Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase.

J Clin Invest (UNITED STATES) Jul 15 1996, 98 (2) p345-51

Mitochondria were isolated from skin fibroblast cultures derived from healthy individuals (controls) and from a group patients with complex I (NADH-CoQ reductase) deficiency of the mitochondrial respiratory chain. The complex I deficient patients included those with fatal infantile lactic acidosis (FILA), cardiomyopathy with cataracts (CC), hepatopathy with tubulopathy (HT), Leigh's disease (LD), cataracts and developmental delay (CD), and lactic acidemia in the neonatal period followed by mild symptoms (MS). Production of superoxide radicals, on addition of NADH, were measured using the luminometric probe lucigenin with isolated fibroblast mitochondrial membranes. Superoxide production rates were highest with CD and decreased in the order CD >> MS > LD > control > HT > FILA = CC. The quantity of Mn-superoxide dismutase (MnSOD), as measured by ELISA techniques, however, was highest in CC and FILA and lowest in CD. Plots of MnSOD quantity versus superoxide production showed an inverse relationship for most conditions with complex I deficiency. We hypothesize that oxygen radical production is increased when complex I activity is compromised. However, the observed superoxide production rates are modulated by the variant induction of MnSOD which decreases the rates, sometimes below those seen in control fibroblast mitochondria. In turn, we show that the variant induction of MnSOD is most likely a function of the change in the redox state of the cell experienced rather than a result of the complex I defect per se.

Effect of protection and repair of injury of mitochondrial membrane-phospholipid on prognosis in patients with dilated cardiomyopathy.

Blood Press Suppl (NORWAY) 1996, 3 p53-5

We have already proved that the mitochondrial membrane-phospholipid (MMP) injury changes of peripheral lymphocytes in patients with heart failure can be used as an injury indicator of myocardia, and are related to the long-term prognosis. In the present study, MMP localization of the peripheral lymphocytes was performed by modified Demer's tricomplex flocculation method, and we compared the changes, after classification, between the pre-treatment and the 12-week post-treatment, of coenzyme Q10 (Co.Q10) and captopril in 61 hospitalized patients with dilated cardiomyopathy (DCM). They were followed up for 16.1 +/- 7.8 months (mean). The results showed that compared with the placebo, Co.Q10 and captopril could significantly protect against and repair MMP injury and improve the heart function of patients with DCM after 12 weeks, and the 2-year survival rate rose significantly by 72.7% for Co.Q10, and 64.0% for captopril, vs 24.7% for placebo. As for Longrank test, X2 equals 4.660 and 6.318, respectively, with both p < 0.05. The aforementioned results indicate that MMP injury of peripheral lymphocytes can predict the prognosis of the patients with DCM, thus the protection and repairment of MMP injury can improve the life-quality and prolong the life-span of the patients.

[Therapeutic effects of coenzyme Q10 on dilated cardiomyopathy: assessment by 123I-BMIPP myocardial single photon emission computed tomography (SPECT): a multicenter trial in Osaka University Medical School Group]

Kaku Igaku (JAPAN) Jan 1996, 33 (1) p27-32

To evaluate therapeutic effects of Cenzyme Q10 (CoQ10), 15 patients with dilated cardiomyopathy were investigated by 123I-BMIPP myocardial single photon emission computed tomography (SPECT). The BMIPP defect score was determined semiquantitatively by using representative short and long axial SPECT images. Mean BMIPP defect score with CoQ10 treatment was significantly low, 7.7 +/- 6.1 compared to 12.7 +/- 7.4 without CoQ10 treatment. On the other hand, in 8 patients of dilated cardiomyopathy, % fractional shortening using echocardiography was not different before and after CoQ10 treatment. In conclusion, 123I-BMIPP myocardial SPECT was proved to be sensitive to evaluate the therapeutic effects of CoQ10, which improve myocardial mitochondrial function, in the cases of dilated cardiomyopathy.

Italian multicenter study on the safety and efficacy of COENZYME Q10 as adjunctive therapy in heart failure.

Mol Aspects Med (ENGLAND) 1994, 15 Suppl ps287-94

Digitalis, diuretics and vasodilators are considered the standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of COENZYME Q10 (CoQ10) adjunctive treatment in congestive heart failure which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2664 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing study in 173 Italian centers. The daily dosage of CoQ10 was 50-150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two-to seven-point scales. The results show a low incidence of side effects: 38 adverse effects were reported in 36 patients (1.5%) of which 22 events were considered as correlated to the test treatment. After three months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 78.1%, oedema 78.6%, pulmonary rales77.8%, enlargement of liver area 49.3%, jugular reflux 71.81%, dyspnoea 52.7%, palpitations 75.4%, sweating 79.8%, subjective arrhytmia 63.4%, insomnia 662.8%, vertigo 73.1% and nocturia 53.6%. Moreover we observed a contemporary improvement of at least three symptoms in 54% of patients; this could be interpreted as an index of improved quality of life.

[Coenzyme Q10 (ubiquinone) in the treatment of heart failure. Are any positive effects documented?]

Tidsskr Nor Laegeforen (NORWAY) Mar 20 1994, 114 (8) p939-42

COENZYME Q10 is an endogenous substance which has a well established role as electron carrier in the mitochondrial synthesis of adenosine triphosphate (ATP). In addition, coenzyme Q10 also has antioxidant and membrane stabilizing properties. Based on biopsy samples from patients undergoing cardiac surgery and blood samples from patients with congestive heart failure, the existence of a relative Q10 deficiency in patients with cardiac failure has been suggested. A total number of eight double blind, placebo controlled studies in patients with heart failure have been published. Most of these studies include a small number of patients, and various methodological problems have been attributed to these. The results, judged as improvement in ejection fraction or work capacity, are inconsistent. In one large study, COENZYME Q10 was found to have a positive effect on morbidity, and in another on quality of life. However, although some of the results appear to be promising, more studies are needed, including studies designed with mortality as a primary end point, before the effect of the substance in patients with heart failure can be established. (30 Refs.)

