The Evolution of Sulfonylureas as Hypoglycaemic Drugs Over Time, Their Mechanisms and how they Treat Symptoms of Type II Diabetes Mellitus.

Introduction

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.

AliMahdi Meghji, Youth Medical Journal 2022

References

Anon., 2021. Carbutamide. [Online]
Available at: https://www.drugfuture.com/chemdata/carbutamide.html
[Accessed 27 March 2022].

Anon., 2021. Chlorpropamide. [Online]
Available at: https://www.drugfuture.com/chemdata/chlorpropamide.html
[Accessed 29 March 2022].

Anon., 2021. Gliclazide. [Online]
Available at: https://www.drugfuture.com/chemdata/gliclazide.html
[Accessed 30 March 2022].

Anon., 2021. Glipizide. [Online]
Available at: https://www.drugfuture.com/chemdata/glipizide.html
[Accessed 29 March 2022].

Anon., 2021. Glyburide. [Online]
Available at: https://www.drugfuture.com/chemdata/glyburide.html
[Accessed 29 March 2022].

Anon., 2021. Tolbutamide. [Online]
Available at: https://www.drugfuture.com/chemdata/tolbutamide.html
[Accessed 29 March 2022].

Anon., 2022. Glipizide. [Online]
Available at: https://pharmaoffer.com/api-excipient-supplier/glipizide#:~:text=About%20Glipizide&text=It%20was%20first%20introduced%20in,glucose%2Dlowering%20therapy%20following%20metformin.
[Accessed 29 March 2022].

Brange, J. & Langkjoer, L., 1993. Insulin structure and stability, Bagsvaerd: Novo Research Institute.

Brogden, R. N. et al., 1979. Glipizide: a review of its pharmacological properties and therapeutic use. Drugs , 18(5), pp. 329-353.

Fridlyand, L. E. & Philipson, L. H., 2010. Glucose sensing in the pancreatic beta cell: a computational systems analysis. Theoretical Biology and Medical Modelling, 7(1), p. Article 15.

Fu, Z., Gilbert, E. R. & Liu, D., 2013. Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes. Current Diabetes Reviews, 9(1), pp. 25-53.

Fvasconcellos, 2011. General structural formula of a sulfonylurea, highlighting the functional group that gives the class its name and the side chains that distinguish its various members., s.l.: Wikipedia.

Galicia-Garcia, U. et al., 2020. Pathophysiology of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences, 30 August, 21(17), p. 2.

Harrower, A. D., 1991. Efficacy of gliclazide in comparison with other sulphonylureas in the treatment of NIDDM. Diabetes research and clinical practice , 14(2), pp. 65-67.

Kent, M., . Advanced Biology. ed. (): Oxford University Press.

Kleinsorge, H., 1998. Carbutamide–the first oral antidiabetic. A retrospect. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association, 106(2), pp. 149-151.

Knauff, R. E., Fajans, S. S., Ramirez, E. & Conn, J. W., 1959. Metabolic studies of chlorpropamide in normal men and in diabetic subjects.. Annals of the New York Academy of Sciences , 74(3), pp. 603-617.

Lacobucci, G., 2021. The British Medical Journal. [Online]
Available at: https://www.bmj.com/content/375/bmj.n2453
[Accessed 2 March 2022].

Loubatières-Mariani, M.-M., 2007. The discovery of hypoglycemic sulfonamides. Journal de la Société de Biologie, 201(-), pp. 121-125.

Monash University, 2021. The Science of Medicines MOOC, Melbourne: Future Learn.

National Center for Biotechnology, 2005. PubChem Compound Summary for CID 9564, Carbutamide. [Online]
Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Carbutamide
[Accessed 18 March 2022].

Panten, U., Schwanstecher, M. & Schwanstecher, C., 1996. Sulfonylurea receptors and mechanism of sulfonylurea action.. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association, 104(1), pp. 1-9.

Quianzon, C. C. L. & Cheikh, I. E., 2012. History of current non-insulin medications for diabetes mellitus. Journal of Community Hospital Internal Medicine Perspectives , 2(3), p. 19081.

Scheen, A. J., 2021. Sulphonylureas in the management of type 2 diabetes: To be or not to be?. Diabetes Epidemiology and Management, Volume 1, p. Article 100002.

