Potential applications of free drug level monitoring in cardiovascular therapy.

Cardiovascular drugs, as a class, have low therapeutic indices, but also have great therapeutic potential. Plasma concentration information is therefore often of value when using these drugs. Unfortunately, the total plasma concentration may not reflect the concentration of pharmacologically active free drug, since a number of factors including disease states, heparin anticoagulation, non-linear binding characteristics, and in vitro artefacts can affect the protein binding of these agents. This may also explain their poor dose-response relationships and great interindividual variability in plasma concentration data. Careful studies relating bound and free drug concentration to pharmacological response may provide the clinician with a better guide to therapy, and enhance the usefulness of these drugs.

Effects of oral contraceptives on lipoprotein lipids: a prospective study.

One hundred sixty-nine healthy women, aged 17 to 29 years, nonsmokers or light smokers (fewer than ten cigarettes per day), were assigned randomly to take one of five oral contraceptives: 1) 100 micrograms mestranol plus 0.5 mg ethynodiol diacetate (100 M + 0.5 ED); 2) 100 micrograms mestranol plus 1.0 mg ethynodiol diacetate (100 M + 1.0 ED); 3) 50 micrograms ethinyl estradiol plus 1.0 mg ethynodiol diacetate (50 EE + 1.0 ED); 4) 30 micrograms ethinyl estradiol plus 2.0 mg ethynodiol diacetate (30 EE + 2.0 ED); or 5) 30 micrograms ethinyl estradiol plus 0.15 mg levonorgestrel (30 EE + 0.15 NG). One hundred forty-seven women completed the study. When assessed for within-group differences, all preparation caused a statistically significant increase in total triglyceride (from 17.0 to 46.4 mg/dL), total cholesterol (from 6.3 to 24.4 mg/dL), and low-density lipoprotein (LDL) cholesterol (from 7.0 to 10.3 mg/dL). Effects on high-density lipoprotein (HDL) cholesterol varied widely. The product 100 M + 0.5 ED markedly increased (9.9 mg/dL) HDL cholesterol. Neither 100 M + 1.0 ED nor 50 EE + 1.0 ED altered HDL cholesterol levels, whereas both preparations containing 30 micrograms estrogen showed decreases: the preparation containing 2.0 mg ethynodiol diacetate lowered HDL cholesterol by 3.6 mg/dL and that containing 0.15 mg levonorgestrel lowered it by 6.9 mg/dL. Specific between-group comparisons revealed no statistically significant differences between differing amounts of estrogen (50 EE + 1.0 ED versus 100 M + 1.0 ED).(ABSTRACT TRUNCATED AT 250 WORDS)

Antiarrhythmic therapy: clinical pharmacology update.

Currently available antiarrhythmic agents are limited by side effects and the potential for increasing arrhythmias. In addition, drug interactions, altered disposition of drug as a result of changes in protein binding or concomitant disease processes, active metabolites, and poorly defined therapeutic ranges with great interpatient variability are some of the factors which complicate therapy. An awareness of the possible contribution of these factors in the use of antiarrhythmics is invaluable in both the choice of agent and the establishment of an optimum benefit-to-risk ratio for the patient.

Antiinflammatory properties of a hydroperoxide compound, structurally related to acetylsalicylic acid.

3-Hydroperoxy-3-methylphthalide (3-HMP), a structural analog of acetylsalicylic acid (ASA), was found to have some antiinflammatory properties which are distinct from those of ASA. 3-HMP inhibits human platelet aggregation and ATP release in response to low concentrations of collagen but is less effective than ASA. 3-HMP inhibits prostaglandin and thromboxane production from exogenous [14C]arachidonic acid by human platelet lysates in vitro and does so at lower concentrations than ASA (3-HMP IC50 = 10 microM; ASA IC50 = 50 microM). 3-HMP is also more effective than ASA as an inhibitor of prostacyclin-like activity production by rings of rabbit aorta. Human polymorphonuclear (PMN) leukocyte [14C]arachidonic acid metabolism is inhibited by 3-HMP but not ASA. In urethane-anesthetized rats, 3-HMP (10 mg/kg intravenously) is effective in inhibiting PMN leukocyte accumulation in response to intrapleural carrageenan administration whereas ASA is ineffective (100 mg/kg intravenously). This hydroperoxy analog of ASA has antiinflammatory activity which may result from a combination of the ASA-like and hydroperoxide-related pharmacological properties.

Atenolol in the treatment of essential hypertension.

In a large, open-label study of 522 patients diagnosed as essential hypertensives, atenolol was both effective and well tolerated. In 392 patients whose blood pressure was measured at the initial visit and after at least four weeks of atenolol therapy, average reductions of 21 mm Hg and 14 mm Hg, were noted in the systolic and diastolic blood pressure respectively. Forty-three patients stopped taking atenolol because of side-effects. The incidence of CNS side-effects was particularly low, and the drug was well tolerated by diabetic patients. Among eight asthmatics who took atenolol, asthma worsened in two. By virtue of its hydrophilicity, cardioselectivity and long half-life, atenolol appears to be a suitable and well-tolerated beta-blocker in the majority of patients.

