower, three studies carried out concluded that gliclazide is a potent hypoglycaemic agent, which compares favourably with others of its type (Harrower, 1991).
Figure 7 Structure of Gliclazide
Conclusion
Sulfonylureas are one of several groups of drugs used to treat type 2 diabetes. Through research and trials, they have developed significantly over time, to become one of the most prescribed medications in the effective treatment of type 2 diabetes.
The sulfonylureas discussed above represent significant developments in physiology and pharmacology of the group, since their initial discovery. Other sulfonylurea drugs have been synthesised and tested over the years, such as tolazamide and acetohexamide, however these are less commonly prescribed because of their disadvantages in potency and safety. The discovery of the ability to modify the left and right sides of the drug’s common structure has led to many new forms within this class, with varying properties in potency, metabolism, efficacy, and safety. The experimentation of the chemical structures over time has led to the production of more effective treatments for the disease. Currently, Glipizide and Gliclazide are the two most commonly prescribed sulfonylureas, due to their high potencies and suitable half-lives, while maintaining minimal side effects. These now provide an effective treatment in helping reduce the symptoms of type 2 diabetes and thus improving quality of life for those suffering with the disease.
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Chimeric antigen receptor (CAR) T-cell therapy is a novel form of treatment for primarily blood cancers. CAR-T cell therapies involve engineering individual patients’ T-cells to target specific cancer cells. First, blood is taken from a patient to acquire their T-cells. Secondly, CAR-T cells are produced in the lab where the CAR genes are inserted into the T-cells. Afterward, CAR proteins appear on the surface of the T-cells and they are then reproduced millions of times so that they can be infused into the patient. Then the goal for the CAR-T cells becomes binding to cancer cells to kill them (National Cancer Institute, 2019). This is as illustrated below in figure 1:
Figure 1: How CAR-T cell therapies work (National Cancer Institute, 2019).
Hodgkin’s lymphoma (HL) is a type of cancer that manifests itself in the lymphatic system and the cancer presents itself with supra-diaphragmatic lymphadenopathy meaning swollen lymph nodes above the diaphragm. The cancer cells are characterized as Hodgkin and Reed-Sternberg (HRS) cells.
Additionally, it is one of the most prevalent cancer types in adolescents. The B-cell lymphoproliferative disorder can be divided into classical HL (cHL) and nodular lymphocyte-predominant HL (NLPHL), however, cHL accounts for over 90% of the cases, which is why it will be the main focus of this article. Though, one thing that all HL subtypes have in common is that they all share an immunophenotypic pattern of CD15+, CD30+ as well as CD45-, antigens that indicate Hodgkin’s lymphoma.
HL has various treatment options ranging from chemotherapy to radiotherapy. The treatments have high rates of curability, even in cases of a patient advancing through the stages of HL (Shanbhag & Ambinder, 2017).
When CAR-T cell therapy should be considered the favorable treatment option
Most cases of HL are sufficiently cured with first-line therapy. However, 15% of HL patients relapse or acquire primary refractory disease, which means they do not go into complete remission. The usual first-line therapy alternative is high-dose chemotherapy and autologous stem cell transplantation (aSCT). aSCT refers to capturing stem cells before going into treatment and injecting them back into the body following the treatment. Around 50% of individuals going through this treatment relapse after transplantation. The issues with the alternative treatment to aSCT are that allogeneic stem cell transplantation (alloSCT) results in high morbidity as well as mortality, even though it provides the most optimal chances for achieving sustained remission. alloSCT shares similarities with aSCT, however the difference in alloSCT is that stem cells are extracted from a donor instead to replace damaged stem cells as a result of radiation or chemotherapy (Ramos et al., 2020).
In July 2021 in America, the treatment for early-stage cHL was comprised of doxorubicin (or adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD), a series of chemotherapies. The former is the most common front-line therapy there is, but this form of treatment does not come without side effects. Generally, cHL patients will be at risk for long-term complications such as cardiopulmonary toxicities, secondary malignancies, and quality of life (QoL) impairment. The latter is, among other things, why the spotlight has been on improving the side effects of being treated with front-line therapy. The first, second, and third line of treatment is shown below in figure 2 (Mohty et al., 2021).
Figure 2: Lines of treatment for cHL in advanced stages (Mohty et al., 2021).
