Biomedical subjects
M Gibaldi
Publications and source records attributed to M Gibaldi.
Are phytoestrogens a "natural alternative" to estrogen replacement therapy?
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Regulating angiogenesis: a new therapeutic strategy.
Angiogenesis is the proliferation of endothelial and smooth muscle cells to form new blood vessels. Largely muted after adolescence, angiogenesis may be reignited by cancerous cells. Neoangiogenesis plays a primary role in tumor growth and metastases. Antiangiogenic therapy to limit and even reverse the growth of tumors are under investigation and showing promise. A derivative of fumagillin, TNP 470, is the first angiogenesis inhibitor to be given to humans. Surprisingly, several potent inhibitors are derived from tumors themselves. Researchers nowc recognize that stimulation of angiogenesis may have a place in the treatment of cardiovascular disease. Reestablishing blood flow to ischemic tissue through angiogenesis may provide a biologic "bypass" for patients with ischemic heart disease. The same applies to the treatment of peripheral vascular disease.
Prevention and treatment of osteoporosis: does the future belong to hormone replacement therapy?
Estrogen replacement therapy (ERT) after menopause prevents the development of osteoporosis and reduces the risk of fracture. Other potential benefits are cardioprotection--probably related to the effects of estrogen on lipid profile and fibrinogen levels--and a delay in the onset of Alzheimer's disease and perhaps amelioration of the disease. ERT, however, increases the risk of endometriosis and endometrial cancer unless given with a progestin for at least 10 days per menstrual cycle. It also results in a small but real increase in breast cancer. Alendronate, a bisphosphonate, is the first serious competitor of conjugated equine estrogen for the treatment of osteoporosis. Nearing FDA approval are so-called designer estrogens (e.g., raloxifene), which may selectively prevent osteoporosis with little or no effects on endometrial and breast tissue.
Intention-to-treat analysis in randomized trials: who gets counted?
This article discusses the rationale and implications associated with the selection and use of analysis strategies for randomized clinical trials as they relate to protocol deviations. The topics addressed specifically are the conceptual and methodologic approaches and biases of clinical efficacy and effectiveness assessment. Examples are provided that highlight the consequences of different analytic strategies, particularly regarding intention-to-treat analysis. Favored by statisticians intention-to-treat analysis seeks to answer the question, "Is it better to adopt a policy of treatment A if possible, with deviations if necessary, or a policy of treatment B if possible, with deviations if necessary?" This is a relevant question, sometimes more relevant than "Is treatment A better than treatment B?" The authors suggest that different analytic strategies may be more or less appropriate depending on the intended audience.
Prevention and treatment of stroke: where do we stand?
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The eleventh international conference on AIDS: cautious celebration in Vancouver.
For the first time in the short but turbulent history of the International Conference on AIDS (acquired immune deficiency syndrome), participants found themselves in the midst of a sea change in the treatment of human immunodeficiency virus (HIV) disease. Scientists, health policy experts, politicians, and AIDS activists alike shared the anticipation. Report after report heralded improved outcomes in patients receiving combination therapy rather than monotherapy with reverse transcriptase inhibitors, particularly when investigators combined these agents with newly available protease inhibitors. The drug combinations dramatically reduced viral load in plasma, in some cases to undetectable levels, resulting in sharp rebounds in immune function. Even more encouraging is the pipeline for new and possibly more effective strategies. The cost of the new therapy for HIV disease, however, will limit the benefit to no more than 10% of the world's population infected with the virus.
Antioxidant vitamins and health.
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Treating elevated cholesterol levels: the great Satan in perspective.
The purpose of this review is to provide perspective on the developments leading to the recognition of high cholesterol levels as a risk factor for coronary heart disease (CHD). Another objective is to consider the unfolding controversies regarding the relative value of cholesterol-lowering drug therapy in primary and secondary prevention. Should physicians use lipid-lowering drugs to treat patients with elevated cholesterol levels but no clinical evidence of coronary disease, or limit intervention to patients with a previous history of angina, coronary angioplasty, coronary artery bypass surgery, or myocardial infarction? This review finds inadequate data to support a recommendation for screening large populations for the presence of elevated cholesterol levels or for primary prevention in those known to have high cholesterol. On the other hand, there is mounting evidence to support vigorous intervention in those with known coronary disease. Further study is needed to determine whether a subset of patients with one or more well-defined risk factors would benefit from primary prevention.
Failure to comply: a therapeutic dilemma and the bane of clinical trials.
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Contemporary use of and future roles for heparin in antithrombotic therapy.
Although heparin therapy is an established component of the prevention and treatment of thromboembolic disease, recent advances have resulted in improvements in the clinical use of this agent. Studies have shown that weight-based dosing influences significantly both the time to reach a therapeutic intensity of anticoagulation and the incidence of thromboembolic recurrence. It is now considered the standard of care. A growing understanding of the variability among activated partial thromboplastin time (aPTT) reagents and the influence of these differences on aPTT outcomes has led to the use of reagent-specific therapeutic ranges for heparin monitoring. Many practitioners now choose to adjust the therapeutic range to correspond to heparin serum concentrations of 0.2-0.4 U/mL rather than the more common practice of prolonging aPTT to 1.5-2.5 times the mean normal aPTT. Pharmaceutical companies have developed low molecular weight heparins to minimize adverse effects associated with unfractionated heparin. More specific thrombin inhibitors are also under investigation with the aim of improving clinical outcomes in coronary syndromes now treated with heparin. Low molecular weight heparins or specific thrombin inhibitors are unlikely to replace unfractionated heparin in the near future. Therefore, optimum dosing and appropriate monitoring of heparin are critically important in the management of thromboembolic disease.
