Cyclosporine A: clinical experience and therapeutic drug monitoring

This article updates current studies on the concentration-effect relationship for cyclosporine A using specific analytical methodology in whole blood. Most of the existing documentation concerns renal transplantation. Trough level monitoring is recommended as the standard monitoring technique. However, there is a need to compare trough level monitoring with monitoring of the area-under-the-concentration-versus-time curve in prospective controlled trials. Further, there is a continuous need to update the concentration-effect relationship when introducing new immunosuppressive drug regimens.     

Clinical pharmacology and therapeutic drug monitoring in neonates and children

From a pharmacotherapy perspective, the process of development and growth represents an unstable and dynamic condition. Age-related changes in drug absorption, distribution, and metabolism among neonates, infants, and prepubescent children create a unique situation that may increase drug toxicity of some agents and protect from toxicity of other agents. Understanding the age-related changes in drug disposition that are relevant for therapeutic response and toxicity is essential for optimizing pharmacotherapy at different stages of childhood.     

Trandolapril. An update of its pharmacology and therapeutic use in cardiovascular disorders

Trandolapril is an orally administered angiotensin converting enzyme (ACE) inhibitor that has been used in the treatment of patients with hypertension and congestive heart failure (CHF), and after myocardial infarction (MI). Trandolapril is a nonsulfhydryl prodrug that is hydrolysed to the active diacid trandolaprilat. Trandolapril 2 mg once daily provides effective control of blood pressure (BP) over 24 hours in patients with mild to moderate hypertension, with a trough/peak ratio of BP reduction (as determined by 24-hour ambulatory monitoring) consistently > or = 50%. Trandolapril has similar antihypertensive efficacy to enalapril as indicated by several clinical trials. Combined therapy with trandolapril and sustained-release verapamil has a significantly greater antihypertensive effect than either agent alone. Only limited data are available on the use of trandolapril in patients with CHF, although ACE inhibitors as a class are recommended as first line therapy in such patients. In the Trandolapril Cardiac Evaluation (TRACE) study, trandolapril 1 to 4 mg once daily resulted in an early and long term reduction in all-cause mortality, including cardiovascular mortality, in patients with left ventricular (LV) dysfunction after an MI. Trandolapril therapy was commenced a mean 4.5 days after acute MI and continued for 24 to 50 months. At study end, the relative risk of death from any cause with trandolapril versus placebo was 0.78 (p = 0.001). The tolerability profile of trandolapril is similar to that of other ACE inhibitors. Most adverse events are mild and transient in nature, and include cough, asthenia, dizziness, headache and nausea. Trandolapril has no adverse effect on lipid or carbohydrate metabolism. Conclusions: trandolapril has a favourable pharmacological profile and an antihypertensive efficacy at least comparable to that of other ACE inhibitors. The pharmacological characteristics of trandolapril allow it to provide good 24-hour control of BP with once-daily administration. Trandolapril has also demonstrated some efficacy in a small number of patients with CHF. In addition, trandolapril provides long term protection against all-cause mortality in patients with LV dysfunction after MI. The results of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) study will determine its potential as a cardioprotective agent in patients with coronary artery disease and preserved LV function. Thus, trandolapril represents an effective, well-tolerated and convenient treatment option for patients with mild to moderate hypertension or LV systolic dysfunction after MI.     

Delivery of therapeutic drug monitoring services: survey of Australasian clinical pharmacology laboratories

Therapeutic drug monitoring (TDM) services, like many diagnostic services in public hospitals, have been under scrutiny over recent years as funding has decreased. The Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) sought to review clinical pharmacology departments to consider how the changes that have been implemented have affected the delivery of TDM in recent years. A questionnaire was sent to such departments and all those known to be delivering TDM services responded. The survey demonstrated that of the 11 departments contributing TDM assays, 10 had lost tests and staffing to general biochemistry departments; eight departments had been delivering research and development in TDM. The TDM tests retained in clinical pharmacology were typically the more complex chromatographic or labor-intensive toxicology tests or the more expensive immunoassays. If this direction in Australasia is typical of the situation internationally, it should be a matter of great concern to all those with a particular interest in TDM. Is the future of TDM to be one in which only rapid immunoassays will be provided, and by a staff not fully able to provide pharmacokinetic support and interpretation of such tests (i.e., to become simply number-generating services) despite all the pharmacoeconomic data that is increasingly available?     

