A journey from Aspirin to personalized medicine: A brief history of drug development

Medicine as we know it has been around for just over 100 years. Before this, alcohol and opium were the main forms of pain relief in Europe. The development of the first vaccine to prevent disease in the late 18^th century, as well the continued improvements in our understanding of the human body, and the discovery of X-rays in the late 19^th century, helped continual advances in the field of medicine [1]. However, it was not until the 20^th century that what we now consider drugs started to emerge; Aspirin and an antibiotic for the treatment of syphilis, Salvarsan, were two of the first.

Many of the earliest pharmaceutical products have been withdrawn from the market over safety concerns (e.g., the painkiller Phenacetin), but today there are thousands of medicines available—in 2018, the FDA reported that there were more than 19,000 prescription drug products approved for marketing [2]—with more in various stages of research and development. In this article, we summarize some of the key milestones in pharmaceutical development that helped us reach this point.

Analgesics (pain medication)

Morphine (1805)

Around 1805, Friedrich Serturner isolated a substance from crude opium (which had been used for centuries for both pain relief and recreational drug use) that was better at relieving pain than opium. He called it morphine. Although side effects included euphoria, other psychiatric effects, constipation, and addiction, the development of the hypodermic needle meant it quickly became popular, and it was produced commercially from the mid-1800s. However, addiction, a lack of regulation, and the development of heroin from morphine to counter morphine addiction eventually led to strict regulations regarding its use [3]. Morphine is still used today as effective pain relief in a clinical setting.

Phenacetin (1887)

One of the first pain medications was Phenacetin, introduced in 1887. It was used for decades until a role in kidney disease was identified, and it was withdrawn from the market in most countries between 1977 and the mid-1980s [4].

Aspirin (1897)

Naturally occurring salicyclic acid found in the white willow tree had been used medicinally for thousands of years to treat fever and inflammation [5], leading researchers to study it in an attempt to find out how it worked. The chemical structure was determined in 1859 and the first clinical trial for pain relief occurred in 1876. This paved the way for Dr Felix Hoffman to produce a stable compound called acetylsalicyclic acid in 1897, which was made commercially available by Friedrich Bayer and Co (Bayer AG) as Aspirin in 1899 [6].

Sedative-hypnotic agents

Chloral hydrate (1832)

First synthesized by Justin Liebig in 1832, and introduced in 1869 for hypnotic or sedative purposes, chloral hydrate was one of the first synthetic drugs. Highly efficacious but highly addictive, its safety has now been questioned, its use greatly diminished, and newer, safer sedatives are available [7, 8].

Barbitol (1881)

The first barbiturate drug, barbital, was synthesized in 1881 and marketed in 1901. Over time, as many as 2500 different agents were synthesized from barbital, leading to the discovery of phenobarbital, the first effective treatment for epilepsy. Although many barbiturates were subsequently developed, their use today is limited to very specific indications, due to the addictive nature and other side effects [9].

Anesthetics

Chloroform (1831)

Chloroform was discovered in 1831 independently in the USA (by Samuel Guthrie), in France (by Eugène Soubeiran) and in Germany (by Justus von Liebig). However, it was not until 1847 when Professor James Y. Simpson, a Scottish obstetrician, gave it as pain relief to women during childbirth that it became a popular anesthetic. It was even given to Queen Victoria for the births of her children, Prince Leopold (1853) and Princess Beatrice (1857) [10].

First ether anesthetic (1846)

The first demonstration of anesthesia took place at Massachusetts General Hospital in Boston on October 16, 1846. William T.G. Morton successfully used ether to anesthetize patient Edward Gilbert Abbott, allowing surgeon John Warren to perform surgery on the semi-conscious but pain-free patient [11]. News spread and in December of the same year, a dentist in London extracted a tooth under ether anesthesia, and surgeons in Dumfries, Scotland and London, England, performed limb amputations under ether anesthesia [10, 11].

Nitrous oxide (1860s)

In the late 1860s, the use of nitrous oxide became popular for dental extractions [11] and the field of anesthesia continued to develop towards the end of the century with the use of cocaine as a local nerve-blocking agent [10].

Modern anesthetics

Further developments followed, including the use of tubes to control the airways. In 1942, curare was successfully used as the first anesthetic muscle relaxant, reducing the amount of anesthetic required to induce unconsciousness [10, 12]. In 1956, the first modern brominated general anesthetic, halothane, was used in a clinical setting by Dr. Michael Johnstone in the UK, leading to the development of further inhaled anesthetics throughout the rest of the 20^th century [10].

Antibiotics

Salvarsan (1909)

Paul Ehrlich and Sahachiro Hata discovered Salvarsan to treat syphilis in 1909. Salvarsan is an antibiotic, but it was discovered as part of a drive by Ehrlich to find chemicals to treat disease, which he called chemotherapy [17, 18].