Italian multicenter study on the safety and efficacy of COENZYME Q10 as adjunctive therapy in heart failure (interim analysis). The CoQ10 Drug Surveillance Investigators.

Clin Investig (GERMANY) 1993, 71 (8 Suppl) pS145-9

Digitalis, diuretics, and vasodilators are considered standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure, which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2500 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing drug surveillance study in 173 Italian centers. The daily dose of CoQ10 was 50-150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two- to seven-point scales. Preliminary results on 1113 patients (mean age 69.5 years) show a low incidence of side effects: 10 adverse reactions were reported in 8 (0.8%) patients, of which only 5 reactions were considered as correlated to the test treatment. After 3 months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 81%, edema 76.9%, pulmonary rales 78.4%, enlargement of the liver area 49.3%, jugular reflux 81.5%, dyspnea 54.2%, palpitations 75.7%, sweating 82.4%, arrhythmia 62%, insomnia 60.2%, vertigo 73%, and nocturia 50.7%.

Effect of COENZYME Q10 therapy in patients with congestive heart failure: a long-term multicenter randomized study.

Clin Investig (GERMANY) 1993, 71 (8 Suppl) pS134-6

The improved cardiac function in patients with congestive heart failure treated with coenzyme Q10 supports the hypothesis that this condition is characterized by mitochondrial dysfunction and energy starvation, so that it may be ameliorated by COENZYME Q10 supplementation. However, the main clinical problems in patients with congestive heart failure are the frequent need of hospitalization and the high incidence of life-threatening arrhythmias, pulmonary edema, and other serious complications. Thus, we studied the influence of COENZYME Q10 long-term treatment on these events in patients with chronic congestive heart failure (New York Heart Association functional class III and IV) receiving conventional treatment for heart failure. They were randomly assigned to receive either placebo (n = 322, mean age 67 years, range 30-88 years) or COENZYME Q10 (n = 319, mean age 67 years, range 26-89 years) at the dosage of 2 mg/kg per day in a 1-year double-blind trial. The number of patients who required hospitalization for worsening heart failure was smaller in the COENZYME Q10 treated group (n = 73) than in the control group (n = 118, P < 0.001). Similarly, the episodes of pulmonary edema or cardiac asthma were reduced in the control group (20 versus 51 and 97 versus 198, respectively; both P < 0.001) as compared to the placebo group. Our results demonstrate that the addition of coenzyme Q10 to conventional therapy significantly reduces hospitalization for worsening of heart failure and the incidence of serious complications in patients with chronic congestive heart failure.

Role of metabolic therapy in cardiovascular disease.

Clin Investig (GERMANY) 1993, 71 (8 Suppl) pS124-8

The pathophysiological basis for the use of metabolic therapy in the treatment of heart failure is analyzed. Bioenergetical processes related to ATP bioavailability play a central role in regulating myocardial contractility at rest and on effort. Furthermore, a significant correlation has been demonstrated in diseased heart between ATP content, revealed at endomyocardial biopsy, and systolic and diastolic left ventricular indexes evaluated with invasive and noninvasive methods. Several international investigations demonstrate the beneficial effects of ubiquinone (COENZYME Q10) in the treatment of heart failure. Here the results of a study are reported that was conducted on patients with heart failure treated with ubiquinone. After 7 months of oral drug administration (100 mg/day), a significant improvement was observed in echocardiographic indexes of systolic function, cardiothoracic ratio, and clinical signs and symptoms of congestive heart failure. In conclusion, the introduction of metabolic drugs, such as ubiquinone, in the treatment of heart failure opens new horizons in the therapeutic approach to an ailment that entails substantial human and social costs.

Cardiac performance and COENZYME Q10 in thyroid disorders

Endocrinol Jpn (JAPAN) Dec 1984, 31 (6) p755-61

To investigate the relationship between serum levels of COENZYME Q10 and cardiac performance in thyroid disorders, we studied the cardiac performance and assessed serum levels of thyroid hormones and COENZYME Q10 in 20 patients with hyperthyroidism, 5 patients with hypothyroidism and 10 normal subjects. A significant inverse correlation between thyroid hormones and Coenzyme Q10 levels was found by performing partial correlation analysis. Because low serum levels of COENZYME Q10 were found in thyrotoxic patients and congestive heart failure may occur as a result of severe hyperthyroidism, 120 mg of COENZYME Q10 was administered daily for one week to 12 hyperthyroid patients and the change in cardiac performance was assessed. Further augmentation of cardiac performance was found in hyperthyroid hearts, which were already augmented, after the administration of COENZYME Q10. It appears, therefore, that the COENZYME Q10 dose actually has a therapeutic value for congestive heart failure induced by severe thyrotoxicosis.

A clinical study of the effect of COENZYME Q on congestive heart failure.