Rapamycin: distribution, pharmacokinetics and therapeutic range investigations: an update

The prevalence of hepatitis C virus (HCV) infection increases with advancing age, but the disease has been poorly studied in the elderly. A population-based study was therefore carried out to investigate the prevalence of HCV infection and the severity of HCV-related chronic liver disease in the elderly. One thousand and sixty-three people (> or = 60 years of age) were screened for antibodies to HCV (anti-HCV) and for possible abnormalities of common liver function tests. Positive subjects and sex and age-matched anti-HCV-negative controls were recalled 12 months later for measurements of liver enzymes, confirmatory testing of anti-HCV, HCV RNA analysis and HCV genotyping. All subjects answered a specific questionnaire concerning medical history and possible risk factors. Forty-four subjects were positive for anit-HCV, the prevalence being 4.1%. Thirty-five positive subjects and 35 controls were investigated further. Risk factors for acquiring HCV were found to be: blood transfusion, surgical intervention and the use of non-disposable syringes. Abnormal alanine aminotransferase levels were found in 13 patients (37.1%). HCV RNA genotyping showed type 1b in three (15.8%), type 2a in 13 (68.4%) and not classified in three (15.8%) patients. There was no relationship between abnormalities of serum aminotransferase, the rate of HCV RNA positivity and HCV genotypes. Ultrasound abnormalities were present in 13 (37.1%) patients. In this elderly population the relatively high prevalence of HCV infection was thought to be caused by previous parenteral exposure. The low incidence of liver disease could be related to the prevalence of HCV genotype 2a in the majority of these patients, and hints at the possibility of an HCV carrier state in elderly individuals.     

Diagnostic and therapeutic update on primary duodenogastric reflux

The authors, after some remarks on the pathophysiology of primary alkaline gastritis, analyze the main methods, available at present, for diagnosis; they particularly consider the importance of endoscopy and histology, gastroesophageal 24-hours pH-metry and 99mTc HIDA scintigraphy. Successively, they present the criteria for the identification of patients who will predictably benefit from surgical treatment, and examine advantages and limits of the two main corrective surgical techniques for the duodenogastric reflux in patients not previously operated on the gastrointestinal tract: duodenal extramucosal myotomy according to Mattioli, relatively easy to perform, and the "duodenal switch" according to De Meester, technically more complex, but pathophysiologically more acceptable, completely eliminating the duodenogastric reflux.     

The pharmacology and therapeutic utility of bisphosphonates

Bisphosphonates have clinical application in diseases associated with increased bone turnover that inhibit osteoclast-mediated bone resorption by direct and indirect actions on osteoblasts and macrophages. Bisphosphonates are the treatment of choice for Paget's disease of bone, in which they return to normal the increased rate of bone turnover and slow radiographic disease progression. The agents reduce hypercalcemia associated with malignancy, and may reduce bone pain and prevent radiographic progression of metastatic bone disease. In patients with postmenopausal osteoporosis, they prevent further bone loss and reduce fracture rates. The drugs also ameliorate osteoporosis associated with long-term corticosteroid treatment. Bisphosphonates are well tolerated; gastrointestinal disturbances are the most common adverse events. Potential bone mineralization defects that occur with first-generation bisphosphonates are not of concern with therapeutic doses of newer ones.     

Metronidazole. A therapeutic review and update

The nitroimidazole antibiotic metronidazole has a limited spectrum of activity that encompasses various protozoans and most Gram-negative and Gram-positive anaerobic bacteria. Metronidazole has activity against protozoans like Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis, for which the drug was first approved as an effective treatment. Anaerobic bacteria which are typically sensitive are primarily Gram-negative anaerobes belonging to the Bacteroides and Fusobacterium spp. Gram-positive anaerobes such as peptostreptococci and Clostridia spp. are likely to test sensitive to metronidazole, but resistant isolates are probably encountered with greater frequency than with the Gram-negative anaerobes. Gardnerella vaginalis is a pleomorphic Gram-variable bacterial bacillus that is also susceptible to metronidazole. Helicobacter pylori has been strongly associated with gastritis and duodenal ulcers. Classic regimens for eradicating this pathogen have included metronidazole, usually with acid suppression medication plus bismuth and amoxicillin. The activity of metronidazole against anaerobic bowel flora has been used for prophylaxis and treatment of patients with Crohn's disease who might develop an infectious complication. Treatment of Clostridium difficile-induced pseudomembraneous colitis has usually been with oral metronidazole or vancomycin, but the lower cost and similar efficacy of metronidazole, coupled with the increased concern about imprudent use of vancomycin leading to increased resistance in enterococci, have made metronidazole the preferred agent here. Metronidazole has played an important role in anaerobic-related infections. Advantages to using metronidazole are the percentage of sensitive Gram-negative anaerobes, its availability as oral and intravenous dosage forms, its rapid bacterial killing, its good tissue penetration, its considerably lower chance of inducing C. difficile colitis, and expense. Metronidazole has notable effectiveness in treating anaerobic brain abscesses. Metronidazole is a cost-effective agent due to its low acquisition cost, its pharmacokinetics and pharmacodynamics, an acceptable adverse effect profile, and its undiminished antimicrobial activity. While its role as part of a therapeutic regimen for treating mixed aerobic/anaerobic infections has been reduced by newer, more expensive combination therapies, these new combinations have not been shown to have any therapeutic advantage over metronidazole. Although the use of metronidazole on a global scale has been curtailed by newer agents for various infections, metronidazole still has a role for these and other therapeutic uses. Many clinicians still consider metronidazole to be the 'gold standard' antibiotic against which all other antibiotics with anaerobic activity should be compared.     