Penicillin (1928)

Sir Alexander Fleming famously discovered penicillin in 1928, when he observed that mold growing on his petri dishes in the laboratory inhibited the growth of the colonies of Staphylococcus aureus [13]. Our understanding of the causative role of bacteria in infections grew and when Penicillin became commercially available in the 1940s it transformed the way bacterial infections were treated [14, 15]. Although still used to treat infections today, some previously susceptible species of bacteria have developed resistance, meaning penicillin is not effective in treating the infection. This is due in part to over use and incorrect use in people, as well as in animals and plants [16]. Furthermore, multi-drug resistant bacteria is an increasing and worrisome problem.

Chemotherapeutic agents

First chemotherapeutic substances (1948)

Although Salvarsan was the first chemotherapeutic agent [17, 18], it was not until 1943 when it was noted that exposure to nitrogen mustard gas caused bone marrow and blood changes, that modern chemotherapy was born. Alfred Gilman and Louis Goodman at Yale studied the therapeutic effects of using mustard agents to treat lymphoma in mice. Encouraged by the success of their experiments, together with Gustaf Lindskog, they treated a patient with non-Hodgkin’s lymphoma, and found that the patients tumor mass reduced for a few weeks after treatment before they needed to return for more treatment. They published their findings in 1946 [19].

In 1948, Sidney Farber and colleagues found the substances related to folic acid were effective in treating children with acute lymphoblastic leukemia and producing remission [19]. This paved the way for new chemotherapy drugs, and a similar substance, methotrexate, is still in use today [20].

Vinca alkaloids (1960s)

In the 1950s, research on plant alkaloids from Vinca rosea at Eli Lilly, led in the 1960s, to the introduction of vinca alkaloids as anticancer agents that work by blocking cell division to treat Hodgkin’s disease and pediatric leukemia [20]. They are still used today. In the late 1960s, researchers began to investigate combination chemotherapy treatments, with successes including testicular cancer, and combination chemotherapy is still used for some types of cancer today [18–20].

Monoclonal antibodies

Orthoclone (1986)

Since the first monoclonal antibody, Orthoclone OKT3 (muromonab-CD3), was licensed for use in 1986 to prevent kidney transplant rejection, methods of development have changed considerably leading to more products with improved safety and efficacy profiles, albeit with high financial cost. Orthoclone was withdrawn from the market in 2010 [21].

Today, monocolonal antibodies are used in immunology and hematology, and most frequently in oncology [22] where they are often used in combination with chemotherapeutic agents [18]. They are used for targeted therapy in cancer treatment, an expanding field that uses drugs to target the genetic changes that cause healthy cells to become cancerous [23].

Hormones

Insulin (1921)

One of the most famous drug discoveries of all time is the discovery in 1921 of insulin by Sir Frederick G Banting, with the help of Charles H Best, John Macleod and James Collip [24].

Insulin is produced in the pancreas and is essential for the movement of glucose from your blood into cells to use as energy and therefore in the management of blood sugar levels. If there is not enough insulin or the body produces too much insulin and does not respond properly to it (insulin resistance), glucose remains in the blood leading to high blood sugar levels and ultimately to diabetes [25]. Insulin became commercially available in 1923 [26], and the production of insulin for injection revolutionized diabetes treatment and it remains key to the treatment of diabetes.

The future of drug development

The field of pharmacogenomics – the study of how our genes affect our response to medication- is revolutionizing drug treatment. It can help a physician to determine whether a medicine is suitable for someone or whether he or she will have side-affects [27]. An example is Trastuzumab (Herceptin®) used to treat breast cancer that only works for people with tumors that overproduce the HER2 protein (HER2-positive breast cancer). By testing the tumors of breast cancer sufferers, physicians can determine whether this treatment may be effective, allowing them to prescribe only a treatment with some potential and potentially improving efficiency and healthcare costs.

Pharmacogenomics is central to the idea of personalized medicine, which is medicine (diagnosis and treatment) personalized to an individual’s genetic make-up, allowing physicians to tailor medication, combinations, and dosage.

The use of existing medications and the development of new ones will continue to be influenced as we learn ever more about the genetic causes of diseases. Furthermore, approaches including gene therapy and gene editing are emerging as techniques to treat or prevent genetic disease [28].

Conclusion

From the arsenic containing Salvarsan to treat syphilis to monoclonal antibodies for the treatment of cancer, the number and type of drugs available has increased dramatically. With so many medicines now available (more than 19,000 in 2018 [2]), we often take the existence of a drug to treat any ailment for granted. However, there are still many untreatable diseases, including most rare diseases, but researchers, scientists and physicians continue to work hard to develop new drugs or to investigate how to repurpose existing drugs for new indications.

As with much scientific research, achievements in drug development are not linear and current research builds on previous findings from research that has been done before. Furthermore, as scientists discover evermore about the molecular nature of disease, there is an increasing potential for drug development, as well as other techniques including gene therapy and gene editing to prevent or treat disease.

References

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