Jpn Heart J (JAPAN) Jan 1976, 17 (1) p32-42

Expecting activation of myocardial energy liberation, COENZYME Q was applied as a treatment to 55 patients suffering from congestive heart failure. Daily doses of 50 to 100 mg of coenzyme Q7 were injected intravenously in 21 cases for 3 to 35 days. Daily doses of 60 mg of coenzyme Q7 were administered perorally in 17 cases for 14 to 196 days. Daily doses of 30 mg of COENZYME Q10 were administered perorally in 17 cases for 7 to 182 days. Clinical effects were evaluated within 4 weeks by the criteria using a scoring method of severity of congestive heart failure which was devised by the authors. In summary a certain effect was found in 20 cases and a mild effect was observed in 29 cases. No significant changes were observed in heart rate and blood pressure. Exanthema appeared in 2 patients of the group of COENZYME Q7 intravenous injection. In conclusion the therapeutic effect of COENZYME Q was thought to be mild but stable in supplement to digitalis therapy in cases of congestive heart failure.

Effects of coenzyme Q10 administration on pulmonary function and exercise performance in patients with chronic lung diseases.

Clin Investig (GERMANY) 1993, 71 (8 Suppl) pS162-6

Serum coenzyme Q10 (CoQ10) levels were measured at rest and during incremental exercise in 21 patients with chronic obstructive pulmonary disease (COPD) and 9 patients with idiopathic pulmonary fibrosis (IPF). The mean serum CoQ10 levels at rest in patients with COPD and IPF were 0.56 +/- 0.20 and 0.45 +/- 0.16 microgram/ml, respectively. In both groups these levels were decreased compared with those of healthy subjects. In the patients with COPD, CoQ10 levels were significantly correlated with body weight, however, there was no correlation between CoQ10 levels and ventilatory function, PaO2, VO2/kg at rest, or maximal VO2. In eight of nine patients whose PaO2 at rest was lower than 75 torr, serum CoQ10 levels were lower than 0.5 microgram/ml. We studied the effects of the oral administration of CoQ10 at 90 mg/day for 8 weeks on pulmonary function and exercise performance in eight patients with COPD. Serum CoQ10 levels were significantly elevated in association with an improvement in hypoxemia at rest, whereas pulmonary function was unaltered. Oxygen consumption during exercise was not changed, whereas PaO2 was significantly improved, and heart rate was significantly decreased compared with the results obtained at an identical workload at baseline. Furthermore, lactate production was suppressed during the anaerobic exercise stage after CoQ10 administration, and exercise performance tended to increase. These data suggested that CoQ10 has favorable effects on muscular energy metabolism in patients with chronic lung diseases who have hypoxemia at rest and/or during exercise

Unrecognized pandemic subclinical diabetes of the affluent nations: Causes, cost and prevention

Journal of Orthomolecular Medicine (Canada), 1996, 11/2 (95-99)

Regarding populations on the industrialized 'western affluent diet', arguments are made that: (1) plasma glucose values commonly seen and accepted as normal are abnormal; (2) their glucose tolerance is innately unstable; (3) most of their morbidity and mortality is produced by hyperglycemia far below glycosuria and/or arteriosclerosis which can occur independently or together; (4) simple low cost methods for preventing and treating both have been in the literature for decades (correction of the sugar, fat and protein excesses; and controlled supplementation of pyridoxine (vitamin B6). Mg, Cr and coenzyme Q10); and (5) these lessons were missed by main stream medicine because of the vast size of the literature, enforcement of 'treatment of choice', and lack of computer aided diagnosis. Cited as striking evidence of this tragic situation is the failure of mainstream clinical medicine to understand the cause of the remarkable decline in CVD in the 1960s and 1970s that followed U.S. enrichment of cereals with pyridoxine (vitamin B6). Recommendations are made for correction of unnecessary costly delays between publication and implementation of such research findings.

[Effect of biological membrane stabilizing drugs (coenzyme Q10, dextran sulfate and reduced glutathione) on adriamycin (doxorubicin)-induced toxicity and microsomal lipid peroxidation in mice]

Gan To Kagaku Ryoho. 1996 Jan. 23(1). P 93-8

The protective effects of the biological membrane stabilizing drugs, coenzyme Q10 (CoQ), dextran sulfate (DS) and reduced glutathione (GSH), on doxorubicin (adriamycin, ADM)-induced toxicity and microsomal lipid peroxidation were studied in mice. The mice administered ADM with combined treatment of CoQ, DS or GSH showed a significantly longer survival time than the ADM control group (which were injected with 15 mg/kg of ADM twice). The optimum protective doses of these drugs against ADM-induced toxicity were 10 mg/kg/day (p.o.) for CoQ, 100 mg/kg/day (s.c.) for DS and 100 mg/kg/day (i.p.) for GSH. The survival times of the mice (expressed as a percent of the treated group per control group) were 224.1% for CoQ, 220.7% for DS and 213.7% for GSH. The groups treated with these drugs showed a significant decrease in mouse liver and heart microsomal lipid peroxidation in comparison to that of the ADM control group. These results suggest that the heart microsomal lipid peroxidation levels may be one of the indications of ADM-induced cardiac toxicity. These drugs tested in the present study may stabilize the heart microsomal membrane lipid or may improve the myocardiac mitochondrial functions over those in ADM-treated mouse.

Coenzyme Q10, plasma membrane oxidase and growth control.