Skillman, T. G. & Feldman, J. M., 1981. The pharmacology of sulfonylureas. The American journal of medicine, 70(2), pp. 361-372.

Sola, D. et al., 2015. Sulfonylureas and their use in clinical practice. Archives of medical science , 11(4), pp. 840-848.

Sorkhy, M. A. & Ghemrawi, R., 2020. Treatment: Projected Modalities for Antimicrobial Intervention. Microbiomics – Dimensions, Applications, and Translational Implications of Human and Environmental Microbiome Research, -(-), pp. 279-298.

Tattersall, R., 2008. Discovery of the sulphonylureas. TATTERSALL’S TALES, 7(2), p. 74.

Tran, D., 2020. Oral Hypoglycemic Agent Toxicity. [Online]
Available at: https://emedicine.medscape.com/article/1010629-overview#a1
[Accessed 27 March 2022].

World Health Organisation, 2021. WHO model list of essential medicines – 22nd list, 2021. [Online]
Available at: https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.02
[Accessed 30 March 2022].

Advertisement

Ageing, genetics and Parkinson’s

Introduction 

Nowadays vast amounts of misinformation surface the internet, constructing controversies. Within the same spectrum, healthcare professionals seek to support or contradict the argument, through evidence-based judgement. Likewise, contributing factors of Parkinson’s disease stand firm ground between the evaluation of healthcare professionals across the platform. The Parkison’s debate, distinctly separates itself into three categories, enlisted below:

• Pathological process of PD are exaggerations of those processes involved in ageing (Hindle 156-161)
• The ageing process makes us vulnerable to diseases such as PD (Hindle 156-161)
• Pathology of PD is independent of ageing (Hindle 156-161)

Parkison diseases’s pathogenesis combines with complicated interactions between susceptibility factors, and side-effects of ageing, making PD one of the best examples of an age-related disease (Hindle 156-161)

Epidemiology of United Kingdom 

The likelihood of developing Parkinson’s disease increases with age, despite some research indicating Parkinson’s disease developing at any segment of an individual’s life, it has become increasingly common against the elderly population globally. Rationally, Parkinson’s disease is frequently conferred as a degenerative (worsening over the period) and age-related disease. Having said that, correlation between life-expectancy and Parkinson’s prevalence rate varies, between each nation. Taking into account, the United Kingdom, acclaiming one of the highest life-expectancy globally, of 81.65 years  (Macrotrends LLC), prevalence rate was 286.5 per 100,000 person (NICE), whereas throughout age, the prevalence is 4-5 per 100,000 people in people aged 30-39 years, compared with 1696 per 100,000 people aged 80-84 (equivalent to 1.7% of this age group) (NICE). Most studies suggest a mean age of onset in the 70s (Hindle 156-161). 

Interaction Between Neurodegeneration and Aging 

Ageing is simply defined as the process in which the human body’s structure and functions deteriorates over time; recent studies have demonstrated an ageing population contributes to having a significant strain on elderly medicine, especially due to underfunding and limitation of accessibility to resources. Through ageing, the likelihood of developing chronic diseases becomes paramount. When perceived through general perspectives, chronic diseases impose risks of developing other diseases and illnesses, leading to management complications, especially amongst elderly dependents with underlying health risk factors (these health risk factors may be inherited or attributed by their surrounding environment, usually they are classed as non-modifiable and modifiable factors). Despite neurons being susceptible to the combined impacts of ageing, neuronal death is not programmed to occur at a particular time (Hindle 156-161). Cellular and molecular changes of ageing interact with genes and environmental factors to determine which cells age successfully and which succumb to neurodegeneration (Hindle 156-161). However, it is not yet explicit how selective vulnerability diverges, creating various patterns of neurodegeneration in numerous chronic diseases. 

