eTute 3 - New Drugs from Disease Model TestingeTute 3 - New Drugs from Disease Model Testing Flashcards
In the early days, the animal models were often rodents that were simply infected with bacterial pathogens known to cause disease in humans:
infection of mice with Staphylococcus helped during the discovery of Prontosil
Treponema-infected rabbits aided the discovery of Salvarsan and Neosalvarsan
Synthetic versus natural drugs
Late in the nineteenth century, the pharmaceutical industry began moving from traditional pharmacognosy - the science of medicinal plants and their bioactive ingredients - to exploring and using more and more synthetic drugs.
Using these animal models, researchers could now test molecules as potential drugs by seeing how well they could kill pathogens in infected animals. But rather than just relying on molecules extracted from plants, advances in chemistry (and industry) meant that researchers could now access synthetic compounds, greatly expanding the pool of potential new drugs.
With time, animal models became available for other types of diseases, including high blood pressure, allergies, metabolic disease, immunological disorders, pain and neurological disease. Sometimes traditional animal breeding methods were used to obtain inbred rat strains that were vulnerable to particular diseases, such as the Zucker diabetic rat or the Spontaneously Hypertensive Rat (SHR). These two longstanding animal models assisted the search for drugs used in the treatment of cardiovascular and metabolic diseases.
Coupled with advances in synthetic chemistry, this disease model testing approach soon began providing drugs for many significant diseases. During the twentieth century, most new drugs were discovered by screening libraries of synthetic compounds in lab animals that had been subjected to experimental treatments that reproduced aspects of a particular human disease. Many far-reaching pharmacological breakthroughs resulted from this effort.
In more recent times, powerful gene-manipulating techniques have allowed the creation of transgenic mice: mice that contain the same mutated genes that are detected in disease-affected tissues in humans. These are closer to many human diseases such as cancer than traditional animal models. The ability to grow tumours within mice has been another important tool during the search for anticancer drugs.
Coal tar is a smelly, oily residue which is a rich source of small organic molecules that serve as building blocks for assembling more complex molecules. In the early days, coal tar constituents were mainly used to manufacture dyestuffs for the fabric and textiles industry, but with time the pharmaceutical industry began using coal tar-derived molecules to produce new synthetic drugs.
The German pharmaceutical industry expands
The widespread use of coal during the Industrial Revolution produced vast quantities of coal tar, a waste product formed when refining coal into coke, a process that involves distillation of bituminous coal at high temperatures. Until the early twentieth century, coke was a popular fuel source for many industrial processes.
In eTute 2, we noted that some major pharmaceutical companies started out as apothecaries selling plant-based medicines in the nineteenth century or even earlier (e.g. Merck, Schering, etc.). As synthetic drug discovery gathered steam, dyestuff manufacturers began moving into pharmaceuticals production. Some modern drug companies that started out as nineteenth century dye or synthetic chemical producers include Pfizer, Bayer, Hoechst, Ciba, Geigy and Sandoz.
Much of the early growth of the chemical and pharmaceutical industries occurred in Germany. The nineteenth century German chemical industry was ahead of its time in establishing in-house research labs and encouraging partnerships between industry researchers and academics, university departments and their research students.
Due to the rich mixture of compounds in coal tar, we’re still using it today to treat various skin disorders (e.g. rashes, fungal infections, and dandruff). However, the greatest contribution of coal tar to the pharmaceuticals sector was in supplying many building blocks used by organic chemists to make synthetic medicines.
According to historians, finding new drugs by testing synthetic molecules in disease-affected animals was the dominant discovery paradigm in the global pharmaceutical industry from about 1900 to 1970. During this period, many new drugs became available for use in treating pain, inflammation, infectious disease, cancer and allergies. Since it unleashed many cheap synthetic drugs that are still used today, some old-time medicinal chemists nostalgically call this period the Golden Age of the modern pharmaceutical industry.
The supremacy of synthetic medicinal chemistry during the twentieth century is seen in how we classify many classic synthetic drugs from that era according to the broad chemical class to which they belong. Think of such common drug classes as barbiturates, amphetamines, arylpropionic acids or benzodiazepines, for example. Nowadays, we tend to classify new drugs according to the biological process they target - for example, beta-blockers.
Although these synthetic drugs were far from ideal, they represented a major gain in the effectiveness of medical treatments for syphilis, a sexually-transmitted disease that has long taken a heavy toll on individuals and human societies. Although its initial manifestations can seem modest, if untreated this condition can have serious consequences for patients.
The stages of syphilis
The development of syphilis typically involves three stages, with distinct signs and symptoms occurring in each phase. The disease is typically acquired during direct contact with a syphilitic lesion possessed by a sexual partner. Infection occurs when Treponema pallidum (T. pallidum), a flexible bacterium with a twisted or spiral appearance, enters host tissue via gaps or breaches in the epithelium layer of target tissues such as skin.
- Case study: Part I - syphilis
The first demonstration of the power of the disease model testing approach to drug discovery occurred in the work of Paul Ehrlich, the legendary German scientist who laid the foundation for the antibiotics era by discovering the first antibacterial drugs, Salvarsan and Neosalvarsan.
1) The first or primary stage of syphilis
involves the appearance of sores or skin lesions at the first site of infection (i.e. where the spirochete entered the body). Depending on the sexual behaviour of the affected individual, the lesions develop on or around the genitals, around the anus or in the rectum, or in or around the mouth. The primary lesions are typically firm and painless (the image below shows a chancre, or syphilis lesion, on a human tongue).
2) The second stage, known as secondary syphilis,
involves various symptoms including skin rash, swollen lymph nodes, sore throat, patchy hair loss, headaches, weight loss, muscle aches, and fatigue together with a rise in body temperature or fever. These symptoms typically emerge days or weeks after the primary lesions appear to heal.
2) The second stage, known as secondary syphilis,
The signs and symptoms of the first and second stages of secondary syphilis can sometimes seem mild, and some affected individuals are even unaware that they are infected. Very often however, these secondary symptoms subside and most patients appear to make a full recovery, entering the so-called latent stage which is free of signs or symptoms. This phase can last for many years, even decades. Many patients do not progress beyond this phase. The image shows secondary syphilitic lesions on a human back.
3) The final tertiary stage of syphilis
involves patients experiencing a series of serious medical problems. These typically include deterioration of the cardiovascular system due to damage to the heart and blood vessels, damage to brain and central nervous system, often resulting in dementia, as well as injury to other body organs, particularly the eyes (causing a loss of vision).
- Case study: Part II - Paul Ehrlich, the organo-arsenicals, and the first disease model
Who was Paul Ehrlich?
Working at a time when the German chemical industry was inventing thousands of dyes, Ehrlich became fascinated by the biological properties of these highly coloured molecules, earning him the nickname “the man with the coloured fingers.” While studying the effects of dyes on different blood cells, Ehrlich realised that the molecules were taken up into some cells (e.g. leukocytes or white blood cells) but not others (e.g. red cells or erythrocytes).
Ehrlich made similar observations during studies of the accumulation of coloured dyes within the tissues of living animals such as rabbits and mice. Noting that certain dyes such as methylene blue were taken up by some tissues (e.g. nerves) but not others, Ehrlich proposed the existence of chemoreceptors - structural features on the surface of cells and tissues that interact selectively with foreign molecules.
Ehrlich made similar observations during studies of the accumulation of coloured dyes within the tissues of living animals such as rabbits and mice. Noting that certain dyes such as methylene blue were taken up by some tissues (e.g. nerves) but not others, Ehrlich proposed the existence of chemoreceptors - structural features on the surface of cells and tissues that interact selectively with foreign molecules.
