References

Bollani G, Ferrari R, Bersatti F, Ferrari M, Cattaneo M, Zighetti ML, Visioli O, Assanelli D. [A hyperhomocysteinemia study in a population with a familial factor for acute myocardial infarct and sudden cardiac death at a young age]. Cardiologia. 1999 Jan;44(1):75-81. [Article in Italian]
Abstract: The alterations of the metabolism of methionine determining an accumulation of homocysteine in blood (hyperhomocysteinemia) recognize a multifactorial etiology, hereditary as well as acquired. To date several case-control studies have documented that the condition of hyperhomocysteinemia can be considered an independent risk factor of coronary disease and its noxious effects are dose-dependent. It exerts its effect by different mechanisms both prothrombotic and endothelial. In our study we started from an initial cohort of 2227 subjects (1210 males, 1017 females) aged between 45 and 64 years among which we selected 22 persons with at least 2 first-degree relatives below age 50 who had had either a major cardiovascular event (acute myocardial infarction or sudden death) or angiographically documented cardiac disease. We reconstructed the proper pedigrees obtaining 22 families in whom we identified four main subgroups to carry out analyses and comparisons: case-control, composed respectively of all the subjects who survived a major cardiovascular event or a coronary disease documented angiographically and clinically healthy subjects; affected line and non affected line, composed respectively of members belonging to the family line of the proband and members of collateral family line. Each of the subjects involved in the study underwent a complete history regarding job and sports activities, a standardized physical examination, 12-lead digital ECG according to the European Standard Communication Protocol. A blood sample was taken in fasting conditions to determine total cholesterol, HDL and LDL cholesterol, triglycerides, glycemia, fibrinogen, plasma homocysteine. The results indicate how among the cases there were more subjects with homocysteine higher than the 95 degrees percentile in males alone (p = 0.03), the estimated odds ratio calculated from Fisher's test was 8.34 (95% confidence interval 1.32-52.7). Despite the fact that mean age was significantly lower (p = 0.01) in males of the affected line compared to those of the non affected line, the results show much higher homocysteine values in the affected family line in both males and females: a difference quite evident in the distribution especially as regards the 95 degrees percentile. These results obtained in the subjects belonging to the same families emphasize that familial aggregation, which influences the sharing of the genetic patrimony, socio-cultural environment and food habits can induce a differential risk for homocysteinemia. The study of mutations of genes coding for the key enzymes of the metabolism of homocysteine, methylenetetrahydrofolate reductase and cystathionine beta-synthase, which we prepared, will enable use to evaluate the relative influence feeding habits and genetic factors have in the development of hyperhomocysteinemia.

Brinker F. Herb Contraindications and Drug Interactions. 2nd Ed. Sandy, OR: Eclectic Institute, 1998.

Ferro M, Crivello R, Gianotti A, Conti M. [Treatment of hypertrophic cardiomyopathy with a combination of carnitine and beta blockaders. Review of the literature. Description of a clinical case and long-term follow up]. Clin Ter. 1993 Aug;143(2):109-113. (Review) [Article in Italian]
Abstract: In the past decade, strategies for managing heart failure have changed. The use of beta blockers, although still in the experimental stage, has proved effective in some cases. The protective action of beta-blocking agents against chronic catecholamine stimulation may be enhanced by the combination with L-carnitine. This substance plays an important and synergistic role 1) as an important source of energy due to fatty acid oxidation, and 2) by avoiding the accumulation of lipids in the myocardium. The successful follow-up of a case of dilated cardiomyopathy is critically reviewed. Treatment with the L-carnitine-propranolol combination restored cardiac function in a 52-year-old man with dilated cardiomyopathy: a 50% reduction in mitral EPSS (E Point Septal Separation), from 20 to 10 mm was obtained with the above mentioned therapy; as well as a decrease from 60 to 57 mm in diastolic diameter. Our experience suggests promising benefits in adopting beta blockers combined with L-carnitine therapy in myocardial failure secondary to dilated cardiomyopathy.

Folkers K. Basic chemical research on coenzyme Q10 and integrated clinical research on therapy of diseases. In G. Lenaz, Ed. Coenzyme Q. New York: John Wiley and Sons, 1985.

Folkers K, Langsjoen P, Eds. In: Folkers K, Littarru GP, Yamagami T, Eds. Biochemical and Clinical Aspects of Coenzyme Q, Volume 6. Amsterdam, Elsevier Science Publ, 1991: 449-452.

