Methotrexate, when used in high doses (12 g/m²) in the treatment of osteosarcoma, shows wide between-subject variability (BSV) in its pharmacokinetics. High-dose methotrexate is associated with severe toxicity; therefore, therapeutic drug monitoring (TDM) is carried out to guide rescue therapy and monitor for nephrotoxicity. Mucositis is a commonly encountered dose-limiting toxicity that often leads to delays in subsequent courses of chemotherapy. This, in turn, results in a reduction in the dosing intensity, which is essential in the treatment of osteosarcoma. The aims of this study were to develop a population pharmacokinetic (PK) model from TDM using physiologically relevant covariates and to investigate the correlation between mucositis scores and methotrexate pharmacokinetics. In total, 46 osteosarcoma patients (30 men and 16 women; age, 4-51 years) were recruited, and blood samples were collected for routine TDM once every 24 hours. Mucositis scores, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded for 28 of the patients (18 men and 10 women; age, 8-51 years) predose and postdose. A population PK model was developed in NONMEM VI. A 2-compartment PK model was chosen, and clearance (CL) was divided into filtration and secretion/metabolism components. All parameters were scaled with body weight, and, in addition, total CL was scaled with age- and sex-adjusted serum creatinine. Between-subject variability was modeled for all parameters, and between-occasion variability was included in CL. For a typical 70 kg man of 18 years or older, the parameter estimates for the final model were CL(filt) = 2.69 L/h/70 kg, CL(sec) = 10.9 L/h/70 kg, V₁ = 74.3 L/70 kg, Q = 0.110 L/h/70 kg, and V₂ = 4.10 L/70 kg. Sequential pharmacodynamic modeling consisted of mucositis scores as 5-point ordered categorical data. A significant linear relationship between individual area under the curve (AUC) and mucositis score probability was found, and the probability of having mucositis score ≥ 1 increased with increasing AUC and was almost 50% at the average cumulative AUC after 2 consecutive methotrexate doses.

To report an unanticipated pregnancy during ovarian ablation treatment with goserelin (10.8 mg SC every 12 weeks) in a 26-year old female with breast cancer. Review of the current literature and reports in MEDLINE, PubMED, and EMBASE using searches with keywords "goserelin, pregnancy, breast cancer, breast neoplasms, fertility, ovarian ablation, gonadotropin releasing hormone agonists/analogs, leuprolide, pregnancy complications, teratogens" (July-September 2010). Only 3 other reports of failures with goserelin administration at ablative doses in breast cancer patients were discovered. For physicians and breast cancer patients using a GnRH analog, it is important to be aware of the possibility of inadequate ovarian function suppression and the potential for pregnancy.

Uniovular twin sisters have been diagnosed 10 years ago as having hyperglobulinemic purpura (Waldenstrom) at age 12. The diagnosis was documented by purpura of the lower extremities, increased y-globulin affer serum electrophoresis, and increased 7s component upon ultracentrifugation. In addition, there was an elevated ESR, a positive rheumatoid arthritis latex test, and their LE prep. was negative at that time. At a later date, however, both of them developed polyarthritis. After 9 years for the one and 10 years for the other, their LE prep. became strongly and constantly positive, while their y-globulin remained within abnormal limits.

Pharmacology is defined as the study of the effects of drugs on the function of a living organism. It is an inte­grative discipline that tackles drug/ compound behaviours in varied physiological systems and links these to cellular and molecular mechanisms of action. As a scientific endeavour, pharmacology evolved from the early identification of therapeutic properties of nat­ural compounds, with herbal medicines and relatively complex pharmacopoeias widely used in early cultures. Despite this, lack of understanding of the physio­logical, pathological, and chemical processes governing the human body prevented the early establishment of pharmacology as a scientific discipline. Since then, pharmacology has progressed to be considered a fully developed integrative science that employs techniques and theories from various disciplines, such as chemistry, biochemistry, genomics, medicinal chemistry, physi­ology, and cellular and molecular biology. Collectively, these are applied to study disease causality and the rele­vant mechanistic action of compounds, to establish new treatments. In the last 100 years, the importance of clinical pharmacology has increased in line with the scientific and technological advances in biomedical research. Benefits gained from molecular and cellular approaches have enabled a more comprehensive analysis of drugs and their actions in functional context. Now, clinical pharmacology and therapeutics encompass the dis­covery, development, regulation, and application of drugs in a process that integrates scientific research with clinical practice to better treat illness and preserve health. Within this textbook the principles of pharmacology are discussed by therapeutic area so that the reader can link disease pathophysiology, drug mechanism, and modern prescribing behaviours for conditions commonly seen in clinical practice. There are, however, fundamental concepts that are universal in understanding the interaction between drugs and their ‘targets’, including receptor pharmacology, genomic pharmacology, and pharmacokinetics. The pharmacological receptor models preceded by many years the knowledge of the receptor as an entity. It was not until the last 150 years that a series of contributions from many notable biologists and chemists established the principles that founded modern day pharmacology. They produced a significant paradigm shift in therapeutics, where empirical descriptors of the activities observed (heating, cooling, moistening, emetic, etc.) were replaced by the concept of a ‘target’. After more than a century, the basic receptor concept is still the foundation of biomed­ical research and drug discovery.

Cancer is a common cause of morbidity and mortality in the United Kingdom (UK), affecting approximately two out of every five people during their lifetime. In 2015 there was an estimated 2.5 million people in the UK who had had a cancer diagnosis, an increase of almost half a million in the previous 5 years. The proportion of people living longer after cancer is increasing, and the number of people alive more than 5 years from initial diagnosis is predicted to more than double between 2010 and 2030 to 2.7 million. By the end of 2020, more than a thousand people would have been diagnosed with cancer every day in the UK. Cancer can affect all organs of the body with over 200 types identified. However, only a small number of cancer types account for most cases. Over half of all new diagnoses are due to four cancers (in order of frequency)— breast, pros­tate, lung, and bowel. In 2011 there were approximately 50 000 new diagnoses of breast cancer in the UK. The in­cidence of cancer diagnosis is increasing year on year, in part due to improving diagnostic skills, but also because of an increasing elderly population. Cancer of unknown primary origin accounts for about 3% of total cancers. Although UK statistics show a general improvement in the 5-year survival rates for the majority of common cancers, some have not shown any notable improvement. Survival is not only determined by the type of cancer, but also the age at diagnosis, stage, and co- morbidities such as heart, pulmonary, and renal disease, which can affect the treatment regimen. As well as this, certain cancers carry a significantly worse prognosis than others. For example, 10- year survival for pancreatic and lung cancer are 1% and 5%, respectively. In comparison, the 10- year survival for testicular cancer is over 98% and almost 90% in skin con­fined melanoma. Newer diagnostic strategies are expected to detect all cancers early, allowing prompt intervention, and improving both morbidity and mortality rates further. Cancer is a product of mutations in genes involved in controlling cell growth, differentiation, and death (apop­tosis).