References

[No author given.] Drug Evaluations Subscription. Chicago: American Medical Association, Vol. I, Section 7. Chapter 2, Spring, 1992.

Bar-Or D, Gasiel Y. Calcium and calciferol antagonise effect of verapamil in atrial fibrillation. Br Med J (Clin Res Ed) 1981 May 16;282(6276):1585-1586.

Bassotti G, Calcara C, Annese V, Fiorella S, Roselli P, Morelli A. Nifedipine and verapamil inhibit the sigmoid colon myoelectric response to eating in healthy volunteers. Dis Colon Rectum 1998 Mar;41(3):377-380.
Abstract: BACKGROUND: Constipation is not an infrequent side effect complained of by patients taking calcium channel blockers. This effect may reduce patients' compliance and yield potentially serious consequences. However, the underlying mechanisms for constipation caused by such compounds are not known. AIMS: The purpose of the present study was to assess the effects of nifedipine and verapamil on the sigmoid myoelectric response to eating, a physiologic test of colonic motor function. SUBJECTS AND METHODS: Nine healthy male volunteers with no previous abdominal surgery were recruited for the study and underwent three paired studies at two-week intervals. Myoelectric sigmoid activity was recorded by means of two clip electrodes introduced within the viscus without preparation for 30 minutes basally and 90 minutes postprandially. Each study was preceded by placebo, nifedipine (20 mg), or verapamil (120 mg). RESULTS: Analysis of the tracings revealed that nifedipine strongly inhibited the sigmoid myoelectric response to the meal. This response was also significantly reduced in those taking verapamil compared with the placebo group, although to a much lesser extent than in those taking nifedipine. CONCLUSIONS: We conclude that constipation as a result of some calcium channel blockers may be caused by inhibition of colonic motor activity by nifedipine and, to a lesser extent, by verapamil. The latter compound probably displays other mechanisms (reduced colonic transit, increased water absorption) also responsible for this side effect.

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.

Fox J, Della-Santina CP. Oral verapamil and calcium and vitamin D metabolism in rats: effect of dietary calcium. Am J Physiol 1989 Nov;257(5 Pt 1):E632-638.

Fuhr U. Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance. Drug Saf. 1998 Apr;18(4):251-72. (Review)
Abstract: Concomitant intake with grapefruit juice increases the concentrations of many drugs in humans. The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with a high first pass degradation and in many cases has the clear potential to reach clinical relevance, as shown by an occasional change in drug effects or tolerability. For felodipine, nitrendipine, nisoldipine and saquinavir, the interaction was most marked with median increases of area under the curve (AUC) and/or the maximum (peak) plasma drug concentration after single-dose administration (Cmax) values exceeding 70% of respective control periods. Less pronounced, but possibly relevant, concentration increases were found for nifedipine, nimodipine, verapamil, cyclosporin, midazolam, triazolam and terfenadine. This list is not complete because many drugs have not been studied yet. The components of grapefruit juice which are the most probable causes of the interactions are psoralen derivatives, but the flavonoid naringenin may also contribute. Concomitant grapefruit juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients refrain from drinking grapefruit juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for the drug. It is also recommended that drugs possibly interacting with grapefruit juice should be appropriately labelled. A place for grapefruit juice as a drug-sparing agent in treatment involving expensive medicine cannot be derived from the information currently available on grapefruit juice interactions.