Helicobacter pylori and gastrointestinal disease.
New paradigms are few and far between. The discovery that peptic ulcer disease is the result of an infection by a previously unrecognized microorganism rather than the consequence of excess secretion of gastric acid aptly qualifies as a paradigm shift. Eradication of Helicobacter pylori from the stomach by antibacterial agents heals ulcers at least as effectively as H2-blockers. Further, eradication of the organism results in long-term cures of peptic ulcers. In contrast, the relapse rate in patients successfully treated with H2-blockers exceeds 50% in the first year after healing. Also of interest is the role of H. pylori in gastric cancer.
Stereoselective and isozyme-selective drug interactions.
A surprisingly large number of marketed drugs are racemic mixtures. The pharmacokinetic literature on racemic drugs contains a vast amount of information on drug-drug interactions derived from the measurement of total drug concentrations in plasma and urine. The appreciation of the role of stereochemistry in drug interactions with racemic warfarin resulted in a long-overdue scientific rigor being applied to the study of drug interactions. It also compelled us to recognize that much of the literature was uninterpretable. A better understanding of oxidative metabolism, particularly the complexity of the cytochrome P-450 family of enzymes, has also strengthened the scientific basis of drug interactions. We now recognize that investigators and clinicians must consider both stereoselectivity and isozyme selectivity in the study of drug interactions to understand the nature of the interaction so as to more effectively use new and potent drugs.
What is nitric oxide and why are so many people studying it?
From social outcast to citizen of the year in less than a decade is the stuff of fiction. That is precisely what has happened, however, to a remarkably simple molecule, nitric oxide. Nitric oxide is still an environmental pollutant, suspected carcinogen, and precursor of acid rain, but biologists are looking past its dark side. They now see a molecule that is uniting neuroscience, physiology, and immunology. Its ubiquitous distribution in the body and its multifaceted roles are revising our understanding of how cells communicate and protect themselves. This report examines nitric oxide's role in physiology and pathophysiology and reviews novel therapeutic approaches which involve inhibition or induction of the activity of endogenous nitric oxide.
Meta-analysis. A review of its place in therapeutic decision making.
The potential value of meta-analysis has captured the imagination of many investigators. Epidemiologists have, appropriately, greeted its broad application with considerable caution, yet practical matters, such as the need to consolidate and extract information from available data, have forced a more accepting approach. Meta-analysis has been employed in many clinical settings to evaluate efficacy and safety of a variety of therapeutic interventions. It is likely that it will continue to have a role in extrapolating data from clinical trials for use in the clinic.
The mechanism of the interaction between amiodarone and warfarin in humans.
Amiodarone decreased the total body clearance of both (R)- and (S)-warfarin in normal subjects but did not change volumes of distribution. Warfarin excretion products were quantified and clearance and formation clearance values calculated. Amiodarone and metabolites inhibited the reduction of (R)-warfarin to (R,S)-warfarin alcohol-1 and the oxidation of both (R)- and (S)-warfarin to phenolic metabolites. Inhibition of warfarin hydroxylation by amiodarone in human liver microsomes was compared with the in vivo results. In agreement, the in vitro data indicates that amiodarone is a general inhibitor of the cytochrome P450 catalyzed oxidation of both enantiomers of warfarin, but the metabolism of (S)-warfarin is more strongly inhibited than that of (R)-warfarin. These data suggest that the enhanced anticoagulant effect observed when amiodarone and warfarin are coadministered is attributable to inhibition of P4502C9, the isozyme of P-450 primarily responsible for the conversion of (S)-warfarin to its major metabolite, (S)-7-hydroxywarfarin.
Mechanisms of the stereoselective interaction between miconazole and racemic warfarin in human subjects.
Miconazole decreased the total body clearance of both (R)- and (S)-warfarin in normal subjects but did not change volumes of distribution. Miconazole inhibited the oxidation of both (R)- and (S)-warfarin to phenolic metabolites, although (S)-warfarin was inhibited to the greater extent. In particular, (S)-7-hydroxylation, the pathway primarily responsible for termination of the anticoagulant effect, was most strongly inhibited. Inhibition of warfarin hydroxylation by miconazole in human liver microsomes and the in vivo results showed a good rank order correlation. The enhanced anticoagulant effect observed when miconazole and warfarin are coadministered may result from inhibition of P4502C9, the isozyme of P450 primarily responsible for the conversion of (S)-warfarin to (S)-7-hydroxy-warfarin. Because miconazole inhibits a number of P450 isozymes, in addition to P4502C9, it can be expected to lead to interactions with other drugs whose primary metabolism is controlled by these enzymes.