When the time finally comes to consider CAR-T cell therapy for treating cHL the potential side-effects and the efficacy of CAR-T cell therapy must be taken into consideration.
CAR-T cell therapy has one significantly dangerous side effect, which is cytokine release syndrome (CRS) (National Cancer Institute, 2019). CRS is a condition where an abundance of cytokines are released as a result of immunotherapies like CAR-T cell therapy. The danger lies in the cytokines’ function. They are meant to maintain a healthy amount of blood cells and immune cells, but this becomes difficult when the body is overloaded with cytokines (Cleveland Clinic, 2022). The more cancer cells there are in the body the more likely it is to experience CRS when treated with CAR-T cells. Mild courses of CRS are mostly controllable with first-line therapies and more serious cases of CRS are becoming easier to treat as well, as more experience with CAR-T cell therapies is gained through research. CAR-T cell therapy becomes ineffective when it has to deal with solid tumors. This is especially true for tumor heterogeneity, which is the diversity of cancer cells in a tumor. The latter is due to the fact that solid tumors can vary a lot when it comes to the individual person and sometimes this applies to one patient’s body itself. The molecular diversity in the solid tumors makes it incredibly difficult to treat because the molecular diversity can contribute to the CAR-T cells being unable to function properly (National Cancer Institute, 2019).
The magic of CAR-T cell therapy in cHL shines through when the patient has relapsed or has experienced primary refractory diseases. A study shows that responses to Anti-CD30 CAR-T cell therapies are superior to bendamustine in patients who have previously been treated with bendamustine. In addition to this, when the CAR-T cell therapy was used following fludarabine-containing lymphodepletion regimens it resulted in 59% of complete responses out of 32 patients. The most prevalent toxicities were grade 3 or higher hematologic adverse events. The overall response rate of patients that received fludarabine-based lymphodepletion was 72% (Ramos et al., 2020).
The bottomline is that CAR-T cell therapy should be done when patients are relapsing or experiencing refractory diseases in relation to cHL, because the safety of use is incredible while also maintaining high response rates.
Mohty, R., Dulery, R., Bazarbachi, A. H., Savani, M., Hamed, R. A., Bazarbachi, A., & Mohty, M. (2021). Latest advances in the management of classical Hodgkin lymphoma: the era of novel therapies. Blood Cancer Journal, 11(7), 1–10. https://doi.org/10.1038/s41408-021-00518-z
Ramos, C. A., Grover, N. S., Beaven, A. W., Lulla, P. D., Wu, M.-F., Ivanova, A., Wang, T., Shea, T. C., Rooney, C. M., Dittus, C., Park, S. I., Gee, A. P., Eldridge, P. W., McKay, K. L., Mehta, B., Cheng, C. J., Buchanan, F. B., Grilley, B. J., Morrison, K., & Brenner, M. K. (2020). Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma. Journal of Clinical Oncology, 38(32), 3794–3804. https://doi.org/10.1200/jco.20.01342
Shanbhag, S., & Ambinder, R. F. (2017). Hodgkin lymphoma: A review and update on recent progress. CA: A Cancer Journal for Clinicians, 68(2), 116–132. https://doi.org/10.3322/caac.21438
Sterner, R. C., & Sterner, R. M. (2021). CAR-T Cell therapy: Current Limitations and Potential Strategies. Blood Cancer Journal, 11(4), 1–11. https://doi.org/10.1038/s41408-021-00459-7
Type 2 diabetes mellitus can be a difficult disease to live with and can severely affect one’s quality of life. Diabetes mellitus is a chronic condition in which your body cannot regulate your blood glucose levels, the two main types being type 1 and type 2. These are due to either an inability to produce insulin (type 1) or when the insulin produced is ineffective (type 2). Type 2 diabetes, or non-insulin dependent diabetes mellitus, can occur as a result of lifestyle factors, such as diet and obesity. These lead to insulin resistance or the inability to produce enough insulin as necessary. Currently, there are 4.1 million people in the UK with diabetes, with 90% of these cases due to type 2 diabetes. It is estimated that 1 in 10 adults will develop type 2 diabetes by 2030 (Lacobucci, 2021)
One treatment for type 2 diabetes is the use of sulfonylureas – a group of oral drugs with hypoglycaemic effects (ability to lower blood glucose levels). Since their discovery in the 1940’s, medicinal chemists have changed the structure of these drugs, to make them more effective for clinical use. These modifications have led to more favourable properties in metabolism, potency, efficacy and safety, which have made the drugs a more effective, safe and convenient treatment for type 2 diabetes mellitus. These will be discussed later on in the article.
