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Articles

Gender May Affect the Action of Garlic Oil on Plasma Cholesterol and Glucose Levels of Normal Subjects^{1 ,2 ,3}

Xiao-Hua Zhang, Derek Lowe^*, Paul Giles, Stephen Fell, Martin J. Connock^** and David J. Maslin⁴

Division of Biomedical Sciences and Human Biology, School of Health Sciences, University of Wolverhampton, Wolverhampton WV1 1DJ, UK; ^* Astraglobe Limited, Mossley, Cheshire, UK; Biochemistry Department, Walsall NHS Trust, The Manor Hospital, Walsall WS2 9PS, UK; and ^** School of Applied Sciences, University of Wolverhampton, Wolverhampton WV1 1SB, UK

⁴To whom correspondence should be addressed. E-mail: D.Maslin{at}wlv.ac.uk.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Early trials of garlic preparations on blood lipids mainly supported a lipid-lowering effect, whereas later well-designed garlic tablet trials were mainly entirely null. However, enteric simulation tests suggest that this discordance may result from ineffective delivery of bioactive agents from the brands of garlic powder (GP) and cyclodextrin-bound garlic oil (GO) tablets tested in some recent negative trials. In contrast, enteric simulation tests show that the preformed bioactive agents present in "traditional" gelatin capsules of GO are efficiently released, although such capsules have rarely been investigated in lipid-lowering trials. It was hypothesized that gelatin capsules of GO given to normal subjects would improve specified coronary heart disease risk factors. Effects of a GP preparation were also investigated. Subjects (n = 51; men and women, mean age 27 y) were randomly assigned to receive either 8.2 mg/d of GO (allyl sulfides) or placebo for 11 wk. Another 27 subjects received garlic powder (GP) of similar biopotential (7.8 mg allicin/d). Outcome measures were 95% confidence intervals (CI) between GO and placebo groups for differences between baseline and subsequent sample times. Men and women combined showed no significant differences save for an improved total antioxidant capacity at 6 wk (P = 0.01). Hence, no benefit from GO after 11 wk is one plausible conclusion. However, there were significant differences in effect of GO between men and women for HDL cholesterol (HDL-C) (P = 0.004) and total cholesterol (TC)/HDL-C (P = 0.003). Women showed favorable effects in terms of CHD risk factors (i.e., increases in HDL-C and reductions in TC/HDL-C), whereas men had small adverse effects. There was a significant difference in the GO effect for glucose (P = 0.006), with a reduction seen for men and an increase for women. The gender effects were unexpected and such analyses were not planned in advance. Confirmation of these findings with larger numbers of subjects would have importance for the use of garlic against CHD and for the design of future garlic studies.

KEY WORDS: • plasma lipids • antioxidants • gender • garlic • normal men and women

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Reduction in coronary heart disease (CHD)⁵ risk is an objective of affluent societies and has become a major reason for garlic consumption (1) . The pharmacologic activities of garlic, including its claimed lipid-lowering effects, depend upon sulfur-rich compounds, most notably allicin (2 ,3) . Allicin and its derivatives give rise to the characteristic odor and taste of garlic (3) . Allicin (allyl 2-propene thiosulfinate) is formed instantaneously when garlic is crushed because cellular disruption brings the enzyme alliinase into contact with its substrate alliin (allylcysteine sulfoxide). Allicin itself has limited stability; thus, commercial products containing garlic powder (GP), the preparations used in most human trials (2) , rely for their allicin delivery, not upon allicin content, but upon the retention of their alliin and alliinase intact until the intestine is reached. Heat, as applied during cooking or the commercial steam distillation of garlic to produce steam-distilled garlic oil (GO), converts the allicin of crushed garlic to allyl sulfides (2) .

Numerous studies have demonstrated biological activity for allicin and a variety of its derivatives including allyl sulfides (2 ,3) . However, in vivo, such garlic derivatives have no detectable metabolites in blood or urine (3) so that direct pharmacokinetic studies are lacking, and the active components of garlic derivable from allicin remain uncertain. Recent breath analysis studies using gas chromatography indicated rapid metabolism of garlic and appear to offer a feasible means of assessing the bioavailability of garlic materials (3 ,4) .