Relationship of inhibition of prostaglandin synthesis in platelets to anti-aggregatory and anti-inflammatory activity of some benzoic acid derivatives.

The relationships between inhibition of platelet prostaglandin (PG) synthesis and aggregation, and suppression inflammation were investigated with a number of benzoic acid (aspirin-like) chemicals. The compounds studied were 2-acetylbenzoic acid (ABA), 3-methylphthalide (3-MP), 3-propionyloxybenzoic acid (3-PBA) and 2-propionyloxybenzoic acid (2-PBA). At 0.5--0.6 mM, 3-MP inhibited the second phase of ADP-induced aggregation in human platelets, and reduced collagen-induced aggregation by 50%. Previous studies have shown 2-PBA to inhibit aggregation at similar concentrations. In contrast, ABA required 10 times higher concentrations, and low concentrations actually potentiated aggregation. Inhibition of PG synthesis from 14C-arachidonic acid (AA) by human platelets was shown for 2-PBA, but not to 3-BPA, or ABA. At high concentration (1 mM), 3-MP showed modest inhibitory activity. Significant inhibition of AA aggregation was produced by ASA (83%), 2-PBA (76%) and 3-MP (69%), an order reflecting their inhibition of PG synthesis, where ABA and 3-PBA did not inhibit AA aggregation. Carrageenin-induced edema of the rat paw was suppressed by 3-MP, ABA and 2-PBA; all being roughly equipotent with aspirin. In contrast, 3-PBA did not suppress edema. Following oral administration of the drugs to rats, PG synthesis from labeled AA by rat platelets showed similar profiles to effects of the drugs on PG synthesis in human platelets. This suggests that biotransformation or species differences are not explanations for the observed differences in activity in the various test systems. The results indicate that, in a related series of chemicals there is not a good correlation between ability to inhibit platelet PG synthesis, anti-aggregatory activity and anti-inflammatory activity. Multiple mechanisms of action, differing sensitivities of various tissue PG synthetases, or unidentified factors could be involved.

Use of the cu-7 device in a family planning clinic.

The experience of 707 women undergoing a first insertion of the Cu-7® at the Family Planning Clinic, Edmundston, has been assessed.The majority (67.3%) of patients were parous, and 77.2% were 20-29 years of age. Insertion of the Cu-7 was considered easy in both nulliparous and parous patients.Two years of use have been completed by 136 women (7,917 woman months of use). Relevant life-table discontinuation rates for the first two years of use, respectively, were: involuntary pregnancy 1.50%, 1.39%; expulsion 6.60%, 1.11%; removal of the Cu-7 for some medical reason 19.83%, 14.85%.Removals for pain among nulliparous women were significantly more frequent than among parous patients (p<.001).

The effects of an ASA-like hydroperoxide compound on adenosine diphosphate induced platelet aggregation.

A hydroperoxide compound structurally related to acetylsalicylic acid, 3-hydroperoxy-3-methylphthalide, inhibits both the first and second phases of adenosine diphosphate induced, biphasic, human platelet aggregation. This occurs over the same concentration range (0.05-0.5 mM) that acetylsalicylic acid inhibits second phase aggregation and the release reaction only. The complete inhibition of adenosine diphosphate induced aggregation is a unique pharmacological property for an acetylsalicylic-acid-like compound.

Pharmacology, electrophysiology, and pharmacokinetics of mexiletine.

Mexiletine is a class I antiarrhythmic agent that is active after both oral and intravenous administration and similar in structure and activity to lidocaine. It decreases phase O maximal rate of depolarization (Vmax) by fast sodium channel blockade. The marked rate dependence of Vmax depression may explain mexiletine's lack of effect on normal conduction and its efficacy against ventricular tachyarrhythmias. Mexiletine significantly decreases the relative refractory period in His-Purkinje fibers without changing the sinus rate or atrioventricular and His-Purkinje conduction times. Action potential duration is usually shortened. Mexiletine may aggravate preexisting impairment of impulse generation and conduction. Uptake and distribution of mexiletine are rapid, systemic bioavailability is about 90%, and tissue distribution is extensive. Mexiletine is primarily metabolized in the liver; 10% to 15% is excreted unchanged in the urine. Elimination half-life is 9 to 11 hours after intravenous or oral administration. Microsomal enzyme induction shortens mexiletine's elimination half-life, whereas hepatic disease and acute myocardial infarction prolong it. Renal disease has little effect, although hemodialysis increases mexiletine clearance. Plasma concentrations from 0.75 to 2.0 mg/L are usually associated with a desirable therapeutic response.