Mol Aspects Med. 1994. 15 SupplP s1-11

The plasma membrane of eukaryotic cells contains an NADH oxidase which can transfer electrons across the membrane. This oxidase is controlled by hormones, growth factors and other ligands which bind to receptors in the plasma membrane. Oncogenes also affect activity of the oxidase. Natural serum components such as diferric transferrin and ceruloplasmin which stimulate proliferation also stimulate membrane oxidase activity. Additional growth factors can be required to complement the proliferative effect. Electron transport across the plasma membrane can be measured by the reduction of impermeable electron acceptors, such as ferricyanide, which also stimulate cell growth. The oxidants activate growth-related signals such as cytosolic alkalinization and calcium mobilization. Antiproliferative agents such as adriamycin and retinoic acid inhibit the plasma membrane electron transport. Flavin, Coenzyme Q and an iron chelate on the cell surface are apparent electron carriers for the transmembrane electron transport. Coenzyme Q10 stimulates cell growth, and Coenzyme Q analogs such as capsaicin and chloroquine reversibly inhibit both growth and transmembrane electron transport. Addition of iron salts to the depleted cells restores activity and growth. The ligand-activated oxidase in the plasma membrane introduces a new basis for control of signal transduction in cells. The redox state of the quinone in the oxidase is proposed to control tyrosine kinase either by generation of H2O2 or redox-induced conformational change. Refs: 38.

Protective effects of various drugs on adriamycin (doxorubicin)-induced toxicity and microsomal lipid peroxidation in mice and rats.

Biol Pharm Bull. 1993 Nov. 16(11). P 1114-7

The protective effects of clinically used drugs on the toxicity and microsomal lipid peroxidation induced by doxorubicin (adriamycin, ADM), an anthracycline type antitumor agent, were studied in mice and rats. Regarding the effects of anthracyclines (aclarubicin, ACL; daunorubicin, DAU; ADM; epirubicin, EPI; pirarubicin, PIR) on rat liver microsomal lipid peroxidation, ACL had the smallest effect, and effectiveness increased in the order of PIR, ADM, DAU and EPI. The increasing effect of lipid peroxidation induced by these drugs was closely correlated with the decrease in the body weight of mice administered intraperitoneally at a dose of 20 mg/kg and in rats at LD50 of the drugs. The survival times of ADM-administered mice (which were injected 15 mg/kg of ADM twice) treated with the following drugs, expressed as a percent of that of the control group, were 236% for adenosine triphosphate, 224% for coenzyme Q10 (Co Q), 235% for dextran sulfate (DS), 123% for dipyridamole, 121% for flavin adenine dinucleotide, 213% for reduced glutathion, 155% for inositol nicotinate, 157% for nicardipin and 297% for nicomol. The rat heart microsomal lipid peroxidation levels in vivo may be one of the indications of ADM-induced toxicity. The levels treated with DS correlated well with the development of ADM-induced toxicity: mouse survival time, change of body weight and tissue wet weight loss. Another type of drug, such as Co Q, may improve the myocardiac mitochondrial functions compared to those of ADM-administered mice.

Tissue concentration of doxorubicin (adriamycin) in mouse pretreated with alpha-tocopherol or coenzyme Q10.

Acta Med Okayama. 1991 Jun. 45(3). P 195-9

The tissue concentration of doxorubicin (adriamycin; ADM) and its major metabolite (aglycone I) was examined in mice pretreated with alpha-tocopherol (VE) or coenzyme Q10 (CoQ). In VE-pretreated group, the concentrations of aglycone I of the liver (1, 3 and 5 h after the administration), kidney (1 and 3h) and heart (3h) were significantly higher than those in the saline group. The clinical application of VE or CoQ concomitant with anti-tumor drugs especially ADM, requires caution.

[Electrocardiogram analysis of adriamycin cardiotoxicity in 160 cases]

Chung Hua Chung Liu Tsa Chih. 1991 Jan. 13(1). P 71-3

From January 1986 to May 1989, 160 cancer patients proven by pathology were treated by combined chemotherapy with adriamycin (ADM) as the chief agent. Of them, 20 were given simultaneous cyclophosphamide (CTX) and 14 had received mediastinal irradiation. 40 mg/m2 of ADM was given by rapid IV bolus injection which was repeated every 3 weeks. All but 9 had normal electrocardiogram (ECG) before ADM administration. In these 9 patients, when ADM reached certain accumulated dose, ECG showed no further changes. Thirty-seven (24.5%) cases had various types of abnormal ECG, manifested as arrhythmia in 11, non-specific ST-T changes in 12 and low voltage in 14. Of these 37 patients, fatal congestive heart failure developed in 4 cases. To reduce ADM cardiotoxicity, its indication should be strictly adhered to; ADM may be divided to two fractions on Day 1 and 2, for those patients receiving simultaneous CTX or who had had mediastinal irradiation, ADM accumulated dose should be limited to 400 mg/m2; ADM should never be given to patients with lowered QRS voltage greater than or equal to 30% of the normal value or with obvious ST-T changes; the accumulated doses should range from 450 to 550 mg/m2, simultaneous anti-histamines, anti-adrenaline, coenzyme Q10 and vitamin E are indicated.

Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases.

Biochem Biophys Res Commun (UNITED STATES) Jul 6 1995

Over 35 years, data and knowledge have internationally evolved from biochemical, biomedical and clinical research on vitamin Q10 (coenzyme Q10; CoQ10) and cancer, which led in 1993 to overt complete regression of the tumors in two cases of breast cancer. Continuing this research, three additional breast cancer patients also underwent a conventional protocol of therapy which included a daily oral dosage of 390 mg of vitamin Q10 (Bio-Quinone of Pharma Nord) during the complete trials over 3-5 years. The numerous metastases in the liver of a 44-year-old patient "disappeared," and no signs of metastases were found elsewhere. A 49-year-old patient, on a dosage of 390 mg of vitamin Q10, revealed no signs of tumor in the pleural cavity after six months, and her condition was excellent. A 75-year-old patient with carcinoma in one breast, after lumpectomy and 390 mg of CoQ10, showed no cancer in the tumor bed or metastases. Control blood levels of CoQ10 of 0.83-0.97 and of 0.62 micrograms/ml increased to 3.34-3.64 and to 3.77 micrograms/ml, respectively, on therapy with CoQ10 for patients A-MRH and EEL.

