CCR 20th Anniversary Commentary: Determining a Pharmacokinetic/Pharmacodynamic Relationship for Sunitinib­A Look Back.

The article by Mendel and colleagues, published in the January 1, 2003, issue of Clinical Cancer Research, described their novel preclinical approach to developing a thorough understanding of the exposure-activity relationship for sunitinib, a multitargeted receptor tyrosine kinase inhibitor being developed for oncology therapy. This work successfully set exposure guidelines to identify a biologically active dose in early clinical trials.

Tyrian purple: the first four thousand years.

Some of the long history ofshellfish purple is recounted Understanding how the dye is produced from molluscs, the composition of the pigment and the chemistry involved has only been achieved as a result of the advances in analytical chemistry in the twentieth century, but some mysteries remain. Other diverse aspects such as the taste of the molluscs, the actual colour of the dye, the smell associated with the production and even the application in photography contribute to the fascination of the subject.

[Tinctorial plants, their therapeutic applications in ancient times. The particular case of Isatis]. / Les plantes tinctoriales, leurs applications thérapeutiques aux époques antiques. Le cas particulier des Isatis.

Three tinctorial plants were systematically used in Europe in the Middle Ages: Woad, Madder and Weld. Their therapeutic properties were also described by classical authors, least two of them were known on all the continents: woad for blue and madder for red. Modern laboratories have been able to show clearly some therapeutic active principles derived from the indol of woad (Isatis sp.).

Sir William Osler's perceptions of urolithiasis and the case of the indigo calculus.

BACKGROUND: Sir William Osler published his textbook, The Principles and Practice of Medicine, in 1892. It became the definitive treatise on a wide variety of diseases. The section on nephrolithiasis clearly presents the etiology, pathology, symptoms, diagnosis, and treatments. What remains a mystery is the mention, under rare forms of human stones, of a type called "indigo." MATERIALS AND METHODS: A search of Index Medicus starting from 1909 backward to its inception in 1879 was performed for key words "indigo," "calculus," "renal" or "bladder stones" and "indicanuria." Twelve textbooks of urology published before 1940 were scrutinized for references to indigo calculi. RESULTS: Only two references to indigo were found, both related to its use for treating constipation (1887 and 1891). Of the 12 textbooks, only 4 make passing reference to "indigo stones." They all mention that such calculi are very rare, but direct references to cases are lacking. One textbook references a study of blue stones from Egyptian mummies. CONCLUSION: It is unlikely that Osler's reference to an indigo calculus was taken lightly during his writing of The Principles and Practice of Medicine. The case of the indigo calculus is fascinating and perhaps enlightening if only for the source of Osler's intrigue.

The evolution of cancer research and drug discovery at Lilly Research Laboratories.

This review highlights the discovery and development of chemotherapy at Eli Lilly & Company over the past 30 years from the Vinca alkaloids-vincristine, vinblastine, and vindesine-to targeted therapy. During the late 1970s, Lilly began an exploration of new synthetic compounds based on solid tumor screening models. Several novel antimetabolites with the potential to treat solid tumors were identified. Two such agents, gemcitabine and pemetrexed, underwent clinical development and are now among Lilly's portfolio of approved anticancer drugs. Gemcitabine, a pyrimidine nucleoside that has a profound effect on DNA synthesis, has been approved for the treatment of pancreatic, non-small cell lung, bladder, and most recently, breast, and ovarian cancer. Pemetrexed, a novel antifolate with potent cytotoxic effects, is distinguished from other antifolates by virtue of its ability to inhibit multiple folate-dependent enzymes. Pemetrexed, given in combination with cisplatin, has been recently approved for the treatment of malignant pleural mesothelioma and as second-line treatment for non-small cell lung cancer. Spurred by advances in the understanding of cancer as a disease process, Lilly's anticancer drug program began to transition to a more "targeted" approach during the 1990s. These efforts have recently culminated in the identification and development of enzastaurin, a PKCbeta inhibitor with potent anti-angiogenic properties. Enzastaurin has shown promising single-agent activity in patients with relapsed diffuse large B-cell lymphoma and recurrent glioblastoma multiforme, and is an excellent candidate for combination with cytotoxic agents.