Underlined by the Parliamentary Office of Science and Technology, there are four primary factors contributing towards ageing, detailed below:

• DNA Mutations (Parliamentary Office of Science and Technology)
  • Mutations occur when the process of mitosis becomes uncontrollable, resulting from excessive exposure to harmful chemicals, or electromagnetic radiation from the environment. Also, a decline in the body’s DNA repair mechanism (Parliamentary Office of Science and Technology), can also influence the rate of ageing.
• Chromosome shortening
  • Chromosome shortening is caused by the incomplete replication of chromosomes, therefore some chromosomes may be lost or completely damaged as mitosis continues to occur.
• Age-related deposition
  • Synucleins are small, soluble proteins expressed primarily in neural tissues and in certain tumours (Stefanis 1) which experience age-related decline. When mutations in α-synuclein occur, the protein commences to accumulate abnormally in Parkinson’s disease, Alzeihimer’s disease, and several other neurodegenerative diseases (Stefanis 1).
• Mis-folded proteins
  • The function of almost every cell in your body, containing a nucleus, depends on the folding of protein. As the process of ageing occurs, the mechanisms responsible for right folding such protein into a particular shape, to form an enzyme-substrate complex, start to decline. Having said, the knock-on-effect becomes toxic to cells and is linked to age-related conditions such as Parkinson’s and cataracts. (Otín et al. 5-6)

Biology Behind Causes of Parkinson’s 

Interestingly, Parkinson’s disease concerns a significant decline of the chemical transmitter: dopamine, in the substantia nigra. The substantia nigra, is a black melanin pigment found within the dopamine cells, hence its name. It has been acknowledged for a long time that there is a frank loss of neurons primarily in this highly localised region, where the dopamine cells are distributed as a thin arching sheet on either side of the brain (Greenfield). However, for any problems with movement, a minimum seventy per-cent of dopamine neurons in the substantia nigra must be lost, consequently the whole population declines. Outlined, the domino-effect is at work, as once a small percent of cells becomes damaged, theoretically the causes complete extinction of the brain region, conferring it as a representation of neurotic death: neurogeneration (Greenfield). 

In response, the significant loss of dopaminergic neurons, is immediately increased by the amount of dopamine released from the remaining cells, although direct explanation of the mechanism is not yet confirmed, a possible explanations of how the cells in the substantia nigra would be gradually killed in this way stems from the normal metabolism of dopamine (Greenfield). 

Complexity of Diagnosis and Symptoms 

Parkinson’s being a progressive disease further implicates the severity of symptoms developing, for example, slight tremor and shaking of hands may indicate early symptoms of Parkinson’s. Often, diagnosis of Parkinson’s evolves as a misdiagnosis of common changes, experienced due to ageing. Gradual yet continuous tremor can aggregate to developing bradykinesia, alternatively referred impaired or slowed movement; the basal ganglia is responsible for movement and physical functioning. Alongside, it is also dependent on dopamine (produced by dopaminergic neurons) to increase the action of direct pathway between dopamine receptors. As a result, when there is a consistent reduction upon dopamine acting through a direct pathway, it leads to delayed physical responses.

Parkinson’s disease may also impact the sensory system, this consists of problems with hearing, smelling or sight, principally due to a reduction in dopamine, there is a detrimental impact upon the mobility of the visual cortex. The visual cortex is responsible for the normal functioning of the eye, inclusive of blinking, movement of the eyelids and the retina. Furthermore, Parkinson’s disease can deteriorate the individual’s working memory, therefore encoding information from the season to the short-term memory becomes complex, as well as retrieving information from the long-term to the short-term memory. Primarily, due to the fluctuating levels of dopamine the prefrontal cortex, which is responsible for the functioning of the short term memory, becomes impaired.

Conclusion 

Conclusively, the likelihood of developing Parkinson’s disease increases significantly, however there are environmental and genetic factors which contribute towards the diagnosis. Often the mental and abstract impact of Parkinson’s disease is frequently ignored, primarily due to the stigma encountered, especially by elderly dependants who are stereotypically conditioned to develop chronic diseases due to ageing.Consequently, it remains of utmost importance that both health care professionals and society at large continues to establish a positive rapport with elderly dependents, specifically when experiencing loneliness and distress throughout the post and pre-diagnosis process. 

Sheza Dewan, Youth Medical Journal 2022

References:

Greenfield, Susan A. Exploring the Brain. Lecture 13: Parkinson’s Disease. 20 November 1997. Gresham College, Gresham College, https://www.gresham.ac.uk/sites/default/files/20nov97susangreenfield_parkinsonsdisease.pdf. Accessed 19 August 2022.

Hindle, John V. “Ageing, neurodegeneration and Parkinson’s.” Age and Ageing, vol. 39, no. 2, 2010, pp. 156-161. Oxford Academic, https://doi.org/10.1093/ageing/afp223.