Many animal studies (2 ,3 ,5) have suggested that garlic favorably influences CHD risk factors. Of the >60 human trials of the lipid-lowering effects of garlic, most provided alliin/allicin standardized GP tablets, and most were positive in outcome (3) , as were two meta-analyses (1 ,6) showing significant decreases in total cholesterol (TC) averaging 10%. However, many studies, including some incorporated into meta-analyses, have been criticized for shortcomings of design and description (7 ,8) . The latest meta-analysis (9) revealed a relatively small (5.8%) overall reduction in TC, reflecting the inclusion of several recent well-designed trials that were entirely negative (10 11 12 13) . Ten of the 13 trials in this meta-analysis, including all but one of the recent entirely negative trials, tested the same alliin-standardized GP tablet product ("Kwai," Lichtwer Pharma GmbH, Berlin, Germany). For 23 trials of Kwai reported between 1986 and 1994, almost uniformly significant reductions (11%) in serum cholesterol were reported (3) . However, scrutiny of label descriptions revealed that the formulation of Kwai was altered in 1992–1993, possibly affecting the bioavailability of allicin (14 ,15) . That this was the case is supported by the investigation of batches of tablets from 1994 to 1997 using USP Method 724A to simulate gastrointestinal conditions. This found very low release, with only 14–18% of the potential allicin yield. In contrast, batches dating from 1989 to 1992 released 36–61% of their possible allicin yield. In view of their timing, it seems likely that the wholly negative studies of Kwai conducted since 1995 (10 11 12 ,16 ,17) utilized the reformulated tablets that apparently had very low allicin availability. A negative study of GO tablets (13) , which was also included in the most recent meta-analysis (9) was the first well-designed trial of the TC-lowering effects of GO. However, subsequent tests using USP Method 724A as well as fecal examination indicated low bioavailability of GO from the tablets used, in which GO is bound to cyclodextrin (40) . Thus, the smaller TC reductions compared with earlier estimates that were identified in the most recent meta-analysis (9) may merely reflect poor bioavailability of alliin-derived garlic components in several of the included trials.

In the two most recent trials of lipid-lowering, results for GP tablets were null (18) and positive (19) , respectively. Application of USP Method 724A revealed no detectable allicin for the unnamed GP tablet brand of the null trial, whereas in the positive trial, the significant reduction of TC and LDL cholesterol (LDL-C) reported was associated with intake of enteric-coated (acid-resistant) GP tablets for which complete allicin release was indicated (15) .

Summarizing, the current controversy associated with recent studies reporting null effects of garlic may have resulted mainly from low bioavailability of alliin derivatives in the garlic preparations consumed; thus, they should not overinfluence judgments concerning the TC-lowering ability of garlic.

Relative to TC, less attention has been paid to effects of garlic on plasma triglycerides (TG), although a meta-analysis of eight studies (1) indicated a significant 13% reduction, and >30 earlier (i.e., pre-1993) studies almost uniformly showed reductions that were mostly significant (2) .

In an early study (20) , large reductions in the blood and urine sugar levels of two diabetic subjects were observed after ingestion of 10–15 g fresh garlic/d. More recent animal studies (21 ,22) and a single recent human trial using GP tablets (23) indicated that garlic can lower blood glucose. Increased levels of insulin were observed in ethanol-fed rats given GO (24 ,25) , although when given in very large doses (100 mg/kg), a major constituent of GO, diallyl disulfide, was reported to be hyperglycemic (26) .

In vitro and whole-animal studies indicate an antioxidant action of garlic (2 ,27) . Reduced susceptibility of LDL to copper-catalyzed oxidation was reported for samples from healthy human subjects administered Kwai GP tablets in an early study (28) . Negative results with Kwai that followed (16 ,29) are questionable because of likely low allicin bioavailability (see above, 15 ) which may also explain the inability of Harris to replicate his earlier positive findings (Harris W. S., Lipid and Diabetes Research Center, Saint Luke’s Hospital, Kansas City, MO, personal communication). Null effects of GO on plasma and LDL total antioxidant capacity (TAOC) were recently reported for male runners (30) .

Aspects of dose strategy may be important factors influencing the response of human subjects to garlic, but few trials have compared different dose levels (31 32 33) . Moreover, most trials included in meta-analyses have provided garlic only as a single daily dose of 600–900 mg Kwai GP (equivalent to 1.5–2.3 g fresh clove with "allicin potential" of 3.6–5.4 mg). However, these garlic doses could be rather low because, on the basis of traditional knowledge, daily doses of "4 g fresh garlic cloves or 8 mg volatile oil [i.e., GO]" has been recommended for qualification as a pharmaceutical garlic product (34) .

