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LE Magazine January 1999

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Blood Cholesterol Debate: a History
Despite a preponderance of evidence, agency foot-dragging retarded progress


Federal Register: 12/10/59

Status of Articles Offered to the General Public for the Control or Reduction of Blood Cholesterol Levels and for the Prevention and Treatment of Heart and Artery Disease Under the Federal Food, Drug, and Cosmetic Act

(a) There is much public interest and speculation about the effect of various fatty foods on blood cholesterol and the relationship between blood cholesterol levels and diseases of the heart and arteries. The general public has come to associate the term "cholesterol" with these diseases. A number of common food fats and oils and some other forms of fatty substances are being offered to the general public as being of value in the control or reduction of blood cholesterol levels and for the prevention or treatment of diseases of the heart or arteries.

(b) The role of cholesterol in heart and artery diseases has not been established. A causal relationship between blood cholesterol levels and these diseases has not been proved. The advisability of making extensive changes in the nature of the dietary fat intake of the people of this country has not been demonstrated.

(c) It is therefore the opinion of the Food and Drug Administration that any claim, direct or implied, in the labeling of fats and oils or other fatty substances offered to the general public that they will prevent, mitigate, or cure diseases of the heart or arteries is false or misleading, and constitutes misbranding within the meaning of the Federal Food, Drug, and Cosmetic Act.


Federal Register: 5/18/65

Oils, Fats, and Fatty Foods for Regulating Intake of Fatty Acids in Dietary Management: Proposal To Require Label Statements

There was published in the Federal Register for December 10, 1959, a statement of policy by the Food and Drug Administration concerning the status of articles offered to the general public for the control or reduction of blood cholesterol levels and for the prevention and treatment of heart and artery disease under the Federal Food, Drug, and Cosmetic Act. The policy statement expressed the view that any claim, whether direct or implied in the labeling of fats and oils or other fatty substances offered to the general public, that such food will prevent, mitigate, or cure heart or artery disease is false and misleading and is considered misbranding under the Federal law.

At the time of publication of the statement of policy, the Food and Drug Administration pointed out that the policy statement does not interfere in any way with legitimate research and clinical evaluation of the possible role of unsaturated fats in the diet in lowering blood cholesterol and preventing heart disease.

In May 1964, the Food and Drug Administration reported the results of a consumer survey which showed that labeling terms such as "polyunsaturated," "unsaturated," "low in cholesterol," and similar statements misled many people to believe that these foods reduce blood cholesterol and thus are effective in treating or preventing heart and artery diseases. Other misleading phrases include "ask your doctor," "better for people's health," "are you concerned about saturated fats," and "better for you because it's made from 100 percent golden corn oil."

In the light of the survey results, in 1964 the Food and Drug Administration reaffirmed its official statement policy of December 10, 1959. The commissioner again pointed out that the policy statement did not and does not interfere in any way with legitimate research and clinical evaluation of unsaturated fats in the diet, but does intend to prevent the promotion of foods to the lay public for their use without medical supervision in attempting to reduce blood cholesterol.

Since the release of the consumer survey report, the Food and Drug Administration has received a recommendation from the clinicians working in this field of medicine that labeling statements be allowed to assist them in recommending food to their patients that would help guide the patient in selecting the kind of diet his physician has prescribed for him....

Also, the Food and Drug Administration has received a recommendation from the American Diabetes Association that labeling requirements be established that would provide for label statements of precise percentages of the polyunsaturated, monounsaturated and saturated fatty acid content of edible oils and fats.

Therefore, in response to such requests, and without in any way modifying the prior statement of policy or of endorsing these proposals, and pursuant to the authority provided in the Federal Food, Drug, and Cosmetic Act...the following regulations are proposed in order to provide proponents an opportunity to support a regulation that will carry out their recommendations.

ยง 125-Label statement relating to oils, fats, and fatty foods used as a means of regulating the intake of fatty acids in dietary management.

(a) If a food purports to be or is represented for special dietary use by man by reason of its use as a means of regulating the intake of fatty acids, its label shall bear an accurate statement of the number of grams of saturated fatty acids, the number of grams of monounsaturated acids, and the number of grams of polyunsaturated fatty acids contained in an ordinary serving, and in 100 grams of the food.

(b) Compliance with the provisions of subparagraph (a) of this section shall not be construed as relieving any food from compliance with the requirements of section 403(a) of the Federal Food, Drug, and Cosmetic Act.