Macrotrends LLC. “U.K. Life Expectancy.” Macrotrends, https://www.macrotrends.net/countries/GBR/united-kingdom/life-expectancy. Accessed 19 August 2022.

NICE. “Parkinson’s Diseases: How common is it?” National Institute of Health and Care Excellence, National Institute of Health and Care Excellence, January 2022, https://cks.nice.org.uk/topics/parkinsons-disease/background-information/prevalence/. Accessed 19 August 2022.

Otín, Carlos López, et al. “The Hallmarks of Aging.” Europe PubMED Central, vol. 6, no. 153, 2013. PUBMed, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/pdf/emss-55354.pdf. Accessed 19 August 2022.

Parliamentary Office of Science and Technology. The Ageing Process and Health. no. 571, February 2018. Babraham Institute, Houses of Parliament, https://www.babraham.ac.uk/sites/default/files/media/files/post%20note%20-%20the%20ageing%20process%20and%20health%20-%200571.pdf.Stefanis, Leonidas. “α-Synuclein in Parkinson’s Disease.” Cold Spring Harb Perspect Med, vol. 2, no. 2, 2012, p. 1. National Library of Medicine, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/. Accessed 19 August 2022.

Dostarlimab: Hope or Hype?

Introduction

Cancer is very often placed at the forefront of medical research and with an estimated 1 in 2 people expected to develop cancer at some point in their lives¹ it is becoming increasingly important that novel drugs and therapies are discovered to mitigate the impacts. Over the years, we have seen the development of powerful treatment methods, from chemotherapy to radiotherapy, however more recently there has been a rise in the use of immunotherapy. One recent form of immunotherapy, a drug called Dostarlimab, has taken the medical world by storm after a small study reported a 100% complete clinical response. 

How does it Work?

The drug works by enhancing the body’s immune response against tumour cells. It does this through two types of proteins PD-L1 and PD-L2 (programmed death ligand 1 and 2) which typically play a role in weakening our immune response when bound to a complementary receptor on a T-cell. This plays an important physiological role in preventing excessive destruction to non-harmful cells, as well as preventing the onset of autoimmune diseases.² 

However, some tumour cells express these proteins on their surface, which when bound to a T-cell inhibits the cell-mediated immune response, and the cancer cells remain undestroyed.³ Dostarlimab is a monoclonal antibody which binds to PD-1, the complementary receptor on the T-cell, and therefore prevents the interaction between the tumour and T-cells. This enables both identification and reactivates cytotoxic activity, allowing the cancer cells to be attacked.

Fig: Images showing the interactions without (left) and with (right) Dostarlimab³

Usage of the Drug

Although the drug has only recently risen to fame in mainstream media, the drug had already begun rollout across the NHS in February 2022 as a treatment method for endometrial cancer.⁴ Alternative options such as surgery and chemotherapy tend to be more invasive and often leave patients with a poor prognosis, which is why Dostarlimab serves as an innovative drug. It requires only four half-an-hour sessions over a 12 week-period, offering patients quicker, safer and more effective treatment.

It was only more recently that a small trial involving 12 rectal cancer patients saw a 100% remission rate.⁵ The patients involved suffered from a particular subset of rectal cancer caused by mismatch repair deficiency (cells with many DNA mutations), which is affected by blockage of the PD-1 receptor on T-cells caused by Dostarlimab. Despite the small sample size, a high confidence interval of 95% and no severe side effects suggest that the drug holds a lot of potential. 

Limitations of the Drug

Despite the fact that the drug has only been proven effective on one particular form of the disease, it is estimated that 5-10% of rectal cancers are due to mismatch repair deficiency⁶. With over 700,000 people diagnosed with rectal cancer each year⁷, even a small proportion of those cases being treated represent a significant triumph. 

However, the results of this trial must not be taken as a definitive yes for the use of Dostarlimab, as a follow-up study with a larger sample size would increase the validity and reliability of the study. Additionally, the patients were followed up for between 6 to 25 months ⁵ in order to assess any recurrence, but ideally, longer follow-up times would allow researchers to better ascertain the long term efficacy. A further obstacle which may hinder large scale roll out is cost, which is particularly a challenge in countries where private healthcare is dominant. According to the New York Times⁸, each dose cost $11,000 and with several doses required over a 6 month period, the drug may prove to be unaffordable for many. 