Garlic dose periods of 3 mo or less have been used in most lipid-lowering studies (2) , and the greatest cholesterol-lowering response has been reported for dose periods of this duration (1) . Longitudinal studies (35 ,36) have been infrequent, and data describing dose "washout" responses are unavailable, thus potentially limiting the validity of garlic crossover trials (13 ,16 ,33 ,37 ,38) . Few trials of GO (13 , 39) and only one other randomized controlled trial of GO in its "traditional" gelatin capsule format (in which allicin-derived sulfides are diluted in vegetable oil) (30) have been reported. This is remarkable because GO is long-established as a garlic preparation (40) and tests indicate that traditional GO capsules possess good bioavailability (41) . Although garlic is widely consumed (41) by those without overt CHD risk and trials of normal healthy persons are especially relevant, only a few such trials have been reported.(30 ,42 43 44)

In summary, although >60 trials of lipid-lowering have been reported, our knowledge of the response to garlic is limited with respect to effective doses, types of garlic preparation and human subject categories. Here we have sought to monitor any beneficial influence of garlic preparations on a range of CHD risk factors. Thus, decreased CHD risk is a feasible benefit of reductions in plasma TC and LDL-C (45) , TG (46) and fasting glucose (47) . Similarly, increases in plasma HDL cholesterol (HDL-C) (48) and plasma antioxidant status (49) measured as plasma TAOC [a potential marker of antioxidant protection of LDL against oxidative modification (50) ] would likely have benefit. Our study measured these variables and included several novel features, i.e., the use of traditional GO capsules in parallel with GP, the use of "traditional" dose levels of 8 mg allicin equivalent (34) with quantitation of the trial dose, inclusion of measurements obtained on occasions during and after dosing and the use of subjects lacking overt CHD risk. The aim here was to test the hypothesis that garlic supplements would reduce specified risk factors for CHD in male and female subjects at low risk of CHD. Our main findings were that "traditional" GO capsules had no significant effects but that gender differences may occur in the influence of garlic on CHD risk factors.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects.

Subjects were recruited by personal invitation; most were students or academic staff of the University of Wolverhampton. The study was conducted from October 1994 to March 1995. Subjects gave informed consent following the procedures laid down in the Helsinki agreement with revisions. Eligibility criteria included the age range 18–65 y and (self-identified) good health. Exclusions were medical diagnosis of any of the following: diabetes mellitus; cardiovascular disease; hyperlipoproteinemia; bleeding disorders; infectious blood diseases; and heavy consumption of aspirin, onion or garlic. Ethical permission for the study was given by the Research Ethics Committee of the University of Wolverhampton. Body weights were recorded at the beginning of the study.

Diet control and assessment.

Diet control consisted of asking subjects at recruitment to keep to their usual diet throughout the study and especially not to alter their garlic or onion intake. Diet assessment took the form of a qualitative assessment of dietary change by questionnaire at the end of the dose period.

Design.

The sample size was comparable to that of studies reviewed in two meta-analyses (1 ,6) ; it was greater than that of earlier trials of normal persons (2) and was chosen to be similar to one such trial (43) . Volunteers were allocated randomly, in a double-blind manner, to GO or placebo by a member of the study team uninvolved in recruitment. Blinding in placebo-controlled garlic trials is complicated by the odorous nature of garlic, and few previous studies have attempted to do this. The GO gelatin capsules used in this study ("Cardiomax," Seven Seas, Hull, UK) were of the same size, ovoid shape and yellow color as placebo capsules, and both contained peppermint oil. The GO dose (2 capsules/d) was determined by HPLC (51) to deliver 8.2 mg [4.09 mg/capsule, CV 0.9%, n = 3] of allyl sulfide/d (52) .

Volunteers for the GP study were recruited separately. The GP gelatin capsules ("Garlicin," Biocare, Birmingham, UK) were of similar size to GO and placebo capsules, but were of distinctive appearance, and had little taste or odor of garlic. A daily dose of 1 g of GP (2 capsules/d) was given and GP samples from the same supplier were determined by HPLC (51) to release 7.8 mg allicin/g (7.77 mg/g, CV 1.4%, n = 3) in water. Thus GO and GP treatments provided similar allicin-equivalent doses. Subjects were asked to compensate for any missed daily dose by taking an extra half-dose on the next 2 d.

