Barry J. Cusack

Hepatic Drug Metabolism and Aging

SummaryAlthough there is considerable variation in the effect of age on drug biotransformation, the metabolism of many drugs is impaired in the elderly. Age-related physiological changes, such as a reduction in liver mass, hepatic metabolising enzyme activity, liver blood flow and alterations in plasma drug binding may account for the decreased elimination of some metabolised drugs in the elderly. It is difficult, however, to separate an effect of aging from a background of marked variation in the rate of metabolism due to factors such as individual metabolic phenotype, environmental influences, concomitant disease states and drug intake. The prevailing data suggest that initial doses of metabolised drugs should be reduced in older patients and then modified according to the clinical response. In most studies the elderly appear as responsive as young individuals to the effects of compounds which induce or inhibit the activity of cytochrome P450 isozymes. Concurrent use of other agents, which induce or inhibit drug metabolism, mandates dose adjustment as in younger patients.Many questions remain unanswered. For instance, limitations of in vitro studies prevent any firm conclusion about changes in hepatic drug metabolising enzyme activity in the elderly. With aging, some pathways of drug metabolism may be selectively affected, but this has not been adequately scrutinised. The possibility that metabolism of stereoisomers may be altered in the elderly has not been adequately tested. The effect of aging on the distribution of polymorphic drug metabolism phenotypes is still not established, despite potential implications for disease susceptibility and survival advantage.

Doxorubicin cardiomyopathy is associated with a decrease in calcium release channel of the sarcoplasmic reticulum in a chronic rabbit model.

Doxorubicin is a highly effective cancer chemotherapeutic agent that produces a dose-dependent cardiomyopathy that limits its clinical usefulness. Clinical and animal studies of morphological changes during the early stages of doxorubicin-induced cardiomyopathy have suggested that the sarcoplasmic reticulum, the intracellular membrane system responsible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of doxorubicin. To detect changes in the calcium pump protein or the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum during chronic doxorubicin treatment, rabbits were treated with intravenous doxorubicin (1 mg/kg) twice weekly for 12 to 18 doses. Pair-fed controls received intravenous normal saline. The severity of cardiomyopathy was scored by light and electron microscopy of left ventricular papillary muscles. Developed tension was measured in isolated atrial strips. In subcellular fractions from heart, [3H]ryanodine binding was decreased in doxorubicin-treated rabbits (0.33 +/- 0.03 pmol/mg) compared with control rabbits (0.66 +/- 0.02 pmol/mg; P < 0.0001). The magnitude of the decrease in [3H]ryanodine binding correlated with both the severity of the cardiomyopathy graded by pathology score (light and electron microscopy) and the decrease in developed tension in isolated atrial strips. Bmax for [3H]ryanodine binding and the amount of immunoreactive ryanodine receptor by Western blot analysis using sequence-specific antibody were both decreased, consistent with a decrease in the amount of calcium release channel of sarcoplasmic reticulum in doxorubicin-treated rabbits. In contrast, there was no decrease in the amount or the activity of the calcium pump protein of the sarcoplasmic reticulum in doxorubicin-treated rabbits. Doxorubicin treatment did not decrease [3H]ryanodine binding or the amount of immunoreactive calcium release channel of sarcoplasmic reticulum in skeletal muscle. Since the sarcoplasmic reticulum regulates muscle contraction by the cyclic uptake and release of a large internal calcium pool, altered function of the calcium release channel could lead to the abnormalities of contraction and relaxation observed in the doxorubicin cardiomyopathy.