Hypercalcemia and clodronate

Comparison of three intravenous bisphosphonates in cancer-associated hypercalcemia

Ralston SH, Gallacher SJ, Patel U, Dryburgh FJ, Fraser WD, Cowan RA, Boyle IT
University Department of Medicine, Glasgow Royal Infirmary.
Lancet (1989 Nov 18) 2(8673):1180-2

Three intravenous bisphosphonates were compared in the treatment of cancer-associated hypercalcemia. Forty-eight patients were randomly allocated to one of three treatment groups (each with 16 subjects)-30 mg pamidronate or 600 mg clodronate, both as single intravenous infusions; or etidronate as three infusions of 7.5 mg/kg per day for three consecutive days. Patients were rehydrated with normal saline before bisphosphonate treatment. All three bisphosphonates lowered serum calcium by inhibiting bone resorption; pamidronate was the most potent in this respect. By comparison with the other groups, more patients in the pamidronate group became normocalcemic, and the effect on serum calcium was apparent sooner and lasted longer.


Clodronate and breast cancer

Reduction in new metastases in breast cancer with adjuvant clodronate treatment

Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, Kaufmann M, Bastert G
Department of Obstetrics and Gynecology, University of Heidelberg, Germany.
N Engl J Med (1998 Aug 6) 339(6):357-63

Background: Bisphosphonates are effective against the increased bone resorption caused by certain diseases because they inhibit the activity of osteoclasts. In patients who have breast cancer and metastatic bone disease, the bisphosphonate clodronate (clodronic acid) reduces the frequency of skeletal complications. Experiments in animals and preliminary clinical observations indicate that early clodronate therapy reduces the incidence of new bony metastases in breast cancer.

We investigated the effects of clodronate on the incidence and extent of new metastases in patients with breast cancer.

Methods: Between 1990 and 1995, 302 patients with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastases) were randomly assigned to receive clodronate at a dose of 1,600 mg per day orally for two years (157 patients) or standard follow-up (145 patients). The median length of observation was 36 months. All patients in both groups received standard surgical treatment and customary hormonal therapy or chemotherapy.

Results: Distant metastases were detected in 21 patients in the clodronate group and in 42 patients in the control group (P<0.001). The incidence of both osseous and visceral metastases was significantly lower in the clodronate group than in the control group (P=0.003 for both osseous and visceral metastases). Six patients in the clodronate group died, as did 22 in the control group (P=0.001). The mean number of bony metastases per patient in the clodronate group was roughly half that in the control group (3.1 vs. 6.3).

Conclusions: Clodronate can reduce the incidence and number of new bony and visceral metastases in women with breast cancer who are at high risk for distant metastases.


Clodronate efficacy

Clodronate.

Kanis JA, McCloskey EV
World Health Organization Collaborating Centre for Metabolic Bone Diseases, Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, United Kingdom.
Cancer (1997 Oct 15) 80(8 Suppl):1691-5

Clodronate is a second-generation bisphosphonate of intermediate potency between etidronate and aminobisphosphonates. It is an effective inhibitor of bone resorption, but unlike etidronate does not impair the mineralization of bone. Unlike pamidronate, it can be given both intravenously and orally. There is wide experience in the use of clodronate in the management of patients of hypercalcemia. The most widely used therapeutic regimen is 300 mg intravenously repeated for 5 days or a single infusion of 1,500 mg. Efficacy is nearly complete in patients with myelomatosis, less complete in solid tumors with hypercalcemia but without skeletal metastases, and intermediate in patients with solid tumors in the presence of skeletal metastases. Variations in effect appear to be due to differences in renal tubular reabsorption of calcium between the three disorders.

Placebo-controlled studies examining the effects of clodronate on bone pain in the absence of hypercalcemia have shown significant decreases in the severity of bone pain. These findings, coupled with the knowledge that suppression of bone resorption persists for the duration of treatment, has led to the long-term use of oral doses of clodronate to decrease the incidence of complications of osteolytic bone disease. The long-term control of bone resorption with oral clodronate has been demonstrated by double-blind histologic studies. The ultimate arbiter of the value of clodronate is whether it decreases the skeletal morbidity associated with osteolysis.

Double-blind prospective controlled studies suggest that the incidence of bone pain, fracture, and hypercalcemia can be decreased significantly in patients with breast carcinoma. In addition, the use of long-term clodronate in patients with myelomatosis significantly decreases the progression of osteolytic bone lesions, the risk of fractures, and the incidence of hypercalcemia. These studies have raised the possibility that bone disease might be prevented in individuals at high risk.