Reviews of subjects were at 0, 4 and 6 wk, at the end of the intervention phase at 11 wk and at 14–15 and 17–18 wk after the start of the intervention phase during the dose washout phase. During the initial visit, subjects were asked to return their dose boxes, together with any remaining capsules at the end of the treatment period. Subjects were questioned about compliance during reviews and those admitting to having not compensated for any missed doses more than occasionally were treated as lost from the study; those who had not fasted for 12 h were asked to return in a fasting state the next day. Venous blood samples were normally collected in the morning at 0800–1000 h, transferred to lithium heparin tubes and stored on ice; plasma was separated within 2 h. At the end of the dose period (end of wk 11), subjects were asked to complete a questionnaire to determine their use of medicines, to further check for dose compliance and to assess major dietary changes.

Laboratory analyses.

Plasma analyses were made on a Beckman Synchron CX7 (Beckman Instruments, High Wycombe, UK) in the Department of Chemical Pathology, the Manor Hospital, Walsall. TC/HDL-C ratios were calculated from the measurement of TC by cholesterol esterase/cholesterol oxidase/peroxidase (CV = 1.8% at 4.5 mmol/L) and HDL-C was measured using dextran sulfate/manganese precipitation (CV = 6% at 1.4 mmol/L). LDL-C was calculated by means of the Friedewald formula (53) from TC, HDL-C and TG values. TG was measured using lipase/glycerol kinase/glycerol phosphate oxidase/peroxidase (CV = 2% at 1.4 mmol/L). Glucose was measured using a glucose oxidase/conductivity electrode method (CV = 1.5% at 6.3 mmol/L). Plasma TAOC measurements were performed using the enhanced chemiluminescence method (54) (CV = 5.2% at 408 mmol Trolox equivalent/L) in the Wolfson Laboratory, Birmingham University, UK.

Statistical analyses.

The Statistical Package for the Social Sciences (SPSS, Version 7.5, SPSS, Woking, UK) was used for the statistical analysis. The distributions of age and triglyceride measurements were skewed; thus, the median and interquartile range were used to describe these.

The main outcomes concerned the changes in plasma values from the beginning to the end of the 11-wk treatment period. Mean changes in plasma for subjects receiving GO were compared with those for subjects receiving placebo by the use of 95% confidence intervals (CI) and by two-sample t tests with probability values considered significant at P = 0.05.

Subgroup analyses by gender, age and body weight were not specified in advance of analysis. For this reason and because many t tests for interaction were done, statistical significance was set at P = 0.01; accordingly, care should be taken in the interpretation of results of borderline significance. The t tests of garlic effect by gender interaction were done according to the method described by Pocock (55) . Gender differences in the effect of garlic were computed with 95% CI. Similar analyses were done for age and body weight groups defined by the median cut-off points for all subjects in the randomized trial.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Seventy-eight volunteers were recruited into the study. Fifty-one of these were entered into the randomized trial to compare GO and placebo, and 27 were recruited separately to receive GP.

An overview of recruitment, loss to follow-up and key stages of data collection and follow-up is given in Figure 1 . Sixty subjects (GO, 19/25; placebo, 21/26; GP, 20/27) remained in the study to the end of the 11-wk treatment period. In terms of measured baseline characteristics, those lost to follow-up were not dissimilar from those who remained (Table 1 ).

View larger version (36K): [in this window] [in a new window]   Figure 1. Study profile showing recruitment and losses of subjects, treatment duration and blood sampling times throughout the trial.

There was a low intake of prescribed drugs [contraceptive pill, hormone replacement therapy (HRT)] and vitamin supplements, which did not differ for the GO, placebo and GP groups. The contraceptive pill had been taken by 4 (placebo), 2 (GO) and 3 (GP) subjects during treatment, whereas 2 (placebo) and 1 (GO) subjects were receiving female HRT, and 1 (placebo), 3 (GO) and 6 (GP) had taken occasional or regular vitamin supplements. No subject took prescribed medicines.

During the fall months, changes in diet were reported as slight, but diets tended to become richer over the Christmas/New Year period as shown by increases in intakes of fatty foods and alcohol and by body weight gain in the GO and placebo groups. Body weight increase was recorded by 11 subjects (7 placebo, 2 GO and 2 GP) during the dose period. Detailed diet composition was not documented, although questionnaire responses did indicate that a few changes had occurred.