Apparent partial remission of breast cancer in 'high risk' patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10.

Mol Aspects Med (ENGLAND) 1994, 15 Suppl

Thirty-two typical patients with breast cancer, aged 32-81 years and classified 'high risk' because of tumor spread to the lymph nodes in the axilla, were studied for 18 months following an Adjuvant Nutritional Intervention in Cancer protocol (ANICA protocol). The nutritional protocol was added to the surgical and therapeutic treatment of breast cancer, as required by regulations in Denmark. The added treatment was a combination of nutritional antioxidants (Vitamin C: 2850 mg, Vitamin E: 2500 iu, beta-carotene 32.5 iu, selenium 387 micrograms plus secondary vitamins and minerals), essential fatty acids (1.2 g gamma linolenic acid and 3.5 g n-3 fatty acids) and Coenzyme Q10 (90 mg per day). The ANICA protocol is based on the concept of testing the synergistic effect of those categories of nutritional supplements, including vitamin Q10, previously having shown deficiency and/or therapeutic value as single elements in diverse forms of cancer, as cancer may be synergistically related to diverse biochemical dysfunctions and vitamin deficiencies. Biochemical markers, clinical condition, tumor spread, quality of life parameters and survival were followed during the trial. Compliance was excellent. The main observations were: (1) none of the patients died during the study period. (the expected number was four.) (2) none of the patients showed signs of further distant metastases. (3) quality of life was improved (no weight loss, reduced use of pain killers). (4) six patients showed apparent partial remission.

Effects of isoprenoids (coQ10) on growth of normal human mammary epithelial cells and breast cancer cells in vitro.

Anticancer Res (GREECE) Jan-Feb 1994

The possible growth regulatory role of isoprenoids (mevalonate-derived products) in secondary cultures of normal human mammary epithelial cells (HMEC), as compared to the two human breast cancer cell lines Hs578T and MDA231, was investigated. All three cell types responded promptly to inhibitors of HMG CoA reductase and thereby became arrested. Whereas the growth of MDA231 cells was totally independent of exogenous growth factors, the proliferation of HMEC and Hs578T was blocked or partially blocked, respectively, following growth factor-depletion. Closer analysis showed that the depressive effects on cell growth, induced by HMG CoA reductase inhibition and growth factor depletion, were from a kinetic point of view identical. These data suggest that the biosynthesis of isoprenoids may comprise one event involved in the intracellular mechanisms lying behind the growth factor-mediated growth of mammary epithelial cells. The effects of addition of different known isoprenoids on growth of cells subjected to HMG CoA reductase inhibition or growth factor depletion were also investigated. It was found that coenzyme Q and dolichol significantly delayed growth arrest in all three cell types. In contrast, cholesterol and isopentenyladenine were ineffective.

Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10.

Biochem Biophys Res Commun (UNITED STATES) Mar 30 1994

Relationships of nutrition and vitamins to the genesis and prevention of cancer are increasingly evident. In a clinical protocol, 32 patients having -"high-risk"- breast cancer were treated with antioxidants, fatty acids, and 90 mg. of CoQ10. Six of the 32 patients showed partial tumor regression. In one of these 6 cases, the dosage of CoQ10 was increased to 390 mg. In one month, the tumor was no longer palpable and in another month, mammography confirmed the absence of tumor. Encouraged, another case having a verified breast tumor, after non-radical surgery and with verified residual tumor in the tumor bed was then treated with 300 mg. CoQ10. After 3 months, the patient was in excellent clinical condition and there was no residual tumor tissue. The bioenergetic activity of CoQ10, expressed as hematological or immunological activity, may be the dominant but not the sole molecular mechanism causing the regression of breast cancer.

An expanded concept of "insurance" supplementation--broad-spectrum protection from cardiovascular disease.

Med Hypotheses (ENGLAND) Oct 1981, 7 (10) p1287-1302

The preventive merits of "nutritional insurance" supplementation can be considerably broadened if meaningful doses of nutrients such as mitochondrial "metavitamins" (coenzyme Q, lipoic acid, carnitine), lipotropes, and key essential fatty acids, are included in insurance supplements. From the standpoint of cardiovascular protection, these nutrients, as well as magnesium, selenium, and GTF-chromium, appear to have particular value. Sophisticated insurance supplementation would likely have a favorable impact on many parameters which govern cardiovascular risk--serum lipid profiles, blood pressure, platelet stability, glucose tolerance, bioenergetics, action potential regulation--and as a life-long preventive health strategy might confer substantial benefit. (111 Refs.)

Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure (interim analysis)

Clin Investig (GERMANY) 1993, 71 (8 Suppl) pS145-9

Digitalis, diuretics, and vasodilators are considered standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure, which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2500 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing drug surveillance study in 173 Italian centers. The daily dose of CoQ10 was 50-150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two- to seven-point scales. Preliminary results on 1113 patients (mean age 69.5 years) show a low incidence of side effects: 10 adverse reactions were reported in 8 (0.8%) patients, of which only 5 reactions were considered as correlated to the test treatment. After 3 months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 81%, edema 76.9%, pulmonary rales 78.4%, enlargement of the liver area 49.3%, jugular reflux 81.5%, dyspnea 54.2%, palpitations 75.7%, sweating 82.4%, arrhythmia 62%, insomnia 60.2%, vertigo 73%, and nocturia 50.7%.