Physical activity and cognitive function in individuals over 60 years of age: a systematic review

Background It is unclear whether physical activity in later life is beneficial for maintenance of cognitive function. We performed a systematic review examining the effects of exercise on cognitive function in older individuals, and present possible mechanisms whereby physical activity may improve cognition. Methods Sources consisted of PubMed, Medline, CINAHL, the Cochrane Controlled Trials Register, and the University of Washington, School of Medicine Library Database, with a search conducted on August 15, 2012 for publications limited to the English language starting January 1, 2000. Randomized controlled trials including at least 30 participants and lasting at least 6 months, and all observational studies including a minimum of 100 participants for one year, were evaluated. All subjects included were at least 60 years of age. Results Twenty-seven studies met the inclusion criteria. Twenty-six studies reported a positive correlation between physical activity and maintenance or enhancement of cognitive function. Five studies reported a dose-response relationship between physical activity and cognition. One study showed a nonsignificant correlation. Conclusion The preponderance of evidence suggests that physical activity is beneficial for cognitive function in the elderly. However, the majority of the evidence is of medium quality with a moderate risk of bias. Larger randomized controlled trials are needed to clarify the association between exercise and cognitive function and to determine which types of exercise have the greatest benefit on specific cognitive domains. Despite these caveats, the current evidence suggests that physical activity may help to improve cognitive function and, consequently, delay the progression of cognitive impairment in the elderly.

Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function.

1 The present study evaluated the time‐dependency of acute anthracycline cardiotoxicity by varying the duration of exposure of rabbit isolated atria to doxorubicin and determing changes (1) in contraction and relaxation and (2) in atrial concentrations of doxorubicin and its C‐13 hydroxy metabolite, doxorubicinol. 2 Following addition of doxorubicin (175 μm) to atria, contractility (dF/dt), muscle stiffness (resting force, RF) and relaxation (90% relaxation time, 90% RT) were monitored for a 3.5 h period. 3 Doxorubicin (175 μm) progressively diminished mechanical function (decreased dF/dt, increased RF and prolonged 90% RT) over 3 h. Doxorubicinol (1.8 μm), however, failed to produce time‐related cardiac dysfunction; it depressed contractile function and increased muscle stiffness during the first 30 min without causing additional cardiac dysfunction during the remaining 3 h of observation. Doxorubicinol had no effect on 90% RT. 4 During treatment with doxorubicin, atria contained considerably more doxorubicin than doxorubicinol (ratio of doxorubicin to doxorubicinol ranged from 778 to 74 at 0.5 and 3 h, respectively). Elevations of doxorubicin and doxorubicinol in atria paralleled the degree of dysfunction of both contraction and relaxation; increases in muscle stiffness, however, were more closely associated with increases of doxorubicinol than doxorubicin. 5 To probe the relation between cardiac doxorubicinol and myocardial dysfunction further, without confounding effects of cardiac doxorubicin, concentration‐response experiments with doxorubicinol (0.9–7.2 μm) were conducted. 6 Plots of doxorubicinol concentrations in atria vs contractility indicated that the cardiac concentration of doxorubicinol, at which contractility is reduced by 50%, is five fold lower in doxorubicin‐treated than in doxorubicinol‐treated preparations. Thus, doxorubicin and doxorubicinol appear to interact to depress contractile function. 7 Cardiac concentrations of both doxorubicin and doxorubicinol, as observed in these studies, were found to stimulate markedly Ca2+ release from isolated SR vesicles, but 3 μm doxorubicinol promoted a 15 fold greater release rate than 3 μm doxorubicin. 8 Our observations coupled with the previously reported finding that doxorubicinol inhibits Ca2+ loading of SR, suggests that doxorubicinol accumulation in heart contributes to the time‐dependent component of doxorubicin cardiotoxicity, through a mechanism that could involve perturbations of Ca2+ homeostasis.

Daunorubicin Cardiotoxicity EVIDENCE FOR THE IMPORTANCE OF THE QUINONE MOIETY IN A FREE-RADICAL-INDEPENDENT MECHANISM