Changes in measured values for CHD risk factors during the treatment period are summarized in Table 3 . There was a mean reduction between baseline (treatment wk 0) and the end of treatment (treatment wk 11) of -0.24 mmol/L in plasma TC in subjects taking GO, and an average reduction in plasma TC of -0.04 mmol/L in subjects taking placebo. The effect of GO on TC was estimated by the difference between these two means, -0.24 - (-0.04) = -0.20 mmol/L, i.e., the effect of GO was to reduce plasma TC levels by 0.20 mmol/L on average. This difference was not significant and the 95% CI (0.59–0.19 mmol/L) included zero difference, as did the CI for GO on other outcome variables and for GP on all outcome variables. One plausible explanation of these results is that there are no beneficial effects of garlic on the plasma CHD risk factors measured.

The effect of garlic at each time point (Table C deposited with NAPS) was estimated as for treatment wk 11 (Table 3) . No significant effect of GO or GP was discernible in wk 4 and 6 (Table C deposited with NAPS) except for TAOC at 6 wk for which an early downward trend in the placebo group was not observed with GO (P = 0.01, Table C deposited with NAPS). The results depicting the influence of gender interaction throughout the trial include those for the post-treatment washout period (Table 5 ).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

Noticeable in the present study were opposing influences of GO on men and women. By canceling each other out, these effects generated a broadly neutral set of results overall. The influence of gender on the response to garlic observed in our study was comparable to that observed with the potent inhibitors of cholesterol biosynthesis, fluvastatin (58) and simvastatin (59) . This effect of garlic was surprising because although some earlier studies described garlic affecting reproductive activities of both male and female fish (60) and mimicry of sex hormones in mice (61) , no reports described gender differences in the response of CHD risk factors to garlic intake.

Gender differences in the incidence of hyperlipidemia (62) and CHD (63) are well known. In men, insulin-induced peripheral uptake of glucose and associated reduction in fasting plasma glucose levels (64 , 65) as well as catecholamine stimulation of hormone-sensitive lipase activity are each greater than in women (66 67 68) . Such differences in metabolic regulation processes could underlie differences in response to lipid-lowering agents between men and women. One endogenous lipid-regulating process influenced by garlic that appears to provide a feasible basis for gender effects is protein phosphorylation by AMP-dependent kinase (AMPK) (69) . The actions of this enzyme include inhibition of hydroxy-methyl-CoA-reductase (HMGR) and acetyl-CoA-carboxylase (70) , which are rate-controlling enzymes for hepatic synthesis of cholesterol and fatty acid, respectively. The activity of AMPK is conditional upon cell energy charge; in rat hepatocytes, it increases together with cellular levels of fructose and fatty acyl-CoA synthesis, both of which deplete ATP and raise AMP. Because inhibition of HMGR by garlic is amplified in the presence of fructose (69) and palmitate (71) , it has been proposed that garlic promotes the phosphorylating action of AMPK (69) . This metabolic basis for any lipid-lowering effects of garlic would likely be significantly influenced by cellular fatty acid availability. The liver clears long-chain fatty acids from plasma more rapidly in women than men (72) , and hepatocytes derived from female rats exhibit a twofold faster uptake of long-chain fatty acids than those from male rats (73) . Greater activation of AMPK in female liver cells is therefore feasible and could be expected to amplify the inhibitory effects of garlic on lipid biosynthesis considerably more in women than in men. Such marked effects on lipid biosynthesis would likely influence the measures of blood lipids and therefore have the potential to explain the gender differences in cholesterol parameters observed in the present study.

The observation of initial TAOC declines in the placebo group may have resulted from seasonal factors influencing plasma vitamin C levels, which have been observed to decline during fall and winter (74) . The concurrent presence of a significantly higher TAOC level in the GO group suggests an improvement of plasma antioxidant status with garlic. Subsequent recovery of placebo values (at wk 11, mid-late January) are a feasible consequence of the (recorded) dietary replenishments of the festive season.