[Effects of 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone (CV-2619) on adriamycin-induced ECG abnormalities and myocardial energy metabolism in spontaneously hypertensive rats]

Nippon Yakurigaku Zasshi (JAPAN) Oct 1982

Antidote actions of CV-2619 and ubiquinone-10 (Q-10) against adriamycin (ADM) cardiotoxicity were studied in spontaneously hypertensive rats. ADM (1 mg/kg/day, i.p.) elicited widening of the QRS complex in the ECG. The widening of the QRS complex was counteracted by a 10-day treatment with CV-2619 (10 and 30 mg/kg/day, p.o.) or Q-10 (10 mg/kg/day, p.o.), which was started on the 15th day of the ADM treatment. CV-2619 or Q-10, however, did not influence ADM-induced decrease in body and heart ventricular weights. Systemic hypotension caused by adriamycin was accelerated by CV-2619 or Q-10. The ADM treatment significantly decreased myocardial glycogen and glucose contents, while it did not affect the lactate content. Furthermore, ADM did not affect the myocardial content of adenine nucleotides, but significantly increased that of creatine phosphate. CV-2619 or Q-10 medication did not counteract changes in these contents by ADM. On the contrary, both agents decreased the lactate content and increased the phosphorylation potential, an index of myocardial energy state. In conclusion, CV-2619 might be as effective as Q-10 to protect the heart against ADM cardiotoxicity, and both test agents improved the myocardial energy state.

Effects of short-term supplementation with coenzyme Q10 on myocardial protection during cardiac operations

Annals of Thoracic Surgery (USA), 1996, 61/3 (829-833)

Background. Coenzyme Q10 (CoQ10) is a naturally occurring vitamin-like substance that may have a beneficial role in ischemia-reperfusion injury. Coenzyme Q10 administered either as an additive to cardioplegia or as long-term preoperative oral supplementation has been reported to ameliorate myocardial injury after cardiac operations. Methods. To determine whether short-term oral supplementation with large doses of CoQ10 (600 mg in divided doses 12 hours before operation) was effective in myocardial protection, 20 patients with well-preserved left ventricular function (ejection fraction greater than 0.50) undergoing elective coronary revascularization were enrolled in a prospective, double-blind, placebo-controlled, randomized trial. Serial concentrations of CoQ10, myoglobin, creatine kinase MB fraction, and cardiac troponin T were measured preoperatively and 1, 6, 24, 72, and 120 hours postoperatively. Efficacy of myocardial protection was also assessed by clinical outcome and serial changes in electrocardiographic indices. Results. The patient groups were similar with respect to preoperative and intraoperative characteristics. There was no significant difference in the preoperative plasma levels of CoQ10. These levels fell significantly in both groups after operation, although the magnitude of the decrease was less in the CoQ10-supplemented group (43% versus 60%). In both groups, there were significant postoperative increases in myoglobin, creatine kinase MB fraction, and cardiac troponin T. The magnitude of increases in cardiac troponin T was greater in the CoQ10-supplemented group, reaching marginal overall statistical significance (p = 0.06). Conclusions. Short-term supplementation with large doses of CoQ10 does not lead to improved myocardial protection in patients undergoing coronary revascularization with well-preserved ventricular function and relatively short ischemic times. (EDITOR=S NOTE: It takes about six weeks of coenzyme Q10 supplementation to fully saturate the tissues. Short-term CoQ10 therapy may have no value.)

Myocardial preservation by therapy with coenzyme Q10 during heart surgery

USA CLIN. INVEST. SUPPL. (Germany), 1993, 71/8 (S 155-S 161)

Coenzyme Q10 (CoQ10) is a natural and essential cofactor in the heart. It is the primary redox coupler in the respiratory chain, a potent free radical scavenger, and a superoxide inhibitor. In this study the myocardial protective effects of CoQ10 were determined in high-risk (n = 10) patients during heart surgery compared to that found in placebo controls (n = 10). In both groups, there was a blood CoQ10 deficiency (<0.6 microg/ml), low cardiac index (CI < 2.4 l/m2 per minute), and low left ventricular ejection fraction (LVEF <35%) before treatment. CoQ10 (100 mg per day) was given orally for 14 days before and 30 days after surgery. Presurgical CoQ10 treatment significantly (P < 0.01) improved blood and myocardial CoQ10 and myocardial ATP compared to that found in the control group. Cardiac functions (CI and LVEF) were improved but not significantly. After cardiac cooling, rewarming, and reperfusion; blood and tissue CoQ10 and tissue ATP levels were maintained in the normal ranges in the CoQ10 patients. Cardiac pumping (CI) and LVEF were significantly (P < 0.01) improved. The recovery course was short (3-5 days) and uncomplicated. In the control group blood and tissue CoQ10, tissue ATP levels, and cardiac functions were depressed after surgery. The recovery course was long (15-30 days) and complicated. Positive relationships between blood and myocardial CoQ10, myocardial ATP, cardiac function, and the postoperative recovery time and course found in both study groups show the therapeutic benefits of CoQ10 in preserving the myocardium during heart surgery. CoQ10 treatment is especially indicated in high-risk cardiac surgery patients who have a natural or clinically induced CoQ10 deficiency.