This article will explain the chemistry of sulfonylureas, the pharmacology behind them and how they have changed over time to make them more effective in the treatment of type 2 diabetes mellitus.
Type 2 Diabetes Mellitus Cause
Type 2 diabetes occurs when there is a deficiency in insulin secretion by the β-cells in the pancreas, or when cells develop a resistance to insulin action (Galicia-Garcia, et al., 2020). This is usually due to obesity and an unhealthy lifestyle, including lack of exercise, and a high fatty and sugar diet. Insulin is a peptide hormone that is secreted by β-cells in the pancreas. It is responsible for lowering blood glucose levels by stimulating the conversion of glucose in the blood into glycogen to be stored in muscle, fat, and liver cells. When there is a deficiency or resistance of insulin it leads to hyperglycaemia (high blood glucose levels), due to the reduced ability to convert glucose into glycogen. This would lead to symptoms such as vomiting, dehydration, confusion, increased thirst, and blurred vision to name a few.
Physiology Behind Insulin Secretion and Structure
To understand the pharmacology of the sulfonylurea compounds,one must first understand the physiology behind the secretion of insulin.
As stated above, insulin is a peptide hormone, so it is made from a polypeptide chain. Transcription of the insulin gene (found on chromosome 11) occurs and the resulting mRNA strands are translated to produce two peptide chains. These chains are held together in a quaternary structure by two disulfide bonds to form the hormone insulin (Brange & Langkjoer, 1993).
Insulin secretion must be tightly controlled to maintain efficient glucose homeostasis. To do so, the secretion of insulin is regulated precisely to meet its demand. The β-cells of the pancreas contain glucose transporter 2, a carrier protein that allows facilitated diffusion of glucose molecules across a cell membrane. These transporters allow glucose to be detected and enter the β-cells. Upon cytoplasmic glucose levels rising, the pancreatic β-cells respond by increasing oxidative metabolism, leading to increased ATP in the cytoplasm (Fridlyand & Philipson, 2010). The ATP in the cytoplasm of the β-cells, can bind to ATP sensitive K+ channels on the cell membrane, causing them to close. This leads to a build up of K+ ions within the cell as they are unable to leave the cell, leading to the depolarisation of the cell. The increasing positive membrane potential, leads to the opening of voltage gated Ca2+ channels, leading to an influx of Ca2+ ions. This further depolarises the cell, which triggers the release of insulin from the cell, packaged in secretory vesicles, by exocytosis (Fu, et al., 2013).
Pharmacology of Sulfonylureas
Sulfonylurea’s act inside the pancreatic β-cells. On the ATP sensitive K+ channel, there are sulfonylurea receptors to which the drug binds, causing them to close. The cascade of events that follows leads to the release of insulin by the pancreatic β-cell. This mimics the activity that occurs when glucose is taken into the cell, as mentioned earlier. (Panten, et al., 1996). (possibly delete this instead as it is repeated)
This process allows more insulin to be released, to lower blood glucose levels when insufficient insulin is produced naturally. Sulfonylureas are only effective in type 2 diabetes, since insulin production is not impaired (as in type 1 diabetes), rather the release of or resistance to insulin is affected.
Common Chemistry of all Sulfonylureas
All the sulfonylurea drugs are characterised by their common sulfonylurea group. This functional group allows this unique group of compounds to bind to SUR on ATP sensitive K+ channels, giving it its hypoglycaemic properties. The common structure of sulfonylureas is shown in figure 1 (Fvasconcellos, 2011), with the blue R groups indicating replaceable side chains, which fluctuates between each drug development over time giving slightly different properties between the drugs. Over time, scientists have improved the drugs efficacy by changing the side compounds. Additionally, scientific research has led to development of other drugs from the same pharmacological group, but with altered side chains (again, giving them different properties) which have also improved the efficacy of the drug. These changes have altered properties of the drug such as potency, metabolism, half-life, tolerance and safety, to make the drug more effective for clinical use.