Double-blind prospective studies in women with recurrent breast carcinoma but no evidence of skeletal metastases showed a small effect of clodronate in decreasing the proportion of women developing metastatic disease. However, there was a large and significant decrease in the number of skeletal metastases associated with a decrease in skeletal morbidity.

These observations suggest that clodronate may modify the natural history of the expression of skeletal disease, and thereby significantly improve the quality of life of affected patients.


Clodronate's effects on osteoclasts

Use of dichloromethylene diphosphonate in metastatic bone disease

Jung A, Chantraine A, Donath A, van Ouwenaller C, Turnill D, Mermillod B, Kitler ME
N Engl J Med (1983 Jun 23) 308(25):1499-501

Dichloromethylene diphosphonate (clodronate), a new compound, has powerful activity against osteoclasts and has been used successfully to treat hypercalcemia associated with cancer. We studied its effects on calcium balance in patients with malignant osteolytic lesions. Ten normocalcemic patients with advanced metastatic bone disease or myeloma were evaluated in a baseline 20-day balance and calcium kinetic study. They were then randomized to a clodronate or placebo regimen, treated intravenously for two weeks and orally for a month, and finally reevaluated in another 20-day balance and kinetic study, conducted while they were still receiving treatment. The results show that both calcium balance and calcium absorption increased from base line in the clodronate group and that these changes were significantly different from those in the placebo group (mean change [+/- S.D.] in calcium balance [clodronate vs. placebo], 203.8 +/- 140.1 vs.-65.2 +/- 98.8 mg [5.1 +/- 3.5 vs.-1.6 +/- 2.5 mmol] of calcium per day, P less than 0.01; change in calcium absorption, 158.8 +/-158 vs. -38.2 +/- 96.0 mg [4.0 +/-4.0 vs. -1.0 +/- 2.4 mmol] per day, P less than 0.05). There was a marginal decrease in bone resorption in the clodronate group and no change in bone accretion. Our results suggest that clodronate may be a useful adjuvant in managing metastatic bone disease.


Pain location

Differences of bone alkaline phosphatase isoforms in metastatic bone disease and discrepant effects of clodronate on different skeletal sites indicated by the location of pain

Magnusson P, Larsson L, Englund G, Larsson B, Strang P, Selin-Sjogren L
Department of Biomedicine and Surgery, Linkoping University Hospital, Sweden. Per.Magnusson@klk.liu.se
Clin Chem (1998 Aug) 44(8 Pt 1):1621-8

We compared clodronate with placebo administration in 42 primarily or secondarily hormone-refractory prostate cancer patients with skeletal metastases and persisting pain. Serum total alkaline phosphatase (ALP), bone ALP isoforms, osteocalcin, cross-linked carboxy-terminal telopeptide of type I collagen, and prostate-specific antigen were analyzed before and after 1 month of treatment. Six ALP isoforms were quantified by HPLC: One bone/intestinal, two bone (B1, B2), and three liver ALP isoforms.

The most apparent difference compared with healthy males was observed for the bone ALP isoform B2. Patients and healthy males had a B2 activity corresponding to 75% and 35% of the total ALP activity, respectively (P<0.0001). We propose that the different bone ALP isoforms reflect different stages of osteoblast differentiation during the extracellular matrix maturation phase of osteogenesis. All bone markers except osteocalcin increased after 1 month of clodronate administration. These increases were associated with pain only in the upper part of the body. We suggest that the uptake of clodronate by the skeleton was not uniform during our treatment period.


Coenzyme Q10 and neuroprotection

Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects

Matthews RT, Yang L, Browne S, Baik M, Beal MF
Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A 1998 Jul 21;95(15):8892-7

Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats, administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.