Hughes HE, Goldstein DA. Birth defects following maternal exposure to ergotamine, beta blockers, and caffeine. J Med Genet. 1988 Jun;25(6):396-399.
Abstract: Ergotamine exposure during pregnancy has been suggested to cause birth defects which have a vascular disruptive aetiology. The present case provides additional support for the possible adverse fetal effects of exposure to ergotamine, caffeine, and propranolol during the first four months of pregnancy. At birth the infant showed evidence of early arrested cerebral maturation and paraplegia. The nature of these defects suggests a primary vascular disruptive aetiology. We hypothesise that ergotamine, acting either alone or in synergy with propranolol and caffeine, produced fetal vasoconstriction resulting in tissue ischaemia and subsequent malformation. This case raises the possibility that fetal malformation may result from concomitant use of multiple vasoconstrictive agents during pregnancy.

Kerns II W, Kline J, Ford MD.  Blocker and calcium channel blocker toxicity.  Emerg Med Clinics of NA 1994;12:2:365-390.

Kishi T, Watanabe T, Folkers K.  Bioenergetics in clinical medicine XV. Inhibition of coenzyme Q10-enzymes by clinically used adrenergic blockers of beta-receptors. Res Commun Chem Pathol Pharmacol. 1977 May;17(1):157-164.
Abstract: Adrenergic blockers for beta-receptors were studied for inhibition of mitochrondrial CoQ10-enzymes. These enzymes are indispensable for the bioenegetics of the myocardium. Propranolol is frequently used to treat hypertension; in some patients, it depresses myocardial function as an adverse reaction. This side effect may be related to the inhibition by propranolol of CoQ10-enzymes of the myocardium. Timolol showed negligible inhibition of the CoQ10-enzyme, NADH-oxidase. Metoprolol was less inhibitory than propranolol. Five alprenolols showed inhibition which approached that of propranolol. The 1-isomer of alprenolol showed weak inhibition of another CoQ10-enzyme, succinoxidase, but the other beta-blockers were essentially non-inhibitory to this enzyme. The drug of choice is timolol, based on negligible inhibition of these bioenergetic enzymes of the heart, which correlates with its pharmacologically low cardiac depressant effects.

Kishi T, Okamoto T, Takahashi T, Goshima K, Yamagami T. Cardiostimulatory action of coenzyme Q homologues on cultured myocardial cells and their biochemical mechanisms. Clin Investig 1993;71(8 Suppl):S71-75.
Abstract: The effect of coenzyme Q (CoQ) homologues on the beating of myocardial cells was investigated in cultured cell sheets from mouse fetuses and quail embryos. Myocardial cell sheets grown in Eagle's minimum essential medium with fetal bovine serum showed very weak and irregular beating when this serum was removed from the medium. However, the depressed beating rate and amplitude recovered almost completely within a few minutes by adding CoQ10 to the medium, and the effect of CoQ10 continued over 1 h. CoQ9 showed a cardiostimulatory effect similar to that of CoQ10, but CoQ8 and CoQ7 showed almost no effect. Short homologues (less than CoQ4) inhibited the beating of cell sheets. The cardiostimulatory effect of CoQ10 was not blocked by atenolol, a selective beta-blocker. In addition, CoQ10 stimulated the formation of ATP, not cAMP. CoQ0 and CoQ3 inhibited beating rates by inhibiting ATP formation. In conclusion, only native CoQ homologues having a nona- or decaprenyl group showed a cardiostimulatory effect on cultured myocardial cells, probably by stimulating mitochondrial ATP formation.

Landgren F, Israelsson B, Lindgren A, Hultberg B, Andersson A, Brattstrom L. Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid. J Intern Med. 1995 Apr;237(4):381-388.
Abstract: OBJECTIVES. Moderate hyperhomocysteinaemia is an independent risk factor for cardiovascular disease which may be causal. We investigated whether the concentration of plasma homocysteine changes between the acute phase of myocardial infarction and follow-up, and whether treatment with oral folic acid was effective in lowering homocysteine levels in patients with myocardial infarction. DESIGN AND SUBJECTS. Plasma total homocysteine levels 24-36 h (baseline) after onset of acute myocardial infarction were compared with the levels obtained at 6 weeks' follow-up and with the levels in the controls. In the same patients, we studied the effect on plasma homocysteine of 6 weeks' treatment with daily oral folic acid doses of 2.5 or 10 mg compared to no treatment. RESULTS. At baseline, 12 of 68 patients (18%) had moderate hyperhomocysteinaemia (> 17.3 mumol L-1; P < 0.05). Between baseline and follow-up, plasma homocysteine levels increased from 13.1 +/- 4.6 to 14.8 +/- 4.8 mumol L-1 (mean +/- SD; P < 0.001). Treatment with nitroglycerin, streptokinase, beta blockers, or acetylsalicylic acid seemed not to have caused this change. Folic acid lowered plasma homocysteine in all but two of 33 treated patients with a mean decrease of 4.4 mumol L-1 (-27%; P < 0.001). There was no difference between the effect of 2.5 and 10 mg of folic acid. In the untreated group (n = 20), plasma homocysteine increased with a mean increase of 0.6 mumol L-1 (+4%; P < 0.05). CONCLUSIONS. Plasma homocysteine seems to increase in the post myocardial infarction period, the cause of which warrants further study. Folic acid appears to be an effective treatment for the reduction of both normal and increased plasma homocysteine concentrations in patients with myocardial infarction. This suggests that folic acid should be used for intervention when studying the effect of homocysteine-lowering therapy on the risk on myocardial infarction.