Figure 1 Sulfonylurea functional group
History and development of the drugs and their chemical structure
Sulfanilamide and IPTD
In 1935, a French research term discovered the active chemical in the antibiotic prontosil, known as sulfanilamide (Sorkhy & Ghemrawi, 2020). Sulfanilamide was found to be a poor antibiotic and so derivatives of it were synthesised and tested. These compounds, such as such as p-amino-sulfonamide-isopropylthiodiazole (IPTD), which was used as an antibiotic for the treatment of typhoid in 1942, revealed unexpected hypoglycaemic side effects. These were discovered by French physician, Marcel Janbon (Quianzon & Cheikh, 2012). However, scientists could not identify how these side effects were caused.
In 1946, Auguste Loubatières, investigated the effect of IPTD on dogs. He administrated the drug to fully pancreatectomized and partially pancreatectomized dogs and found that the drug was ineffective in the fully pancreatectomized ones but effective in the partially pancreatectomized ones. This later lead to his conclusion that the drugs’ hypoglycaemic property was due to its ability to stimulate insulin secretion directly in the pancreatic β-cells (Loubatières-Mariani, 2007).
Carbutamide
The first sulfonylurea to be marketed as a drug for diabetes was Carbutamide. It was synthesised in East Germany by Ernst Carstens and in the early 1950’s, clinical trials for this sulfanilamide derivative Carbutamide were carried out, by Hellmuth Kleinsorge, for the treatment of urinary tract infections. However, during treatment, side effects of hypoglycaemia were also noted (Kleinsorge, 1998) – similar to those experienced by patients treated with IPTD for typhoid in 1942.
These findings were presented to Erich Haak, of the East German Ministry of Health, in 1952, which ultimately culminated in the ban of the drug. Haak later moved to West Germany where he patented the drug to be tested for antibacterial use, without disclosing the side effects of hypoglycaemia. Karl Joachim Fuchs, a doctor who was part of this drug testing, noticed symptoms of ravenous hunger and euphoria upon taking the drug himself, which were found to be due to hypoglycaemia. Following this, studies were undertaken, and a general conclusion was that Carbutamide was most effective in people over 45 years of age, who had had diabetes for less than 5–10 years and had not used insulin for more than 1–2 years (Tattersall, 2008). The use of Carbutamide was short lived as it was found to have fatal side effects in a small number of people, including toxic effects on bone marrow (National Center for Biotechnology, 2005).
The structure of Carbutamide is shown in figure 2 (Anon., 2021). It can be seen, attached to the benzene ring on the left-hand side of the sulfonylurea functional group, can be seen an amine group. Attached to a second amine group on the right side of the functional group is a four-carbon chain. As mentioned previously, it is the sulfonylurea functional group that gives rise to the drugs hypoglycaemic effects. This is the first drug to contain the sulfonylurea functional group (seen in figure 1) and the beginning of many discoveries into the treatment of non-insulin dependent diabetes mellitus.
Figure 2 Structure of Carbutamide
Tolbutamide
After the discovery of the fatal side effects of Carbutamide, the next sulfonylurea drug to be synthesised was Tolbutamide; it was one of the first sulfonylureas to be marketed for controlling of type 2 diabetes, in 1956 in Germany (Quianzon & Cheikh, 2012). There were minimal changes to the chemical structure in this next development of the sulfonylureas. The amine group on the left hand side of Carbutamide was swapped for a methyl group to give Tolbutamide, shown in figure 3 (Anon., 2021), which helped reduce the toxicity of the drug. However, as a result tolbutamide was subsequently being metabolised too quickly (Monash University, 2021), which led to low levels of the (active) drug in the blood. The drugs efficacy was therefore lower than expected, resulting in it having to be administered twice a day, which was an inconvenience for patients.
Figure 3 Structure of Tolbutamide
Chlorpropamide
It was soon discovered that the methyl group attached to the benzene ring in Tolbutamide was the site of its metabolism (Monash University, 2021) and so it was replaced by medicinal chemists with a chlorine atom in the next drug, Chlorpropamide (see figure 4 ), (Anon., 2021). This helped reduce metabolism, giving the drug a longer half-life, so it was not cleared as quickly from the body. Indeed, a University of Michigan study found that chlorpropamide serum concentration declined from about 21 mg/100ml at 15 min to about 18 mg/100ml at 6 hours, whereas the tolbutamide serum concentration fell more rapidly from about 20 mg mg/100ml at 15 min to about 8 mg/100ml at 6 hours. Therefore, it could be seen that under experimental conditions, tolbutamide disappeared from the blood approximately 8 times faster than chlorpropamide (Knauff, et al., 1959). This would mean less frequent dosing with chlorpropamide, which would make the drug much more convenient for patients to treat type 2 diabetes. However, further research subsequently revealed that, due to the longer half-life of chlorpropamide, the hypoglycaemic effects were compounded and lasted longer than previously expected (Sola, et al., 2015). This meant that Chlorpropamide could not be administered for the safe treatment of type 2 diabetes.
