Disease pharmacokinetics

Infectious Disease Pharmacokinetics Laboratory National Jewish Medical and Research Center Denver, Colorado Chapter 72 Tuberculosis... 

Pharmacology The methyixanthines (theophylline, its soluble salts and derivatives) directly relax the smooth muscle of the bronchi and pulmonary blood vessels, stimulate the CNS, induce diuresis, increase gastric acid secretion, reduce lower esophageal sphincter pressure, and inhibit uterine contractions. Theophylline is also a central respiratory stimulant. Aminophylline has a potent effect on diaphragmatic contractility in healthy people and may then be capable of reducing fatigability and thereby improve contractility in patients with chronic obstructive airways disease. Pharmacokinetics ... 

Mechanism of Action A biologic response modifier that induces activation of macrophages in blood monocytes to phagocytes, which is necessary in the body s cellular immune response to intracellular and extracellular pathogens. Enhances phagocytic function and antimicrobial activity of monocytes Therapeutic Effect Decreases signs and symptoms of serious infections in chronic granulomatous disease. Pharmacokinetics Slowly absorbed after subcutaneous administration. Half-life 0.5-1 hr. 

Mechanism of Action Asalicylicacidderivativethat isconvertedtomesalamineinthe colon by bacterial action. Blocks prostaglandin production in bowel mucosa. Therapeutic Effect Reduces colonic inflammation in inflammatory bowel disease. Pharmacokinetics Small amount absorbed. Protein binding 99%. Metabolized by bacteria in the colon. Minimal elimination in urine and feces. Half-life 0.9 hr. 

Mechanism of Action An antiparkinson agent that stimulates dopamine receptors in the striatum. Therapeutic Effect Relieves signs and symptoms of Parkinson s disease. Pharmacokinetics Rapidly and extensively absorbed after PO administration. Proteinbinding 15%. Widely distributed. Steady-state concentrations achieved within 2 days. Primarily eliminated in urine. Not removed by hemodialysis. Half-life 8 hr (12 hr in patients older than 65 yr). 

Yamada S, Yamamota T, Suou T, et al. Clinical significance of benzoate-metabolizing capacity in patients with chronic liver disease pharmacokinetic analysis. Res Commun Chem Pathol Pharmacol 1992 76(1) 53-62. 

Disease Pharmacokinetics altered in disease states, especially of liver and kidney... 

The separation of enantiomers is a very important topic to the pharmaceutical industry. It is well recognized that the biological activities and bioavailabilities of enantiomers often differ [1]. To further complicate matters, the pharmacokinetic profile of the racemate is often not just the sum of the profiles of the individual enantiomers. In many cases, one enantiomer has the desired pharmacological activity, whereas the other enantiomer may be responsible for undesirable side-effects. What often gets lost however is the fact that, in some cases, one enantiomer may be inert and, in many cases, both enantiomers may have therapeutic value, though not for the same disease state. It is also possible for one enantiomer to mediate the harmful effects of the other enantiomer. For instance, in the case of indacrinone, one enantiomer is a diuretic but causes uric acid retention, whereas the other enantiomer causes uric acid elimination. Thus, administration of a mixture of enantiomers, although not necessarily racemic, may have therapeutic value. 

The cl mg discovery process can be envisioned as four interconnected phases (see Figure 8.1). Generally, these are the acquisition of chemicals to be tested for biological activity, the determination of the activity of those chemicals on biological systems (pharmacodynamics), the formulation of the most active of these for therapeutic testing in humans (pharmaceutics), and the determination of adequate delivery of the active drug to diseased tissues (pharmacokinetics). Each of these collections of processes is interconnected with the others and failure in any one of them can halt the development process. It is worth considering each process separately, as well as the relationships between them. 

In clinical life, as outlined in this essay, pharmacokinetics (PK) is used instrumental to improve drug therapy. For this purpose, pharmacokinetics must be presented in general and transmissible terms. The case of kidney failure gives one important example of how disease influences pharmacokinetics and how pharma-cokonetics can be used to produce the same pharmacodynamic effect is such patients. The aim and end... 

Dettli L (1976) Drag dosage in renal disease. Clin Pharmacokinet 1(2) 126—1115. 

In summary, the characteristics of the drug and the disease or condition may suggest a likely route and mode of delivery. Considerable vork is required to develop and optimise an appropriate drug presentation. The suitability of any particular strategy must be verified by undertaking the extensive pharmacodynamic and pharmacokinetic studies that form part of the pre-clinical and clinical trials. 

Ciraulo DA, Jaffe JH Tricyclic antidepressants in the treatment of depression associated with alcoholism. Clin Psychopharmacol 1 146—150, 1981 Ciraulo DA, Nace E Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addict 9 276—284, 2000 Ciraulo DA, Barnhill JG, Jaffe JH, et al Intravenous pharmacokinetics of 2-hydroxy-imipramine in alcoholics and normal controls. J StudAlcohol 51 366-372, 1990 Ciraulo DA, Knapp CM, LoCastro J, et al A benzodiazepine mood effect scale reliability and validity determined for alcohol-dependent subjects and adults with a parental history of alcoholism. Am J Drug Alcohol Abuse 27 339—347, 2001 Collins MA Tetrahydropapaveroline in Parkinson s disease and alcoholism a look back in honor of Merton Sandler. Neurotoxicology 25 117-120, 2004 COMBINE Study Research Group Testing combined pharmacotherapies and behavioral interventions in alcohol dependence rationale and methods. Alcohol Clin Exp Res 27 1107-1122, 2003a... 

A protease-specific model has also been reported in which a replication-defective adenovirus encoding an NS3 protease-SEAP fusion protein is injected into mouse tail veins, resulting in expression of the fusion protein in the liver [82, 83]. Protease activity can be detected both by measuring activity of liberated SEAP or by protease-induced liver damage. Protease activity was found to be reduced by administration of protease inhibitors. This model can be used to show that candidate inhibitors have adequate pharmacokinetic properties in mice to function in the intended target organ, but it is not a true disease model. 

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