Goto K, Yasue H, Okumura K, Matsuyama K, Kugiyama K, Miyagi H, Higashi T. Magnesium deficiency detected by intravenous loading test in variant angina pectoris. Am J Cardiol. 1990 Mar 15;65(11):709-712.
Abstract: To study whether magnesium (Mg) deficiency is present in patients with variant angina, 24-hour Mg retention of low dose Mg (0.2 mEq/kg lean body weight) administered intravenously over 4 hours in 20 patients with variant angina was examined. No patient had received calcium antagonists before or during the study. All had attacks of chest pain associated with ST elevation on electrocardiograms. Twenty-one subjects without ischemic heart disease were studied as control subjects. Ten patients with variant angina were restudied 10 to 529 days (mean 235 +/- 30) after the treatment with calcium antagonists (diltiazem 120 to 240 or nifedipine 40 to 80 mg/day), which resulted in complete suppression of anginal attacks. The mean serum Mg concentrations in the patients with variant angina and the control subjects were 2.1 +/- 0.05 and 2.1 +/- 0.03 mg/dl, respectively (difference not significant). However, 24-hour Mg retention in the patients with variant angina was 60 +/- 5%, while that in the control subjects was 36 +/- 3% (p less than 0.001), suggesting that Mg deficiency is present in at least some patients with variant angina. The mean serum Mg concentrations before and after calcium antagonist treatment in 10 patients with variant angina were 2.1 +/- 0.09 and 2.1 +/- 0.07 mg/dl, respectively (difference not significant). However, 24-hour Mg retention decreased significantly (p less than 0.01) from 60 +/- 6 to 34 +/- 7% after the treatment. There is Mg deficiency in many patients with variant angina and it is corrected after treatment with calcium antagonists.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998, 274-275.

Jameson SJ, Hargarten SW. Calcium pretreatment to prevent verapamil-induced hypotension in patients with SVT. Ann Emerg Med 1992 Jan;21(1):68. (Editorial)

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

King VF, Garcia ML, Himmel D, Reuben JP, Lam YK, Pan JX, Han GQ, Kaczorowski GJ. Interaction of tetrandrine with slowly inactivating calcium channels. Characterization of calcium channel modulation by an alkaloid of Chinese medicinal herb origin. J Biol Chem 1988 Feb 15;263(5):2238-2244.
Abstract: Tetrandrine, a bis-benzylisoquinoline alkaloid derived from the Chinese medicinal herb Stephania tetrandra, is a putative Ca2+ entry blocker whose mechanism of action is unknown. To investigate this mechanism, the effects of tetrandrine were characterized on binding of three chemical classes of Ca2+ entry blockers in cardiac sarcolemmal membrane vesicles. In the range 25-37 degrees C, tetrandrine completely blocks diltiazem binding, partially inhibits D-600 binding, and markedly stimulates nitrendipine binding, with greatest enhancement occurring at 37 degrees C. The potency of tetrandrine is increased 10-fold as temperature is raised from 25 to 37 degrees C. Scatchard analyses indicate that inhibition of diltiazem binding and stimulation of nitrendipine binding result from changes in ligand affinities while inhibition of D-600 binding is due to both an increase in KD and decrease in Bmax of aralkylamine receptors. Ligand dissociation studies reveal that tetrandrine increases D-600 off-rates, decreases nitrendipine off-rates, but has no effect on diltiazem dissociation kinetics. In addition, tetrandrine reversibly blocks inward Ca2+ currents through L-type Ca2+ channels in GH3 anterior pituitary cells. These results indicate that tetrandrine interacts directly at the benzothiazepine-binding site of the Ca2+ entry blocker receptor complex and allosterically modulates ligand binding at other receptors in this complex. These findings suggest that tetrandrine is a structurally unique natural product Ca2+ entry blocker and provide a rationale explanation for the therapeutic effectiveness of this agent.

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.

Krevsky B, Maurer AH, Niewiarowski T, Cohen S. Effect of verapamil on human intestinal transit. Dig Dis Sci 1992 Jun;37(6):919-924.
Abstract: Although constipation is a well-known side effect of calcium channel blockers such as verapamil, this side effect has not been evaluated in a quantitative manner. In a double-blind, randomized, crossover trial, the effect of verapamil (240 mg/day) was compared to placebo in 15 normal male volunteers. Subjects recorded their bowel movements and any side effects. Scintigraphy was used to quantitate gastric emptying, small intestinal transit, and colonic transit. In the study period of four days, verapamil did not change the frequency, consistency, or passage of bowel movements. A significantly increased number of side effects was noted during verapamil treatment--notably abdominal pain and dry mouth. The slope of gastric emptying was not significantly different for verapamil (0.012 +/- 0.02) than for placebo (0.013 +/- 0.001). Distal ileum filling was also not different for verapamil (0.41 +/- 0.13%/min) than placebo (0.33 +/- 0.05%/min). Progression of the colonic geometric center was significantly delayed at 48 hr by verapamil (5.2 +/- 0.4 vs 6.2 +/- 0.23; P less than 0.01). This study suggests that the constipating effect of verapamil is due to a delay of colonic transit and not due to an effect on upper gastrointestinal transit.