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: III. fenotiazinas piperidínicas / Fifty years of antipsychotic drugs in psychiatry: III. piperidine phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica com a redescoberta da clozapina e a introduçäo dos novos antipsicóticos atípicos, é tempo de um inventário das substâncias desenvolvidas nos últimos cinqüenta anos. É feito um breve histórico dos antecedentes dos antipsicóticos tradicionais na era que se encerra. As substâncias introduzidas até o presente poderiam ser reunidas nos grupos tradicionais - fenotiazinas (alifáticas, piperazínicas e piperidínicas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzaminas, indóis, dibenzoxazepinas - e nos grupos químicos mais recentes - diidroindolonas, dbenzodiazepinas, benzisoxazólicos -, além de compostos ainda em desenvolvimento. Neste artigo, o terceiro de uma série concebida com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral piperidínica que tenham demonstrado utilidade na prática clínica e ou guardem importância histórica: mepazina, mesoridazina, nortioridazina, piperacetazina, propericiazina, sulforidazina e toridazina. Com base em bibliografia básica específica, säo discutidos aspectos técnicos e revisado o conhecimento científico acumulado através da experimentaçäo e utilizaçäo clínica destes compostos, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre fórmula estrutural, fórmula molecular, nomes químicos, nomes de fantasia e códigos de cada composto, além de dados sobre eventual comercializaçäo no país

Clinical applications of quinone-containing alkylating agents.

Quinone-containing alkylating agents are a class of chemical agents that have received considerable interest as anticancer drugs. These agents contain a quinone moiety that can be reduced and an alkylating group that can form covalent bonds with a variety of cellular components. The oxidation state of the quinone element can modulate the activity of the alkylating element, and reduction of the quinone is required for activation of the alkylating activity of many of these agents. The quinone element may also contribute to the cytotoxic activity of quinone-containing alkylating agents through the formation of reactive oxygen species during redox cycling. The natural product, mitomycin C, has been the most widely used quinone-containing alkylating agent in the clinic, but other quinone-containing alkylating agents like porfiromycin, diaziquone, carbazilquinone, triaziquone and EO9 have also been used in the clinic for the treatment of cancer. In addition, many other quinone-containing alkylating agents have been tested in preclinical studies and the development of new agents is being actively pursued. This chapter describes the current and past clinical uses of these agents in the treatment of cancer and discusses new agents that are currently in clinical trials.

Blue gods, blue oil, and blue people.

Studies of the composition of coal tar, which began in Prussia in 1834, profoundly affected the economies of Germany, Great Britain, India, and the rest of the world, as well as medicine and surgery. Such effects include the collapse of the profits of the British indigo monopoly, the growth in economic power of Germany based on coal tar chemistry, and an economic crisis in India that led to more humane tax laws and, ultimately, the independence of India and the end of the British Empire. Additional consequences were the development of antiseptic surgery and the synthesis of a wide variety of useful drugs that have eradicated infections and alleviated pain. Many of these drugs, particularly the commonly used analgesics, sulfonamides, sulfones, and local anesthetics, are derivatives of aniline, originally called "blue oil" or "kyanol." Some of these aniline derivatives, however, have also caused aplastic anemia, agranulocytosis, and methemoglobinemia (that is, "blue people"). Exposure to aniline drugs, particularly when two or three aniline drugs are taken concurrently, seems to be the commonest cause of methemoglobinemia today.

From serotonin receptor classification to the antimigraine drug sumatriptan.

After the synthetic serotonin 5-hydroxytryptamine (5-HT) became available in the early 1950s, attempts were soon under way to study the nature of 5-HT receptors. Using the guinea-pig isolated ileum, Gaddum and Picarelli (1957) suggested that 5-HT-induced contractions were mediated by a morphine-sensitive "M" receptor located on the parasympathetic ganglion and a dibenzyline-sensitive "D" receptor located on the smooth muscle. Though this classification ws used during the next three decades, it was realized that some effects of serotonin, for example vasoconstriction within the carotid vascular bed, were not mediated by either "M" or "D" receptors. When radioligand binding studies led to the identification of 5-HT1 and 5-HT2 "receptors" in the rat brain membranes, it became increasingly apparent that the two receptor classifications were not identical. Thus, a new framework for serotonin receptor nomenclature and classification was proposed: 5-HT1-like (5-HT1), 5-HT2 (formerly "D") and 5-HT3 (formerly "M") receptors. At the present time, several subtypes of 5-HT1 receptors as well as a 5-HT4 receptor are also recognized. As the serotonin receptor classification was emerging to indicate that carotid vasoconstriction by serotonin is mediated by a subtype of 5-HT1 receptors, on the migraine front it was being suggested that the disease is associated with vasodilation within the cranial extracerebral circulation and deranged serotonin metabolism and that certain antimigraine drugs caused a selective carotid vasoconstriction, probably via serotonin receptors. Therefore, Humphrey and colleagues conceived that synthesis of serotonin derivatives may lead to a compound that would elicit highly selective carotid vasoconstriction and abort migraine attacks. Indeed, via the synthesis of 5-carboxamidotryptamine and AH25086, sumatriptan was designed. The drug acts as an agonist at the vasoconstrictor 5-HT1 receptor subtype and has proved highly effective in the therapy of migraine attacks.