Figure 4 Structure of Chlorpropamide
Glibenclamide
Glibenclamide is the first of what is known as the second-generation sulfonylureas. Introduced for use in 1984, these mainly replaced the first-generation drugs (Carbutamide, Tolbutamide, Chlorpropamide etc) in routine use to treat type 2 diabetes. Due to their increased potency and shorter half-lives, lower doses of these drugs could be administered and only had to be taken once a day (Tran, 2020). These second-generation sulfonylureas have a more hydrophobic right-hand side, which results in an increase in their hypoglycaemic potency (Skillman & Feldman, 1981). In Glibenclamide, the left-hand side of the drug changed drastically from chlorpropamide, as seen in figure 5 (Anon., 2021). This suggested to medicinal chemists, an innumerable number of possible changes that could be made to the drug, simply by changing the left and right-hand sides, resulting in better potency, safety, efficacy and convenience (Monash University, 2021). Consequently, the metabolism of the drug varied between patients, and this in addition to increased hypoglycaemia and increased incidence of Cardiovascular events (Scheen, 2021), meant that the drug is not a first choice in recommendation to treat type 2 diabetes.
Figure 5 Structure of Glibenclamide
Glipizide
Glipizide, figure 6 (Anon., 2021), shares the same hydrophobic structure on the right-hand side as Glibenclamide, however a few changes have been made to the left-hand group, resulting in faster metabolism. Although it has similar potency to that of Glibenclamide; however, the duration of its effects was found to be much shorter (Brogden, et al., 1979). Glipizide has the lowest elimination half-life of all the sulfonylureas, reducing the risk of the long-lasting hypoglycaemic side effects found in previous developments (Anon., 2022).
Figure 6 Structure of Glipizide
Gliclazide
Gliclazide is the most common sulfonylurea used in current medicine for the treatment of non-insulin dependent diabetes mellitus; it is part of the World Health Organisation’s most recent list of essential medicines (World Health Organisation, 2021). The chemical structure of Gliclazide can be seen in figure 7 (Anon., 2021). Fascinatingly, medicinal chemists returned to the use of a methyl group on the left-hand side of the drug, which was last seen in Tolbutamide. As mentioned before, the left-hand group on the drug, attached to the benzene ring, is responsible for the metabolism of the compound. Returning to the use of a methyl group, allows for a faster metabolism of the drug, which helped to remove the unwanted longer hypoglycaemic side effects, especially for use with elderly patients (Monash University, 2021). The right-hand group of gliclazide is comprised of two hydrophobic rings which, as mentioned previously, are responsible for its increased potency. Gliclazide has also been shown to be one of the most effective sulfonylureas. According to Harrower, three studies carried out concluded that gliclazide is a potent hypoglycaemic agent, which compares favourably with others of its type (Harrower, 1991).
Figure 7 Structure of Gliclazide
Conclusion
Sulfonylureas are one of several groups of drugs used to treat type 2 diabetes. Through research and trials, they have developed significantly over time, to become one of the most prescribed medications in the effective treatment of type 2 diabetes.
The sulfonylureas discussed above represent significant developments in physiology and pharmacology of the group, since their initial discovery. Other sulfonylurea drugs have been synthesised and tested over the years, such as tolazamide and acetohexamide, however these are less commonly prescribed because of their disadvantages in potency and safety. The discovery of the ability to modify the left and right sides of the drug’s common structure has led to many new forms within this class, with varying properties in potency, metabolism, efficacy, and safety. The experimentation of the chemical structures over time has led to the production of more effective treatments for the disease. Currently, Glipizide and Gliclazide are the two most commonly prescribed sulfonylureas, due to their high potencies and suitable half-lives, while maintaining minimal side effects. These now provide an effective treatment in helping reduce the symptoms of type 2 diabetes and thus improving quality of life for those suffering with the disease.
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Youth Medical Journal 