Lefkowitz RJ, Hoffman BB, Taylor P:  Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG (eds):  Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York: McGraw-Hill, 1996:105-139.

Murray MT. The many benefits of carnitine. Am J Natural Med 1996;3:6-14. (Review)

Pepine CJ. The therapeutic potential of carnitine in cardiovascular disorders. Clin Ther. 1991 Jan-Feb;13(1):2-21; discussion 1. (Review)
Abstract: The naturally occurring compound L-carnitine plays an essential role in fatty acid metabolism. It is only by combining with carnitine that the activated long-chain fatty acyl coenzyme A esters in the cytosol are able to be transported to the mitochondrial matrix where beta-oxidation occurs. Carnitine also functions in the removal of compounds that are toxic to metabolic pathways. Clinical evidence indicates that carnitine may have a role in the management of a number of cardiovascular disorders. Supplemental administration of carnitine has been shown to reverse cardiomyopathy in patients with systemic carnitine deficiency. Experimental evidence obtained in laboratory animals and the initial clinical experience in man indicate that carnitine may also have potential in the management of both chronic and acute ischemic syndromes. Peripheral vascular disease, congestive heart failure, cardiac arrhythmias, and anthracycline-induced cardiotoxicity are other cardiovascular conditions that may benefit from carnitine administration, although at this time data on the use of carnitine for these indications are very preliminary.

Prasad K. Homocysteine, a Risk Factor for Cardiovascular Disease. INTERNATIONAL JOURNAL OF ANGIOLOGY 1999 Jan;8(1):76-86.
Abstract: Fasting hyperhomocysteinemia is an independent risk factor for coronary artery disease, stroke, peripheral vascular atherosclerosis, and for arterial and venous thromboembolism. The risk for cardiovascular disease with homocysteine is similar to conventional risk factors. The interaction of hyperhomocysteinemia with hypertension and smoking is strong and the combined effect is more than multiplicative. The combined effect of homocysteine and cholesterol is additive. Homocysteine produces atherosclerosis, thromboembolism, and vascular endothelial cell injury. Vascular dysfunction produced by homocysteine may be due to endothelial cell damage. Homocysteinemia-induced atherosclerosis is probably due to various factors including endothelial cell injury, inability to sustain S-nitroso-homocysteine formation because of imbalance between production of nitric oxide by dysfunctional endothelium and homocysteine, smooth muscle cell proliferation, and thromboembolism. There is strong evidence that endothelial cell injury is associated with oxidative stress produced by homocysteine. Hyperhomocysteinemia is associated with numerous conditions, including coronary disease, stroke, peripheral vascular disease (carotid artery and cerebrovascular atherosclerosis), venous thrombosis, renal disease, diabetes mellitus, and organ transplant. Folic acid, vitamin B12 and B6 have been shown to be beneficial in reducing plasma homocysteine levels. Folic acid is specifically very effective, safe and inexpensive.

Reis RP, Azinheira J, Reis HP, Bordalo-Sa AL, Santos L, Tavares J, Adao M, Pina JE, Correia JM, Luis AS. [Influence of levels of vitamin B2, B12, and folic acid on the values of basal homocysteinemia and after methionine overload]. Rev Port Cardiol. 1998 Jan;17(1):57-61. [Article in Portugese]

Riales R, Albrink MJ. Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men. Am J Clin Nutr 1981 Dec;34(12):2670-2678.
Abstract: Chromium deficiency may cause insulin resistance, hyperinsulinemia, impaired glucose tolerance, and hyperlipidemia, recovered by chromium supplementation. The effect of chromium supplementation on serum lipids and glucose tolerance was tested in a double-blind 12-wk study of 23 healthy adult men aged 31 to 60 yr. Either 200 micrograms trivalent chromium in 5 ml water (Cr) or 5 ml plain water (W) was ingested daily 5 days each week. Half the subjects volunteered for glucose tolerance tests with insulin levels. At 12 wk high-density lipoprotein cholesterol increased in the Cr group from 35 to 39 mg/dl (p less than 0.05) but did not change in the water group (34 mg/dl). The largest increase in high-density lipoprotein cholesterol and decreases in insulin and glucose were found in those subjects having normal glucose levels together with elevated insulin levels at base-line. The data are thus consistent with the hypothesis that Cr supplementation raises high-density lipoprotein cholesterol and improves insulin sensitivity in those with evidence of insulin resistance but normal glucose tolerance.