Chemoprotection

The chemoprotective effect of coenzyme Q on lipids in paint and lacquer industry workers

Dlugosz A, Sawicka E
Department of Toxicology Wroclaw University of Medicine, Poland.
Int J Occup Med Environ Health 1998;11(2):153-63

The influence of coenzyme Q on the lipid parameters in paint and lacquer industry workers is presented. The examinations were carried out in the group of 24 workers employed at paint and lacquer production, who received coenzyme Q10 as a chemoprotective agent. Serum concentration of basic lipid parameters: total cholesterol (TC), high density lipoproteins (HDL), low density lipoproteins (LDL), triglycerides (TG); lipid peroxidation products: malonyldialdehyde (MDA) together with 4-hydroxynonenal (4-HNE) and two antioxidant enzymes: superoxide dismutase (SOD) and glutathione peroxidase (GPx) were examined. The above parameters were measured in workers exposed to organic solvents and then after 4 weeks of coenzyme Q treatment. In order to explain whether the occupational exposure is responsible for the changed level of some parameters. The reference group, not employed in the pain and lacquer industry, was used.

The results indicated that the preliminary blood serum concentration of MDA + 4-HNE in workers exposed to organic solvents was significantly elevated in comparison to the control group. Statistically significant decrease in MDA + 4HNE concentration was observed after coenzyme Q treatment, which led to the conclusion that coenzyme Q could be considered as a protective agent against lipid peroxidation in occupational exposure. The changes in other parameters were statistically insignificant.


CoQ10, arterial tone

Control of arterial tone after long-term coenzyme Q10 supplementation in senescent rats

Lonnrot K, Porsti I, Alho H, Wu X, Hervonen A, Tolvanen JP
Laboratory of Neurobiology, University of Tampere, Medical School, Finland
Br J Pharmacol 1998 Aug;124(7):1500-6

Age-associated deterioration of arterial function may result from long-lasting oxidative stress. Since coenzyme Q (Q10) has been suggested to protect the vascular endothelium from free radical-induced damage, we investigated the effects of long-term dietary Q10 supplementation on arterial function in senescent Wistar rats. At 16 months of age, 18 rats were divided into two groups. The control group was kept on a standard diet while the other group was supplemented with Q10 (10 mg kg-1 day-1). In addition, nine rats (age 2 months) also ingesting a standard diet were used as the young control group. After 8 study weeks the responses of the mesenteric arterial rings in vitro were examined. Endothelium-independent arterial relaxations to isoprenaline and nitroprusside (SNP) were attenuated in aged rats. Increased dietary Q10 clearly enhanced the relaxation to isoprenaline, but did not affect the response to SNP. In addition, vasodilation of noradrenaline-precontracted rings to acetylcholine (ACh), which was also impaired in aged vessels, was improved after Q10 supplementation. Cyclooxygenase inhibition with diclofenac enhanced the relaxation to ACh only in young rats, while it abolished the difference between the old controls and Q10 supplemented rats, suggesting that the improved endothelium-dependent vasodilation observed in Q10-supplemented rats was largely mediated by prostacyclin (PGI2). In conclusion, long-term Q10 supplementation improved endothelium-dependent vasodilation and enhanced beta-adrenoceptor-mediated arterial relaxation in senescent Wistar rats. The mechanisms underlying the improvement of endothelial function may have included augmented endothelial production of PGI2, increased sensitivity of smooth muscle to PGI2, or both.


Hemorrhagic stroke

Hemorrhagic stroke in humans pretreated with coenzyme Q10: Exceptional recovery as seen in animal models

Journal of Orthomolecular Medicine (Canada), 1998, 13/2 (105-109)

Minimizing neurologic injury from Fstoke is still the elusive goal of large scale controlled clinical trials of new synthetic agents whose efficacy is dependent upon prompt post-insult administration. In 26 years of animal model stroke studies, one substance that afforded a markedly higher degree of protection than all others tested was a normal endogenous molecule, coenzyme Q10(Q10). Because of increasing worldwide use of Q10, we are able serendipidously to report on possibly the first observation of a human recovering almost completely from an unexpected cerebral hemorrhage following four weeks of pretreatment with Q10 at a pharmacologic dose commonly employed for a wide variety of disorders. Clearly, clinical studies are needed to confirm the significance of our observed result. These would be facilitated by the safety and efficacy of Q10 already proven in nine large scale international trials in cardiomyopathy, etc., and its apparent benefits in numerous disorders, including AIDS and possibly aging itself. However, the confirmation should be done in trials specifically designed for stroke because of detection difficulty arising from the anticipated protection. If confirmed, this result may facilitate the realization of synthetic stroke agents by decreasing the protective functions needed from the agent.


