On the discovery of UREA. Identification, synthesis and observations that let to establishing the first uraemic retention solute.

Jean Batiste von Helmont (1577-1644) described a salt that "never occurs outside man's body". The substance was further characterized by Hermann Boerhaave from Leiden (1688-1738) in Elementa Chemiae where he described the whole procedure for isolating it from urine of healthy persons. The French scientists Fourcroy and Vauquelin, in 1808, named it "ure" whereas Jean-Etienne Brard from Montpellier established its chemical composition in 1817. The synthesis of urea was accomplished by Friedrich Whler (the first organic substance to be synthesized). Finally in 1851 Friedrich Th. von Frerichs introduced the term "Uraemia".

The history of urea as a hyperosmolar agent to decrease brain swelling.

In 1919, it was observed that intravascular osmolar shifts could collapse the thecal sac and diminish the ability to withdraw CSF from the lumbar cistern. This led to the notion that hyperosmolar compounds could ameliorate brain swelling. Since then, various therapeutic interventions have been used for the reduction of intracranial pressure and brain volume. Urea was first used as an osmotic agent for the reduction of brain volume in 1950. It was associated with greater efficacy and consistency than alternatives such as hyperosmolar glucose. Its use became the standard of clinical practice by 1957, in both the intensive care unit and operating room, to reduce intracranial pressure and brain bulk and was the first hyperosmolar compound to have widespread use. However, the prime of urea was rather short lived. Reports of side effects and complications associated with urea emerged. These included coagulopathy, hemoglobinuria, electrocardiography changes, tissue necrosis with extravasation, and a significant potential for rebound intracranial hypertension. Mannitol was introduced in 1961 as a comparable and potentially superior alternative to urea. However, mannitol was initially purported to be less effective at rapidly reducing intracranial pressure. The debate over the two compounds continued for a decade until mannitol eventually replaced urea by the late 1960s and early 1970s as the hyperosmolar agent of choice due to the ease of preparation, chemical stability, and decreased side effect profile. Although urea is not currently the standard of care today, its rise and eventual replacement by mannitol played a seminal role in both our understanding of cerebral edema and the establishment of strategies for its management.

The race to discover the insect vector of kala-azar: a great saga of tropical medicine 1903-1942.

In the 19(th) century, a devastating epidemic of visceral leishmaniasis (kala-azar) swept through northeast India. After identification of the pathogenic agent, Leishmania donovani, in 1903, the question of its transmission remained to be resolved. In 1904, thanks to work by L. Rogers on cultures of this parasite it became probable that a haematophagous arthropod was responsible for transmission. J.A. Sinton suggested, in 1925, the distribution of the sand fly Phlebotomus argentipes was similar to that of the disease and, thereafter, two independent teams led by H.E. Shortt in Assam and R. Knowles and L. Napier in Calcutta concentrated on this potential vector. Parallel work was in progress in China, directed by E. Hindle and W. S. Patton for the Royal Society Kala-azar Commission, on another species of sand fly. In 1942 the Assam workers transmitted L. donovani to five human volunteers by the bites of colonised P. argentipes and the race was over.

William Prout: early 19th century physician-chemist.

In the early 19th century, the discoveries of new substances in the healthy and diseased body spawned a search for chemical explanations for physiologic phenomena to guide medical diagnosis and control therapy. William Prout's work on the nature and treatment of diseases of the urinary organs established his reputation as one of Britain's most distinguished physiological chemists. Prout was very skeptical of chemical remedies because of possible side effects, but he suggested iodine treatment for goiter. He emphasized that a satisfactory diet should include carbohydrates, fats, protein, and water. In 1824, he showed that the acid of the gastric juice was hydrochloric acid. Prout applied chemical methods and reasoning to physiology and was criticized for his view that the body's vital functions could be explained by chemistry. His remedy for lack of progress in animal chemistry was for physiologists to become chemists. Prout stimulated much discussion on atomic theory by his hypothesis that the atomic weights of all chemical elements are whole-number multiples of the atomic weight of hydrogen and that the chemical elements were condensed from hydrogen atoms.

Amino acids, then and now--a reflection on Sir Hans Krebs' contribution to nitrogen metabolism.

H. A. Krebs made an enormous contribution to our knowledge of amino acid metabolism, beginning with his studies on proteolysis in the early 1930s, progressing through his work on urea synthesis to an extensive series of papers on deamination and, then, to work on gluconeogenesis from amino acids. This paper addresses three of Krebs' early contributions-urea synthesis, glutamine metabolism, and D-amino acid oxidase-and relates them to our modern understanding of amino acid metabolism.

Vitalism and synthesis of urea. From Friedrich Wöhler to Hans A. Krebs.

In 1828, Friedrich Wöhler, a German physician and chemist by training, published a paper that describes the formation of urea, known since 1773 to be a major component of mammalian urine, by combining cyanic acid and ammonium in vitro. In these experiments the synthesis of an organic compound from two inorganic molecules was achieved for the first time. These results weakened significantly the vitalistic hypothesis on the functioning of living cells, although Wöhler, at that time, was more interested in the chemical consequences of isomerism than in the philosophical implications of his finding. However, the chemical synthesis observed by Wöhler does not represent the reaction which is employed in the mammalian liver for urea synthesis. The mechanism of this process was elucidated by the German physician Hans A. Krebs and his medical student Kurt Henseleit in 1932 and was shown to include the ornithine cycle. This 'urea cycle' is only observed in living cells; this apparently vitalistic phenomenon is caused by the compartmentalization of the various enzymatic reactions in mitochondria and cytosol, respectively.