Kuhn M, Schriger DL. Low-dose calcium pretreatment to prevent verapamil-induced hypotension. Am Heart J 1992 Jul;124(1):231-232.

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.

Low AM, Berdik M, Sormaz L, Gataiance S, Buchanan MR, Kwan CY, Daniel EE. Plant alkaloids, tetrandrine and hernandezine, inhibit calcium-depletion stimulated calcium entry in human and bovine endothelial cells. Life Sci 1996;58(25):2327-2335.
Abstract: Depletion of internal Ca2+ stores causes capacitative Ca2+ entry which occurs through non-selective cation channels sensitive to blockade by SK&F 96365. Recently, alkaloids of Chinese herbal medicinal origin, tetrandrine and hernandezine, have been shown to possess actions including inhibition of Ca2+ channels in non-excitable cell types. In this study, we compared the actions of these novel inhibitors to those of SK&F 96365 in fura-2-loaded endothelial cells from human umbilical vein and bovine pulmonary artery. Depletion of Ca2+ from the internal stores was accomplished in Ca(2+)-free medium using an endoplasmic reticulum Ca2+ pump inhibitor, cyclopiazonic acid (CPA) or receptor agonists, histamine and bradykinin. Stimulation with histamine or bradykinin caused a marked and rapid transient increase in Ca2+ signal whereas CPA caused a smaller amplitude increase of longer duration. Restoring Ca2+ to the medium caused marked and sustained increases in the fluorescence indicating movement of Ca2+ into the cytosol presumably stimulated by the emptied Ca2+ stores. SK&F 96365 as well as tetrandrine and hernandezine antagonized depletion-induced Ca2+ entry. The results suggest that these putative inhibitors interact with Ca2+ entry triggered by depletion of the internal Ca2+ stores and their action is presumed to be on the non-selective cation channels. Their effectiveness may be enhanced by the mechanisms which lead to the opening of the Ca2+ influx channel.

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. Intl J 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]

Renwart N, Frances H, Simon P. The calcium entry blockers: anti-manic drugs? Prog Neuropsychopharmacol Biol Psychiatry. 1986;10(6):717-722.
Abstract: The reported property of calcium antagonists as antimanic drugs has been investigated in three models of hyperactivity in mice. The hyperactivity was induced by amphetamine, oxolinic acid or reserpine after inhibition of monoamine oxydase (MAO). Nicardipine (a dihydropyridine derivative) reduces the three hyperactivities, verapamil (a diphenylalkylamine derivative) reduces only oxolinic acid hyperactivity, and diltiazem (a benzothiazepine derivative) was active except in the MAOI-reserpine test. Levomepromazine used as a reference drug reduced the three hyperactivities. The three calcium entry-blockers reduce the different hyperactivities at doses which already decrease motor activity. And so, it seems that their action was not specific. On the contrary, levomepromazine antagonizes MAOI-reserpine induced hypermotility at a dose which is not sedative. These results do not strengthen the property of calcium antagonists as antimanic drugs.

Smits P, Thien T, van 't Laar A. Influence of slow calcium-channel blockade on the cardiovascular effects of coffee. Eur J Clin Pharmacol 1986;30(2):171-175.

Stockey IH. Drug Interactions, 4th Edition, London: Pharmaceutical Press, 1996.

Threlkeld DS, ed. Diuretics and Cardiovasculars, Calcium Channel Blocking Agents. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Nov 1992.

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.