Paroxetine. A review of its pharmacology, therapeutic use in depression and therapeutic potential in diabetic neuropathy

Paroxetine is a selective serotonin reuptake inhibitor effective in a once-daily administration regimen in the treatment of depression. In elderly patients (aged > or = 60 years) with major depression, short term (6 weeks) treatment with paroxetine produces clinical improvements significantly superior to those seen with placebo and similar to those with tricyclic antidepressant agents, mianserin and fluoxetine. There is evidence that paroxetine has positive effects on co-existing anxiety and does not precipitate agitation. Paroxetine has also shown potential in the symptomatic treatment of diabetic neuropathy; however, further clinical experience is needed to confirm this preliminary result. Short term paroxetine therapy is associated with fewer anticholinergic and CNS adverse effects, but generally more gastrointestinal disturbances, than tricyclic antidepressants and mianserin. Unlike the tricyclic agents, paroxetine does not significantly affect cardiovascular function or impair psychomotor performance. This tolerability profile should be particularly beneficial in elderly patients, who are generally more susceptible than younger patients to the anticholinergic and CNS adverse events associated with tricyclic antidepressant drugs, and in whom there is a higher prevalence of pre-existing cardiovascular disease. It also suggests an important potential advantage over tricyclic antidepressants in the setting of overdosage. Thus, primarily because of its better tolerability profile and potentially lower toxicity in overdosage and in patients with cardiovascular disease, paroxetine appears to be a more attractive option than tricyclic antidepressants for the treatment of depression in late life. Future research should attempt to define more fully the efficacy of paroxetine as long term prophylactic therapy for recurrent depression and to assess how its overall therapeutic profile compares with other selective serotonin reuptake inhibitors in the elderly.     

Pharmacoeconomics and therapeutic drug monitoring

The ever increasing rate of inflation and the reality that resources for medical care are limited has led to significant changes in the reimbursement for health care services. These influences have convinced health care policy makers to closely evaluate innovative health services in terms of the benefits and costs. New pharmaceutical services must be economically justified in order to exist in the future. This is crucial to the expansion and adoption of pharmaceutical services. Application of economic evaluations is not new to the health care sector. Until recently, there were no incentives to transfer this interest into widespread use. As health care expenditures have escalated over the past two decades, the number of applications of these techniques has increased. Especially significant are cost-benefit and cost-effectiveness evaluations of medical practice, pharmaceuticals, and other health care technologies. Pharmacoeconomic analysis is an important tool to assist in the evaluation of new pharmaceutical services and technologies. Essentially, economic analytical methods are used to weigh the positive and negative consequences of alternative courses of action. The usefulness of pharmacoeconomic analyses is in resource allocation, with the purpose of achieving the highest return on investment or accomplishing a given objective in the least costly manner. Unfortunately, very few pharmacy programs have been evaluated using pharmacoeconomic techniques. The purpose of this article is to present various methods to assess the economic value of therapeutic drug monitoring services in society and for specific patient populations. Additionally, this article will review the previous attempts and various issues surrounding the economic justification of therapeutic drug monitoring.     