Effect of CoQ10 on myocardial ischemia/reperfusion injury in the isolated rat heart

Journal of the Japanese Association for Thoracic Surgery (Japan), 1995, 43/4 (466-472)

It has been reported to CoQ10, ubiquinone, may have a protective effect on the mitochrondrial injury induced by myocardial ischemia and reperfusion during open heart surgery. The purpose of this study was to investigate whether CoQ10 may enhance myocardial protection when given before ischemia, during ischemia or during reperfusion in the isolated working rat heart. Hearts (n = 6 - 9/group) from male Wistar rats were aerobically (37degreeC) perfused (20 min) with bicarbonate buffer. In the first series of studies, this was followed by a 3 min infusion of St. Thomas' Hospital cardioplegic solution containing various concentrations of CoQ10. Hearts were then subjected to 39 min of normothermic (37degreeC) global ischemia and 35 min of reperfusion (15 min Langendorff, 20 min working). The percent recovery of aortic flow (% AF) was 50.5 plus or minus 3.3% in the CoQ10, free controls versus 55.9 plus or minus 4.44, 62.1 plus or minus 5.4, 71.4 plus or minus 3.1% ((*)p < 0.05) in the 29, 44 and 58 micromol/L CoQ10 groups, respectively. Creatine kinase (CK) leakage during Langendorff reperfusion had a tendency to decrease in the 58 micromol/L group. In the second series of studies, 3 min of cardioplegia with 0 or 58 micromol/L of CoQ10 and 20 min working reperfusion. % AF was 53.2 plus or minus 2.7 and 39.2 plus or minus 7.1% in the 0 and 58 micromol/L CoQ10 groups, respectively. CK leakage had a tendency to increase in the 58 micromol/L group. In the third series of studies, 7.5 micromol of CoQ10 was administered over 10 min prior to a 3 min infusion of St. Thomas' Hospital cardioplegic solution. Hearts were then subjected to 36 min of normothermic (37degreeC) global ischemia and 35 min of reperfusion (15 min Langendorff, 20 min working). %AF was 43.8 plus or minus 1.8 and 47.5 plus or minus leakage between the two groups. Thus CoQ10 when given during ischemia, enhanced myocardial protection. This might indicate that CoQ10 could play an important role in the protective effect on mitochondrial dysfunction during myocardial ischemia.

Measurement of the ratio between the reduced and oxidized forms of coenzyme Q10 in human plasma as a possible marker of oxidative stress.

J Lipid Res (UNITED STATES) Jan 1996, 37 (1) p67-75

It has been postulated that lipid peroxidation plays a crucial role in the pathogenesis of atherosclerosis. As CoQ10H2 (reduced form of coenzyme Q10) is easily oxidized to CoQ10 (oxidized form of coenzyme Q10), it has been proposed that the CoQ10H2/CoQ10 ratio may be used as a possible marker of in vivo oxidative stress. However, sample preparation has an important effect on the redox status of coenzyme Q10 due to the extreme sensitivity of CoQ10H2 towards oxidation. We now report a rapid, simple isocratic HPLC procedure for the determination of CoQ10H2 and CoQ10 in plasma isopropanol extracts, and we used this method to investigate conditions by which the CoQ10H2/CoQ10 ratio can be reliably measured. Our results indicate that CoQ10H2 is unstable in whole blood, plasma, and isopropanol extracts; subsequently the CoQ10H2/CoQ10 ratio changes considerably soon after a blood sample has been obtained. The time period since blood sampling and HPLC analysis, as well as the sample pretreatment procedure, are two factors that have a profound effect on the pre-analytical variation in the determination of the CoQ10H2/CoQ10 ratio. If these two factors are properly controlled, the CoQ10H2/CoQ10 ratio may be a sensitive and practical way to measure in vivo oxidative stress. Furthermore, this indicator is independent from plasma total cholesterol concentrations, implying that groups who differ with respect to cholesterol levels may be compared directly.

The role of free radicals in disease

Australian and New Zealand Journal of Ophthalmology (Australia), 1995, 23/1

Evidence is accumulating that most of the degenerative diseases that afflict humanity have their origin in deleterious free radical reactions. These diseases include atherosclerosis, cancer, inflammatory joint disease, asthma, diabetes, senile dementia and degenerative eye disease. The process of biological ageing might also have a free radical basis. Most free radical damage to cells involves oxygen free radicals or, more generally, activated oxygen species (AOS) which include non-radical species such as singlet oxygen and hydrogen peroxide as well as free radicals. The AOS can damage genetic material, cause lipid peroxidation in cell membranes, and inactivate membrane-bound enzymes. Humans are well endowed with antioxidant defences against AOS; these antioxidants, or free radical scavengers, include ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), beta-carotene, coenzyme Q10, enzymes such as catalase and superoxide dismutase, and trace elements including selenium and zinc. The eye is an organ with intense AOS activity, and it requires high levels of antioxidants to protect its unsaturated fatty acids. The human species is not genetically adapted to survive past middle age, and it appears that antioxidant supplementation of our diet is needed to ensure a more healthy elderly population.

Coenzyme Q10 and coronary artery disease

CLIN. INVEST. SUPPL. (Germany), 1993, 71/8

It has been postulated that oxidatively modified low-density lipoprotein (LDL) contributes to the genesis of atherosclerosis. Ubiquinone has been suggested to be an important physiological lipid-soluble antioxidant and is found in LDL fractions in the blood. We measured plasma level of ubiquinone using high-performance liquid chromatography and plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in 245 normal subjects (186 males, 59 females) and in 104 patients (55 males, 49 females) who had coronary artery disease not receiving pravastatin and 29 patients (12 males, 17 females) receiving pravastatin. In the normal subjects, the plasma ubiquinone levels did not vary with age. In the patient groups, the plasma total cholesterol and LDL levels were higher and the plasma ubiquinone level lower than in the normal subject group. The LDL/ubiquinone ratio was higher in the patient groups. We found that ubiquinone level, either alone or when expressed in relation to LDL levels, was significantly lower in the patient groups compared with the normal subject group. The 3-hydroxy-3-methylglutaryl coenzyme A (HMC CoA) reductase inhibitor is thought to prevent atherosclerosis, however, it also inhibits ubiquinone production. The present study revealed that HMG CoA reductase inhibitor decreased plasma cholesterol level, and that it did not improve either the ubiquinone level or the LDL/ubiquinone ratio. From these results, the LDL/ubiquinone ratio is likely to be a risk factor for atherogenesis, and administration of ubiquinone to patients at risk might be needed.