Roeback JR Jr, Hla KM, Chambless LE, Fletcher RH. Effects of chromium supplementation on serum high-density lipoprotein cholesterol levels in men taking beta-blockers. A randomized, controlled trial. Ann Intern Med 1991 Dec 15;115(12):917-924.
Abstract: OBJECTIVE: To determine the efficacy of glucose tolerance factor (GTF)-chromium for increasing serum levels of high-density lipoprotein (HDL) cholesterol in patients taking beta-blockers. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Mixed primary and referral-based outpatient clinic at a university-affiliated VA Medical Center. PATIENTS: Referred sample of 72 men receiving beta-blockers, mainly for hypertension. Sixty-three patients (88%) completed the study. INTERVENTIONS: Current medications, including beta-blockers, were continued. During the 8-week treatment phase, patients in the chromium group received a total daily dose of 600 micrograms of biologically active chromium divided into three equal doses; control patients received a placebo of identical appearance and taste. MEASUREMENTS: Serum levels of total cholesterol and HDL cholesterol were measured. MAIN RESULTS: Mean baseline levels of HDL and total cholesterol (+/- SD) were 0.93 +/- 0.28 mmol/L and 6.0 +/- 1.0 mmol/L (36 +/- 11.1 mg/dL and 232 +/- 38.5 mg/dL), respectively. The difference between groups in adjusted mean change in HDL cholesterol levels, accounting for baseline HDL cholesterol levels, age, weight change, and baseline total cholesterol levels, was 0.15 mmol/L (5.8 mg/dL) (P = 0.01) with a 95% Cl showing that the treatment effect was greater than +0.04 mmol/L (+1.4 mg/dL). Mean total cholesterol, triglycerides and body weight did not change significantly during treatment for either group. Compliance as measured by pill count was 85%, and few side effects were reported. Two months after the end of treatment, the between-group difference in adjusted mean change from baseline to end of post-treatment follow-up was -0.003 mmol/L (-0.1 mg/dL). CONCLUSION: Two months of chromium supplementation resulted in a clinically useful increase in HDL cholesterol levels in men taking beta-blockers.

Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezler R, Vermaak WJ. The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J Clin Invest 1996 Jul 1;98(1):177-184.
Abstract: Homocysteine, an atherogenic amino acid, is either remethylated to methionine or metabolized to cysteine by the transsulfuration pathway. The biochemical conversion of homocysteine to cysteine is dependent upon two consecutive, vitamin B-6-dependent reactions. To study the effect of a selective vitamin B-6 deficiency on transsulfuration, we performed oral methionine load tests on 22 vitamin B-6-deficient asthma patients treated with theophylline (a vitamin B-6 antagonist) and 24 age- and sex-matched controls with a normal vitamin B-6 status. Both groups had normal circulating vitamin B-12 and folate concentrations. Methionine loading resulted in significantly higher increases in circulating total homocyst(e)ine (P < 0.01) and cystathionine (P < 0.05) concentrations in vitamin B-6-deficient patients compared with controls. 6 wk of vitamin B-6 supplementation (20 mg/d) significantly (P < 0.05) reduced post-methionine load increases in circulating total homocyst(e)ine concentrations in deficient subjects, but had no significant effect on the increase in total homocyst(e)ine concentrations in controls. The increases in post-methionine load circulating cystathionine concentrations were significantly (P < 0.01) reduced in both groups after vitamin supplementation. It is concluded that a vitamin B-6 deficiency may contribute to impaired transsulfuration and an abnormal methionine load test, which is associated with premature vascular disease.