Such limitations are not completely restricting, as numerous solutions exist to tackle them. For example, subsidies from the government would not only allow for larger studies to be completed, but also increase research in cost reduction. Whilst this presents an opportunity cost to a country’s government, extra funding for the healthcare sector leads to better survival rates, which benefits the economy, hence creating a positive multiplier effect.

Conclusion

The future of Dostarlimab seems to be exciting and may change the way in which we treat rectal cancer. Not only is it an innovative way in which to treat cancer, it’s potential benefits to the fields of endometrial and mismatch repair deficiency cancers are immense. However, in the near future, further trials, or extensions of ongoing ones, are warranted in order to successfully determine whether the drug is a viable treatment method, as well as solutions which address cost reduction. 

The unprecedented results of the trial have been groundbreaking for the medical sector, and provide a great sense of hope that we will continue to discover cancer treatments. Nonetheless, whether it proves to be a miracle cure or not, it is fair to say that immunotherapy in itself has been revolutionary to the world of medicine, and the research gained from such studies conducted will prove to be valuable in the long term. 

Nyneisha Bansal, Youth Medical Journal 2022

References

1. Cancer [Internet]. nhs.uk. 2022 [cited 15 June 2022]. Available from: https://www.nhs.uk/conditions/cancer/

2. Touboul R, Bonavida B. YY1 expression and PD-1 regulation in CD8 T lymphocytes. YY1 in the Control of the Pathogenesis and Drug Resistance of Cancer. 2021;:289-309.

3. How JEMPERLI works [Internet]. Jemperli. 2022 [cited 15 June 2022]. Available from: https://www.jemperlihcp.com/mechanism-of-action/

4. England N. NHS England » New life-extending drug for advanced womb cancer to be rolled out on the NHS [Internet]. England.nhs.uk. 2022 [cited 15 June 2022]. Available from: https://www.england.nhs.uk/2022/02/new-life-extending-drug-for-advanced-womb-cancer-to-be-rolled-out-on-the-nhs/

5. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M et al. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. New England Journal of Medicine. 2022;.

6. Promising rectal cancer study [Internet]. ScienceDaily. 2022 [cited 15 June 2022]. Available from: https://www.sciencedaily.com/releases/2022/06/220605130358.htm#:~:text=A%20scientist%20comments%20on%20the,a%20subtype%20of%20rectal%20cancer.

7. Colorectal Cancer – Statistics [Internet]. Cancer.Net. 2022 [cited 15 June 2022]. Available from: https://www.cancer.net/cancer-types/colorectal-cancer/statistics#:~:text=These%20numbers%20include%20106%2C180%20new,with%20colorectal%20cancer%20in%202020.

8. Kolata G. A Cancer Trial’s Unexpected Result: Remission in Every Patient [Internet]. Nytimes.com. 2022 [cited 15 June 2022]. Available from: https://www.nytimes.com/2022/06/05/health/rectal-cancer-checkpoint-inhibitor.html

ADHD: Over Diagnosed or Loosely Defined?

Introduction

Attention deficit hyperactivity disorder (ADHD) is generally manifested through difficulty focusing. The disorder’s diagnostic criteria, as described in the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), includes a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development, the presence of several inattentive or hyperactive-impulsive symptoms prior to the age of twelve and in two or more settings, clear evidence the symptoms interfere with social, academic, or occupational functioning, and the precedent that the symptoms cannot be explained by another mental disorder. The DSM-5 also provides examples of behaviors that may be indicative of ADHD, including frequent fidgeting, excessive talking, difficulty waiting for a turn, an inability to play quietly, and frequent interruption of others [1]. Many remark that these symptoms are merely traits of being a child and are not signs of a disorder. Accusations of ADHD’s overdiagnosis have been on a rise in recent years, as have diagnosed cases of ADHD. In 1997, the parent-reported percent of children with an ADHD diagnosis in a National Health Institute survey was just under 6%. Ten years later, this figure had risen to 10% [2]. Similar results have fueled a growing debate as to whether these diagnoses are the result of a widening definition of the disorder or a true increase in those afflicted. 

Identifying Over Diagnosis

The commonly-held notion that ADHD is loosely and  inaccurately diagnosed stems from an assumption that many diagnoses are falsely positive. For ADHD to be justifiably labeled as overdiagnosed, there must be evidence that the total number of false positive diagnoses significantly outweighs the number of falsely negative diagnoses [3]. Such evidence has not yet been discovered, thereby establishing the ability to recognize the factors at play in a potential false positive ADHD diagnosis as vital in gaining insight to the overdiagnosis assumption. 