The taxoids. Comparative clinical pharmacology and therapeutic potential

Paclitaxel and docetaxel are 2 compounds from the new taxoid class of anti-cancer agents. Both drugs are very similar in preclinical activity, mechanism of action and spectrum of clinical activity. Some subtle differences in the intracellular retention of docetaxel may account for its lack of schedule-related myelosuppression and greater potency, and may be relevant to the skin toxicity and oedema which it produces. Early data suggest that there may be differing behaviour of anthracycline/taxoid combinations with respect to cardiotoxicity. Paclitaxel has been studied in several first-line combination therapy trials in ovarian cancer. Here, paclitaxel in combination with a platinum compound seems to have proven itself as a standard regimen. It is uncertain if docetaxel will be evaluated in this context. An abundance of clinical data is available for both analogues in the advanced, metastatic setting of breast cancer. Both also have been compared as single agents with doxorubicin with the results suggesting paclitaxel in a 3-hour infusion is inferior to the anthracycline (in terms of response rate), and those of docetaxel suggesting it is superior to the same dose of doxorubicin. This indirect comparison favours the activity of docetaxel; however, it is clear that in the dose/schedules studied, the taxoid compounds are not equitoxic. Either agent by itself, in the treatment of metastatic breast cancer, remains appropriate; however, lack of cumulative toxicity may make paclitaxel more attractive in some situations where prolonged administration is foreseen. Lung cancer trials have also confirmed the activity of both agents, although docetaxel appears to have slightly more promising activity in previously treated patients than paclitaxel. Paclitaxel in combination with cisplatin has been evaluated in randomised trials as first-line treatment of non-small-cell lung cancer (NSCLC). The results of these trials taken together suggest that this combination has an impact on survival similar to other new regimens now considered 'standard' in the front-line setting in this disease. Unfortunately, despite all the phase II data generated in numerous tumour types, little else can be said about the role of either taxoid in the 'standard' management of malignant disease. It will be some years yet before taxoid-based combinations have been evaluated sufficiently in randomised trials such that the impact of this novel class can be adequately assessed in terms of survival and cure rates.     

Nutritional pharmacology and malignant disease: a therapeutic modality in patients with cancer

It is now established that certain nutrients have a significant effect on cellular metabolism and growth, tissue repair and regeneration, and modulation of host defences. So far, however, potential clinical benefits have been difficult to demonstrate. Nevertheless, the use of nutrients in combinations seems to have promise and may be associated with a reduction in infectious complications and length of hospital stay. Nutritional pharmacology in the future may be able to improve tumour response to chemotherapy and may minimize the metabolic effect of cachexia.     

Dimensions of therapeutic skills and techniques: Empirical identification, therapist correlates, and predictive utility.

Administered a 99-item questionnaire to 319 practicing psychotherapists (mean age 43.9 yrs) from 3 professional associations to assess their use of therapeutic techniques and skills as related to the variables of orientation, experience, sex, and personal psychotherapy. The predictive utility of reported interventions in classifying psychotherapists according to orientation was also examined. Principal component analyses yielded 13 scales. Reported therapy interventions varied as a function of the therapist's orientation and, to a lesser extent, as a function of experience, sex, and personal therapy. Eclectics had either the highest or 2nd-highest mean scores on each of the 13 scales, indicating a varied therapeutic arsenal. Across therapist variables, relationship-enhancing behaviors were reportedly most frequently used; flooding and frustration procedures least frequently used. On the basis of 11 scale scores, 90% of behavior therapists and 88% of psychodynamic therapists were correctly classified, but fewer than half of the eclectics were correctly classified. (62 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cross-cultural patterns in emotion recognition: Highlighting design and analytical techniques.

This article highlights a range of design and analytical tools for studying the cross-cultural communication of emotion using forced-choice experimental designs. American, Indian, and Japanese participants judged facial expressions from all 3 cultures. A factorial experimental design is used, balanced n × n across cultures, to separate "absolute" cultural differences from "relational" effects characterizing the relationship between the emotion expressor and perceiver. Use of a response bias correction is illustrated for the tendency to endorse particular multiple-choice categories more often than others. Treating response bias also as an opportunity to gain insight into attributional style, the authors examined similarities and differences in response patterns across cultural groups. Finally, the authors examined patterns in the errors or confusions that participants make during emotion recognition and documented strong similarity across cultures. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug and environmental factors associated with adverse pregnancy outcomes. Part III: Folic acid: pharmacology, therapeutic recommendations, and economics

OBJECTIVE: To review folic acid's mechanism of action, adverse effects, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, homocysteine, and methylenetetrahydrofolate reductase. STUDY SELECTION: Animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included mechanism of action, safety issues, dosing recommendations, compliance with recommendations, and economics. DATA SYNTHESIS: Folic acid decreases neural tube defect risk through an effect on methionine-homocysteine metabolism. In addition, increased folate intake may reduce cardiovascular morbidity and mortality. Since toxicity is minimal, everyone can potentially benefit from increased folate consumption. To help achieve this, the Food and Drug Administration has mandated that cereal grain be fortified with 140 micrograms of folic acid per 100 g of grain, which will add approximately 0.1 mg of folate to the average diet. Studies recommend supplementing with 0.2 mg to promote optimal homocysteine concentrations and for preventing neural tube defects. CONCLUSIONS: Despite fortification, most women will still receive less folate than the 0.4 mg/d recommended by the Public Health Service. All population groups would benefit from increased folate intake. Current studies indicate 200 micrograms/d may be the minimum effective amount of fortification needed for normalizing homocysteine concentrations and preventing a significant number of neural tube defects; thus, a higher level of food fortification may be warranted.