Vikre-Jorgensen J. [Cardiomyopathy caused by carnitine deficiency]. Ugeskr Laeger. 1993 Oct 18;155(42):3390-3392. [Article in Danish]
Abstract: Primary carnitine deficiency often presents as progressive cardiomyopathy. It is due to a defect in the plasma membrane carnitine transport system that is normally present in heart, muscle and kidney. This system serves to maintain intracellular carnitine levels 20-50 times higher than plasma concentrations. Patients with this defect cannot maintain adequate carnitine levels in muscle tissue for fatty acid oxidation. One case of primary carnitine deficiency is described. Two siblings had died earlier probably due to the same disease. The eight month old boy presented with a common cold and cardiomyopathy. He was treated with digoxin and diuretics until the diagnosis was confirmed. The patient's uptake of carnitine in fibroblasts was extremely low, about 5% of the normal range. The father had about 50% reduction of carnitine uptake in fibroblasts, the mother showed no sign of impaired uptake. The boy was treated with oral carnitine, 100 mg/kg/day. There was a normal level of carnitine in serum after two months of treatment and the cardiomyopathy disappeared completely in one year. Primary carnitine deficiency is a treatable disorder and therefore skeletal muscle biopsy and blood chemistry should be performed in all children with undiagnosed cardiomyopathy. Treatment with oral carnitine must be initiated quickly to avoid sudden death.

Wang MM. Fox EA. Stoecker BJ. Menendez CE. Chan SB. Serum cholesterol of adults supplemented with brewer’s yeast or chromium chloride. Nutr Res 1989;9:989-998.
Abstract: Serum glucose, insulin, total cholesterol, high density lipoprotein-cholesterol, triglycerides, urinary chromium and creatinine concentrations were assessed in 30 adults (Mean age = 52 yrs) with a mean total cholesterol concentration of 236 mg/dL. Three groups of 10 participants were supplemented with 9 g (15 ug chromium) brewer's yeast (BY), with 50 ug chromium as chromium chloride (CrCl3) or with placebo (control) for twelve weeks. Fasting blood samples were obtained at 0, 6, and 12 weeks. Serum total cholesterol declined significantly in the CrCl3 group (p < 0.005) and in the BY group (p < 0.05) compared with the control group. Initial mean urinary chromium/creatinine (ng/mg) concentration was 0.21 +/- 0.02; a value similar to that reported in recent literature. Elevated urinary chromium concentrations were found not to be associated with reduced serum cholesterol concentrations in the supplemented groups.

Wolf LR. Adrenergic Blocker Toxicity, in Haddad L, Shannon MW, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose, 3rd ed.  Pennsylvania: WB Sanders Co, 1998:1031-1040.

Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update.Clin Pharmacokinet 1999 Jun;36(6):425-438.
Abstract: Cigarette smoking remains highly prevalent in most countries. It can affect drug therapy by both pharmacokinetic and pharmacodynamic mechanisms. Enzymes induced by tobacco smoking may also increase the risk of cancer by enhancing the metabolic activation of carcinogens. Polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for the induction of cytochrome P450 (CYP) 1A1, CYP1A2 and possibly CYP2E1, CYP1A1 is primarily an extrahepatic enzyme found in lung and placenta. There are genetic polymorphisms in the inducibility of CYP1A1, with some evidence that high inducibility is more common in patients with lung cancer. CYP1A2 is a hepatic enzyme responsible for the metabolism of a number of drugs and activation of some procarcinogens. Caffeine demethylation, using blood clearance or urine metabolite data, has been used as an in vivo marker of CYP1A2 activity, clearly demonstrating an effect of cigarette smoking, CYP2E1 metabolises a number of drugs as well as activating some carcinogens. Our laboratory has found in an intraindividual study that cigarette smoking significantly enhances CYP2E1 activity as measured by the clearance of chlorzoxazone. In animal studies, nicotine induces the activity of several enzymes, including CYP2E1, CYP2A1/2A2 and CYP2B1/2B2, in the brain, but whether this effect is clinically significant is unknown. Similarly, although inhibitory effects of the smoke constituents carbon monoxide and cadmium on CYP enzymes have been observed in vitro and in animal studies, the relevance of this inhibition to humans has not yet been established. The mechanism involved in most interactions between cigarette smoking and drugs involves the induction of metabolism. Drugs for which induced metabolism because of cigarette smoking may have clinical consequence include theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide and estradiol. Cigarette smoking results in faster clearance of heparin, possibly related to smoking-related activation of thrombosis with enhanced heparin binding to antithrombin III. Cutaneous vasoconstriction by nicotine may slow the rate of insulin absorption after subcutaneous administration. Pharmacodynamic interactions have also been described. Cigarette smoking is associated with a lesser magnitude of blood pressure and heart rate lowering during treatment with beta-blockers, less sedation from benzodiazepines and less analgesia from some opioids, most likely reflecting the effects of the stimulant actions of nicotine. The impact of cigarette smoking needs to be considered in planning and assessing responses to drug therapy. Cigarette smoking should be specifically studied in clinical trials of new drugs.