Effects of GO intake on cholesterol-related variables at 4 and 6 wk in the mixed gender group (Table C deposited with NAPS), although statistically null (range of P-values = 0.31–0.57), were consistent in direction. The adverse trends observed are comparable to those reported from some previous longitudinal garlic studies in which lipid-lowering was eventually observed (31 ,36 ,42 ,75 ,76) . Such effects on plasma lipids were construed by Bordia (75) to result from short-term lipid mobilization by garlic. Persistence of gender influences into the washout period (Table 5) would imply a carryover effect of garlic. If supported experimentally, this could have implications for the interpretation of negative crossover studies (13 ,16 ,33 ,37 , 38) . As with recent negative studies using reformulated Kwai GP tablets (14 ,15 and see Introduction), low bioavailability of allicin from GP has to be considered a possible factor in the present study. Thus, subsequent to the commencement of our trial in 1994, similar gelatin-encapsulated GP preparations were shown to disintegrate rapidly in simulated gastric fluid, resulting in alliinase inactivation (40) .

In conclusion, the results obtained for the mixed gender group with GO were statistically null, so that despite positive overall trends for all lipid measurements and glucose, support for the value of garlic supplementation in the reduction of CHD risk in normal subjects was lacking. Opposite responses by men and women were a substantial confounder contributing to this null outcome. The results suggest that for healthy subjects, any benefits of garlic to plasma lipid and glucose levels may differ between men and women. The possible gender effects observed indicate that earlier studies of combined male and female groups may have given a misleading impression of the effects of garlic on CHD risk factors and that the design of future studies into both the metabolic actions and efficacy of garlic should take account of subject gender. The results of this study and one other, which investigated young male athletes (30) , suggest that for normal men, GO doses may have to be substantially greater than traditionally recommended levels (34) to stand a chance of producing significant improvements in plasma lipid risk factors.

	ACKNOWLEDGMENTS

 
Final Year Honors degree students Anthony Allen, Arvinder Gill, Emma Kirkman, Jane Lewis, Samantha-Jo McKinlay, Rimi Obra and Sylvia Perwaiz, who assisted in subject recruitment; L. D. Lawson, Research Director of Plant Bioactives Research Institute, for analysis of the GO capsules; L. D. Lawson, P. Murray and S. Dunmore for critical reading of manuscripts; Seven Seas Limited and BioCare Limited for provision of garlic materials and financial contributions; G. Thorpe, S. Maxwell and Helen Thomason of the Wolfson Laboratory, University of Birmingham for assistance with TAOC analysis; David Roser, MCIM, Director of the Garlic Research Bureau, Bury St. Edmunds, UK; and Willem vas Dias of Seven Seas Limited for encouraging our research into the biological effects of garlic oil.

	FOOTNOTES

 
¹ Presented in part in abstract form at the XXIII Annual Conference, Association of Clinical Biochemists, 27–30 December 1996, Kottayam, India [Maslin, D. J. & Zhang X.-H. (1996) The effects of garlic oil upon the plasma lipid profile of healthy humans. Abs. 006, p. 5] and [Zhang X.-H., Maxwell, S.R.J., Thorpe, G.H.G., Thomason, H., Rea, C. A., Connock, M. J. & Maslin, D. J. (1997) The action of garlic oil upon plasma total antioxidant capacity. Biochem. Soc. Trans. 25: 523s (abs.)].

² Doses and funding from Seven Seas, Limited (UK) and from BioCare Limited (UK).

³ See NAPS document No. 05595 for two pages of supplementary material. This is not a multi-article document. Order from NAPS c/o Microfiche Publications, 248 Hempstead Turnpike, West Hempstead, New York 11552. Remit in advance in U.S. funds only $15.00 for photocopies or $5.00 for microfiche. There is a $25.00 invoicing charge on all orders filled before payment. Outside U.S. & Canada add postage of $4.50 for the first 20 pages and $1.00 for each ten pages thereafter, or $5.00 for the first microfiche and $1.00 for each fiche thereafter.

⁵ Abbreviations used: AMPK, AMP-dependent kinase; CHD, coronary heart disease; CI, confidence interval; GO, garlic oil; GP, garlic powder; HDL-C, HDL cholesterol; HMGR, hydroxy-methyl-CoA-reductase; HRT, hormone-replacement therapy; LDL-C, LDL cholesterol; TAOC, total antioxidant capacity; TC, total cholesterol; TG, triglycerides.

Manuscript received September 20, 2000. Initial review completed October 26, 2000. Revision accepted February 5, 2001.

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