Anthracyclines, such as daunorubicin (Daun), and other quinone-containing compounds can stimulate the formation of toxic free radicals. The present study tests the hypothesis that the quinone moiety of Daun, by increasing free-radical production, disrupts sarcoplasmic reticulum (SR) function and thereby inhibits myocardial contractility in vitro. We compared Daun with its quinone-deficient analogue, 5-iminodaunorubicin (5-ID), using experimental interventions to produce various contractile states that depend on SR function. At concentrations of Daun or 5-ID that did not alter contractility (dF/dt) of steady-state contractions (1 Hz) in electrically paced atria isolated from adult rabbits, only Daun significantly attenuated the positive inotropic effects on dF/dt of increased rest intervals (PRP; post-rest potentiation) or increased stimulation frequencies. Attenuation was to 98+/-6% at 1 Hz, and 73+/-8 and 67+/-8% for 30 and 60 sec PRP, respectively, and 73+/-3 and 63 +/-3% at 2 and 3 Hz, respectively, for 88 microM Daun (P<0.05, vs pre-drug baseline values, mean +/- SEM). These effects of Daun were similar to those of caffeine (2 mM), an agent well known to deplete cardiac SR calcium. We also examined the effect of Daun in isolated neonatal rabbit atria, which lack mature, functional SR; Daun did not alter the force-frequency relationship or PRP contractions. Additional studies in Ca(2+)-loaded SR microsomes indicated that both Daun and 5-ID opened Ca(2+) release channels, with Daun being 20-fold more potent than 5-ID in this respect. Neither anthracycline, however, induced free-radical formation in SR preparations (assayed via nicking of supercoiled DNA) prior to stimulating Ca(2+) release. Thus, our results indicate that Daun impairs myocardial contractility in vitro by selectively interfering with SR function; the quinone moiety of Daun appears to mediate this cardiotoxic effect, acting through a mechanism that does not involve free radicals.

Taurine deficiency and doxorubicin: interaction with the cardiac sarcolemmal calcium pump

An anticancer drug, doxorubicin, and a naturally occurring beta-amino acid, taurine, exert opposing actions on myocardial calcium content and lipid peroxidation. Thus, we tested the hypothesis that the two agents may interact to modify cardiac calcium metabolism and indices of lipid peroxidation. Cardiac taurine levels were reduced by half in rats given tap water containing a beta-amino transport inhibitor, beta-alanine. Taurine deficiency was associated with an increased susceptibility of the heart to doxorubicin-mediated calcium accumulation, a phenomenon commonly associated with doxorubicin cardiotoxicity. Taurine deficiency also predisposed the heart to enhanced formation of malondialdehyde caused by doxorubicin administration. While increases in malondialdehyde levels are often associated with lipid peroxidation, the failure of doxorubicin to cause changes in oxidized glutathione content makes peroxidative mechanisms a less likely explanation for the potentiation of doxorubicin-mediated myocardial calcium accumulation in taurine-deficient rats. A more likely possibility is the interaction between taurine deficiency and doxorubicin to inhibit the sarcolemmal calcium pump. The data also suggest that the interaction between doxorubicin and taurine deficiency does not involve alterations in the pharmacokinetics of doxorubicin or the cardiotoxic metabolite, doxorubicinol. It is concluded that reduction in sarcolemmal calcium pump activity by taurine deficiency may contribute to myocardial calcium accumulation in hearts whose calcium homeostasis has been compromised by doxorubicin.

Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine

Approximately 30% of women afflicted with migraine have menstrually associated attacks. These migraines are often refractory to treatment. Evidence suggests estrogen and progestin fluctuations may influence menstrual migraine. Phytoestrogens have demonstrated estrogenic effects in some tissues, but are without stimulation of the endometrium, suggesting decreased risk with long-term use. This study was undertaken to assess the efficacy of a phytoestrogen combination in the prophylactic treatment of menstrual migraine. Forty-nine patients were randomized to receive either placebo, or a daily combination of 60 mg soy isoflavones, 100 mg dong quai, and 50 mg black cohosh, with each component standardized to its primary alkaloid. Patients received study medication for 24 weeks. Average frequency of menstrually associated migraine attacks during weeks 9-24 was reduced from 10.3 +/- 2.4 (mean +/- s.e.m.) in placebo treated patients to 4.7 +/- 1.8 (P < 0.01) in patients treated with the phytoestrogen preparation.

Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit.