Isoprenoids (coQ10) in aging and neurodegeneration.

Neurochem Int (ENGLAND) Jul 1994, 25 (1) p35-8

During aging the human brain shows a progressive increase in levels of dolichol, a reduction in levels of ubiquinone, but relatively unchanged concentrations of cholesterol and dolichyl phosphate. In a neurodegenerative disease, Alzheimer's disease, the situation is reversed with decreased levels of dolichol and increased levels of ubiquinone. The concentrations of dolichyl phosphate are also increased, while cholesterol remains unchanged. This study shows that the isoprenoid changes in Alzheimer's disease differ from those occurring during normal aging and that this disease cannot, therefore, be regarded as a result of premature aging. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of glycosylation in the diseased brain and the increase in the endogenous anti-oxidant ubiquinone an attempt to protect the brain from oxidative stress, for instance induced by lipid peroxidation.

Muscle biopsy in Alzheimer's disease: Morphological and biochemical findings

CLIN. NEUROPATHOL. (Germany), 1991, 10/4 (171-176)

Recent evidences of a predisposing genetic factor associated with Alzheimer's disease (DAT) suggests that important alterations may be expressed in tissues other than the brain. We present morphological and biochemical studies on muscle obtained from ten patients with Alzheimer's disease and coeval controls. Muscle biopsy examination showed an increased subsarcolemmal mitochondrial oxidative activity in three patients. The biochemical studies showed an increased oxidative enzyme activity only in the DAT group. The CoQ10 level, studied so far in three DAT patients, was greatly reduced (similar50%) compared with controls. Possible new peripheral markers in Alzheimer's disease will be discussed.

Relevance of the biosynthesis of coenzyme Q10 and of the four bases of DNA as a rationale for the molecular causes of cancer and a therapy

Biochemical and Biophysical Research Communications (USA), 1996, 224/2 (358-361)

In the human, coenzyme Q10(vitamin Q10) is biosynthesized from tyrosine through a cascade of eight aromatic precursors. These precursors indispensably require eight vitamins, which are tetrahydrobiopterin, vitamins B6 C, B2, B12, folic acid, niacin, and pantothenic acid as their coenzymes. Three of these eight vitamins (the coenzyme B6 and the coenzymes niacin and folic acid) are indispensable in the biosynthesis of the four bases (thymidine, guanine, adenine, and cytosine) of DNA. One or more of the three vitamins required for DNA are known to cause abnormal pairing of the four bases, which can then result in mutations and the diversity of cancer. The coenzyme B6 required for the conversion of tyrosine to p-hydroxybenzoic acid, is the first coenzyme required in the cascade of precursors. A deficiency of the coenzyme B6 can cause dysfunctions, prior to the formation of vitamin Q10 to DNA. Former data on blood levels of Q10 and new data herein on blood levels of B6, measured as EDTA, in cancer

patients established deficiencies of Q10 and B6 in cancer. This complete biochemistry relating to biosyntheses of Q10 and the DNA bases is a rationale for the therapy of cancer with Q10 and other entities in this biochemistry.

Natural products and their derivatives as cancer chemopreventive agents

Progress in Drug Research (Switzerland), 1997, 48/- (147-171)

This review summarizes currently available data on the chemopreventive efficacies, proposed mechanisms of action and relationships between activities and structures of natural products like vitamin D, calcium, dehydroepidandrosterone, coenzyme Q10, celery seed oil, parsley leaf oil, sulforaphane, isoflavonoids, lignans, protease inhibitors, tea polyphenols, curcumin, and polysaccharides from Acanthopanax genus.

Thesis of coenzyme Q10 and of the four bases of DNA as a rationale for the molecular causes of cancer and a therapy

Biochemical and Biophysical Research Communications (USA), 1996, 224/2 (358-361)

In the human, coenzyme Q10(vitamin Q10) is biosynthesized from tyrosine through a cascade of eight aromatic precursors. These precursors indispensably require eight vitamins, which are tetrahydrobiopterin, vitamins B6 C, B2, B12, folic acid, niacin, and pantothenic acid as their coenzymes. Three of these eight vitamins (the coenzyme B6 and the coenzymes niacin and folic acid) are indispensable in the biosynthesis of the four bases (thymidine, guanine, adenine, and cytosine) of DNA. One or more of the three vitamins required for DNA are known to cause abnormal pairing of the four bases, which can then result in mutations and the diversity of cancer. The coenzyme B6 required for the conversion of tyrosine to p-hydroxybenzoic acid, is the first coenzyme required in the cascade of precursors. A deficiency of the coenzyme B6 can cause dysfunctions, prior to the formation of vitamin Q10 to DNA. Former data on blood levels of Q10 and new data herein on blood levels of B6, measured as EDTA, in cancer patients established deficiencies of Q10 and B6 in cancer. This complete biochemistry relating to biosyntheses of Q10 and the DNA bases is a rationale for the therapy of cancer with Q10 and other entities in this biochemistry.