Ephedrine, caffeine

The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial

Astrup A, Breum L, Toubro S, Hein P, Quaade F
Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Frederiksberg, Copenhagen, Denmark.
Int J Obes Relat Metab Disord (1992 Apr) 16(4):269-77

The sympathomimetic agent ephedrine has potent thermogenic and anti-obesity properties in rodents. The effect is markedly enhanced by caffeine, while caffeine given alone has no effect. This study was undertaken to find out if a similar weight-reducing synergism between ephedrine and caffeine is present in obese patients. In a randomized, placebo-controlled, double blind study, 180 obese patients were treated by diet (4.2 MJ/day) and either an ephedrine/caffeine combination (20 mg/200 mg), ephedrine (20 mg), caffeine (200 mg) or placebo three times a day for 24 weeks. Withdrawals were distributed equally in the four groups, and 141 patients completed the trial. Mean weight losses was significantly greater with the combination than with placebo from week 8 to week 24 (ephedrine/caffeine, 16.6 +/- 6.8 kg vs. placebo, 13.2 +/- 6.6 kg (mean +/- s.d.), P = 0.0015). Weight loss in both the ephedrine and the caffeine groups was similar to that of the placebo group. Side effects (tremor, insomnia and dizziness) were transient and after eight weeks of treatment they had reached placebo levels. Systolic and diastolic blood pressure fell similarly in all four groups. We conclude, that in analogy with animal studies, the ephedrine/caffeine combination is effective, while caffeine and ephedrine separately are ineffective for the treatment of human obesity.


Ephedrine/caffeine vs. dexenfluramine

Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-center trial in general practice

Breum L, Pedersen JK, Ahlstrom F, Frimodt-Moller J
Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Hadsund, Denmark.
Int J Obes Relat Metab Disord (1994 Feb) 18(2):99-103

In previous separate studies, dexfenfluramine (DF) and ephedrine/caffeine (EC) have been shown to promote weight loss in obese patients as compared with placebo. In order to compare the efficacy and safety of these two anorectic drugs, 103 patients with 20-80% overweight were included in a 15-week double-blind study in general practice. Patients were randomized to either 15 mg DF twice daily (n = 53), or 20 mg/200 mg ephedrine/caffeine three times a day (n = 50), supplementary to a 5 MJ/day diet. Forty-three patients from the DF group and 38 from the EC group completed the study. After 15 weeks of treatment, the DF group (n = 43) had lost 6.9 +/- 4.3 kg and the EC group (n = 38) had lost 8.3 +/- 5.2 kg (mean +/- s.d., P = 0.12). In the subgroup of patients with BMI > or = 30 kg/m2 (n = 59), the mean weight loss was 7.0 +/- 4.2 kg in the DF group (n = 29) and 9.0 +/- 5.3 kg in the EC group (n = 30), P < 0.05. Both systolic and diastolic blood pressures were reduced similarly during both treatments. Twenty-three patients in the DF group (43%) and 27 in the EC group (54%) complained of side effects. Central nervous system side-effects, especially agitation, were more pronounced in the EC group (P < 0.05), whereas gastro-intestinal symptoms were more frequent in the DF group (P < 0.05). The side effects declined markedly during the first month of treatment in both groups.


Ephedrine, diabetes

Ephedrine: a new treatment for diabetic neuropathic edema.

Edmonds ME, Archer AG, Watkins PJ
Lancet (1983 Mar 12) 1(8324):548-51

Peripheral edema secondary to diabetic neuropathy is poorly understood and difficult to treat. Ephedrine markedly reduced neuropathic edema in four insulin-dependent diabetics. Mean weight- loss (p less than 0 . 05) after 7 days' treatment was 7 . 43 +/- 4 . 51(SD) kg. The edema returned (mean weight increase 6 . 33 +/- 1 . 73 kg; p less than 0 . 01) when ephedrine was withdrawn but resolved (weight-loss 4.85 +/- 1 . 57 kg; p less than 0 . 01) when ephedrine treatment was repeated. In one patient mean 24-hour sodium excretion increased from 177 +/- 5 . 20 mmol before ephedrine to 502 +/- 78 mmol on ephedrine therapy (p=0 . 028). Ephedrine also reduced excessive peripheral blood flow produced by the neuropathy; both arterial diastolic flow and arteriovenous shunting as demonstrated by Doppler blood velocity profiles were reduced and the pulsatility index increased from 2 . 50 +/- 0 . 61 to 4. 75 +/- 1 . 76 (p less than 0 . 001). Ephedrine continues (12-15 months) to be an effective treatment for neuropathic edema in these four patients.



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