Cumulative dose-related, chronic cardiotoxicity is a serious clinical complication of anthracycline therapy. Clinical and animal studies have demonstrated that continuous infusion, compared to bolus injection of doxorubicin, decreases the risk of cardiotoxicity. Continuous infusion of doxorubicin may result in decreased cardiac tissue concentrations of anthracyclines, including the primary metabolite doxorubicinol, which may also be an important contributor to cardiotoxicity. In this study, doxorubicin and doxorubicinol plasma pharmacokinetics and tissue concentrations were compared in New Zealand white rabbits following intravenous administration of doxorubicin (5 mg·kg−1) by bolus and continuous infusion. Blood samples were obtained over a 72-h period after doxorubicin administration to determine plasma doxorubicin and doxorubicinol concentrations. Rabbits were killed 7 days after the completion of doxorubicin administration and tissue concentrations of doxorubicin and doxorubicinol in heart, kidney, liver, and skeletal muscle were measured. In further experiments, rabbits were killed 1 h after bolus injection of doxorubicin and at the completion of a 24-h doxorubicin infusion (anticipated times of maximum heart anthracycline concentrations) to compare cardiac concentrations of doxorubicin and doxorubicinol following both methods of administration. Peak plasma concentrations of doxorubicin (1739±265 vs 100±10 ng·ml−1) and doxorubicinol (78±3 vs 16±3 ng·ml−1) were significantly higher following bolus than infusion dosing. In addition, elimination half-life of doxorubicinol was increased following infusion. However, other plasma pharmacokinetic parameters for doxorubicin and doxorubicinol, including AUC∞, were similar following both methods of doxorubicin administration. Peak left ventricular tissue concentrations of doxorubicin (16.92±0.9 vs 3.59±0.72 μg·g−1 tissue;P<0.001) and doxorubicinol (0.24±0.02 vs 0.09±0.01 μg·g−1 tissue;P<0.01) following bolus injection of doxorubicin were significantly higher than those following infusion administration. Tissue concentrations of parent drug and metabolite in bolus and infusion groups were similar 7 days after dosing. The results suggest that cardioprotection following doxorubicin infusion may be related to attenuation of the peak plasma or cardiac concentrations of doxorubicin and/or doxorubicinol.

Therapeutic concentrations of theophylline and enprofylline potentiate catecholamine effects and inhibit leukocyte activation

Methylxanthines are primary agents used in treatment of hypersensitivity disease. Because polymorphonuclear leukocyte (PMN) activation is associated with generation of potent inflammatory mediators, xanthine effects on the PMN respiratory burst were studied. Enprofylline, a xanthine with important therapeutic potential, does not antagonize adenosine and was contrasted with theophylline. Although enprofylline was more potent at low concentrations, both drugs exhibited dose-dependent inhibition of PMN activation at concentrations greater than 10 mumol/L (1.8 micrograms/ml). Oxygen metabolite generation was decreased by 30% to 40% at therapeutic drug concentrations and by 85% at 1 mmol/L of theophylline. Inhibition by isoproterenol or prostaglandin E2 but not dibutyryl cAMP was potentiated by either xanthine. Isoproterenol effects were also increased when isoproterenol was evaluated in whole blood specimens obtained from subjects after a loading dose of aminophylline. Although these results were most compatible with cAMP phosphodiesterase inhibition, other commonly proposed mechanisms of methylxanthine activity were also studied. Theophylline but not enprofylline blocked adenosine inhibition of PMN activation. Neither xanthine shifted the calcium dose-response when PMNs were activated with calcium ionophore. Because oxygen metabolites generated by the FMN are mediators of inflammation and hypersensitivity, direct inhibition of PMN activation as well as potentiation of catecholamine activity may be important therapeutic effects of theophylline and enprofylline.

Pharmacokinetic Optimisation of Drug Therapy in Elderly Patients

SummaryWith increasing age, there are a number of physiological changes that affect the handling of drugs in the human body. Increases in body fat percentage as well as decreases in lean body mass, hepatic metabolism and renal elimination capacity are of particular clinical significance. It is important to take these changes into account when choosing drug therapy for older patients in order to minimise adverse effects and maximise potential benefits. This is particularly important when prescribing drugs with a narrow therapeutic index such as digoxin, theophylline, Phenytoin, lidocaine (lignocaine) or warfarin. When available, monitoring of plasma concentrations can assist in the optimisation of drug dosage.