Potential Components of Misdiagnosis

The relative age of schoolchildren is a common explanation for ADHD misdiagnosis. Numerous studies have found that children who are relatively younger than their classmates are at an increased risk of ADHD diagnosis. In a study conducted within a school whose school-age cutoff is December 31, results revealed that boys born in December were 30% more likely to be diagnosed and 41% more likely to be treated for ADHD than their January-born peers. Girls born in December were 70% more likely to be diagnosed and 77% more likely to be treated for ADHD than those born in January [4]. These findings suggest that diagnostic measures have failed to account for the relative developmental immaturity of young children, leaving unnecessary room for subjectivity in diagnosis. 

Early diagnosis provides another point of concern in the misdiagnosis of ADHD, given that most ADHD research has been conducted on older, school-age children, rather than younger preschoolers [4]. Research as to the manifestations of ADHD at such a young age has been limited. Current diagnostic measures are geared toward older children and may lead to false positive diagnoses, especially considering the prevalence of inattention, impulsivity, and hyperactivity at that developmental age [5]. 

The argument of diagnostic inaccuracy has been substantiated in a number of studies, such as a 1993 study that evaluated 92 children previously referred to a specialized ADHD clinic. Of the referrals, only 22% received a primary diagnosis of ADHD and only 37% were given a secondary diagnosis [3]. Variability in assessment among providers may be to blame for these diagnostic inaccuracies that may contribute to an increase in false positive diagnoses. 

Potential gender differences in the manifestations of ADHD may be at blame for deflated diagnoses in girls. It has been hypothesized that boys tend to exhibit the prototypical characteristics of ADHD through disruptive and hyperactive behaviors. Girls, however, may exhibit less externalized and disruptive behavior that had become characteristic of ADHD and increased intellectual impairment [4]. A potential inability to distinguish between different manifestations of the disorder suggests further inaccuracy in the diagnostic criteria. 

Conclusion

It appears to be overwhelmingly evident that ADHD is often misdiagnosed. Fallacies in the diagnostic criteria may be to blame for an inflated number of diagnoses in preschool-age children and developmentally immature children, as well as a deflated number of diagnoses in girls. Although such diagnostic concerns have been supported by a number of studies, sufficient evidence for systematic overdiagnosis remains lacking. Due to the variability in assessment techniques by provider, prevalence rates of ADHD are unreliable and cannot be used to prove that the number of false positive diagnoses drastically outweigh the number of false positive diagnoses. Despite this, the popular idea that ADHD is widely misdiagnosed remains intact, and likely will remain as such. It is important to remember that such claims are generally based on unreliable data and should be deemed untrustworthy by association. 

Alaina Buerger, Youth Medical Journal 2022

References

[1] Reynolds, Cecil and Kamphus, Randy. “Attention-Deficit/Hyperactivity Disorder (ADHD).” DSM-5 Diagnostic Criteria, Pearson, 2013, http://images.pear sonclinical.com/images /assets/basc -3/basc3resources/DSM5_DiagnosticCriteria_ADHD.pdf

[2] “Attention-Deficit/Hyperactivity Disorder (ADHD).” Centers for Disease Control and Prevention, 23 September 2021, https://www.cdc.gov/ncbddd/adhd/timeline.html

[3] Scuitto, Mark. “Evaluating the Evidence For and Against the Overdiagnosis of ADHD.” Journal of Attention Disorders, Sage Publications, September 2007, pp. 106-113, https://t heunbrokenwindow.com/wp-content/uploads/2017/10/ADHD-Overdiagnoses.pdf

[4] Ford-Jones, Polly Christine. “Misdiagnosis of attention deficit hyperactivity disorder: ‘Normal behaviour’ and relative maturity.” Paediatrics & child health vol. 20,4 (2015): 200-2. doi:10.1093/pch/20.4.200

[5] Tandon, Mini et al. “Attention-deficit/hyperactivity disorder in preschool children: an investigation of validation based on visual attention performance.” Journal of child and adolescent psychopharmacology vol. 19,2 (2009): 137-46. doi:10.1089/cap.2008.048