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Biomedical subjects

C Christiansen

Publications and source records attributed to C Christiansen.

At least 127 records · Page 7Linked to original sources

Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits.

BACKGROUND: The beneficial effect of long-term hormone replacement therapy in terms of a decreased risk of cardiovascular disease is now generally accepted. Raloxifene, a selective estrogen receptor modulator, has demonstrated hypolipidemic properties while leaving the endometrium unstimulated. METHODS AND RESULTS: For our study of the effects of raloxifene on atherosclerosis, 75 rabbits were ovariectomized and treated with either raloxifene, 17beta-estradiol, or placebo; 25 rabbits were sham operated and treated with placebo. After 45 weeks, the raloxifene group had two thirds of the aortic atherosclerosis, as evaluated by the cholesterol content of the proximal inner part of the aorta, found in the placebo group (placebo, 577+/-55.1 nmol/mg protein; raloxifene, 397+/-53.6 nmol/mg protein; P<.05); the estrogen group had one third of the aortic atherosclerosis in the placebo group (estrogen, 177+/-32.1 nmol/mg protein; P<.001). The sham-operated group (473+/-59.6 nmol/mg protein) was not significantly different from placebo. These effects were only partly explained by the changes in serum lipids and lipoproteins, and treatment with both estrogen and raloxifene independently predicted the response in aorta cholesterol. Because plasma levels of total raloxifene were low relative to clinical values in postmenopausal women, dose-response data for raloxifene are required. CONCLUSIONS: Our findings indicate that raloxifene hydrochloride has a potentially important antiatherogenic effect, analogous to that observed with estrogen in this model.

Animals↗

Sex steroids and the cardiovascular system.

HRT decreases significantly the risk of cardiovascular disease in postmenopausal women. More and more data indicate that this is true not only for unopposed oestrogen but also for combined oestrogen/progestin therapy. The latter point is of utmost importance since the global treatment strategy for women with an intact uterus includes a progestin.

Animals↗

A 2-year phase II study with 1-year of follow-up of risedronate (NE-58095) in postmenopausal osteoporosis.

This paper presents the results of a two-center, double-masked, placebo-controlled, randomized, oral-dose study of risedronate treatment in postmenopausal osteoporosis. Patients had at least one, but no more than four prevalent vertebral fractures at baseline. They received either 2.5 mg continuous risedronate, 2.5 mg cyclic risedronate, or placebo for 2 years. Both risedronate and placebo were formulated as hard gelatin capsules. All women furthermore received a daily calcium supplement of 1 g which was taken separately from the study drug. During the 1-year of follow-up, all women received only a daily calcium supplement of 1 g. A total of 132 patients were enrolled (44 in each treatment group), of which 73% completed the 2-year treatment period and 70% all 3 years. Generally the outcome of the study was negative. Lumbar spine bone mineral density (BMD) increased 1.2% (NS) and 0.8% (NS) and after 2 and 3 years in the group treated with continuous risedronate, 1.7% (NS) and 2.3% (p < 0.05) in the group treated with cyclic risedronate, and 0.6% (NS) and 1.7% (NS) in the placebo group. BMD in the femoral neck increased 2.9% (p < 0.05) and 0.9% (NS) after 2 and 3 years in the group treated with continuous risedronate, 1.3% (NS) and 2.4% (p < 0.01) in the group treated with cyclic risedronate, and 1.3% (NS) and 2.6% (p < 0.01) in the placebo group. The differences between all three groups in spinal and femoral BMD after 2 years were not statistically significant, but reached statistical significance after 3 years (p < 0.01) in the femoral neck. Only minor changes were observed in the measured markers of bone turnover. Both the incidence and rate of new vertebral fractures showed no overall differences between the groups. The distribution of adverse events was similar across treatment groups. None of the serious adverse events were considered causally related to risedronate. The lack of effect shown in the present study may be explained by insufficient dose regimen and/or impaired absorption from the intestinal tract. Further investigations (ongoing phase III trials) are needed to define future dose regimens in order to validate the effect on bone mass, fracture rate and biochemical markers. In these studies another formulation of the drug and other dosing instructions are used.

Aged↗

Design for an ipriflavone multicenter European fracture study.

In order to investigate the efficacy of ipriflavone (i.p.) on the prevention of vertebral fractures and the effect on bone mineral density (BMD) in women with postmenopausal osteoporosis, a large multicentric European study was designed and is presently ongoing. Included in the study were 460 Caucasian, nonobese postmenopausal women aged > 45 and < 75 years, menopaused for at least 12 months. Inclusion was on the basis of a lumbar bone mineral density (BMD) lower than 2 SD compared with healthy women aged 50 years, corresponding to values below 0.860 g/cm2 (antero-posterior measurement) by Hologic QDR 1000. Women with prevalent vertebral fractures were excluded as well as those presenting secondary osteoporosis or having been treated with medications that could affect bone metabolism. This study was designed as a 3-year, double-blind, placebo-controlled, parallel group study that randomized the women to the oral administration of either 3 x 200 mg/day of i.p. or placebo. All patients received a daily supplement of 500 mg calcium. The primary purpose of the study was to evaluate the efficacy of i.p. in preventing vertebral nontraumatic fractures. Fracture is defined here as a > or = 20% decrease in any anterior, central, or posterior T4-L4 vertebral height. Blinded vertebral X-ray readings and vertebral morphometry have been centralized in an independent Center, with standardized evaluation of two experts. Power calculations have been based on the hypothesis that 21% of placebo-treated patients would fracture within 3 years and that treatment with i.p. would lead to a 50% reduction in the incidence of fracture. Statistical tests have been designed to have a power of 80%, with a type I error equal to 5%. Secondary endpoints were changes in vertebral, radial, and femoral BMD. Centralized controls on 100% BMD scans would ensure the good quality of BMD readings. This study should verify the hypothesis that i.p. significantly decreases the risk of vertebral fracture in postmenopausal, osteoporotic women.

Absorptiometry, Photon↗

The day-to-day variation in insulin sensitivity in non-insulin-dependent diabetes mellitus patients assessed by the hyperinsulinemic-euglycemic clamp method.

The objective was to study the day-to-day variation in insulin sensitivity in non-insulin-dependent diabetes mellitus (NIDDM) and to analyze within- and between-person variances in the glucose infusion rate during steady state (M value). Ten NIDDM patients attending the outpatient clinic at Aarhus Amtssygehus were studied three times under standardized conditions. Each time, a 120-minute hyperinsulinemic-euglycemic clamp was performed. Similar M values were found on the 3 study days, with difference between M values on the 3 days of (mean +/- SD) 0.3 +/- 1.8 mg glucose/kg lean body mass (LBM)/min. The total coefficient of variation (CV) for M values was 57% after the first clamp, 55% after the second, and 53% after the third. Ninety percent of the total day-to-day variation in M values could be ascribed to between-person variation and 10% to within-person variation. Within-person components of variance included all sources of variation other than between-person variation. The within-person CV for M values was 11.9% +/- 7.2% after two clamp studies and 12.1% +/- 7.3% after three (P < .55). In conclusion, under standardized conditions, a valid estimate of insulin sensitivity assessed by the hyperinsulinemic-euglycemic clamp in NIDDM patients is obtained after a single measurement. Because of large between-person variation, paired data should be used when comparing insulin sensitivity in NIDDM patients.

Blood Glucose↗

Photon correlation spectroscopy applied to characterisation of denaturation and thermal stability of human albumin.

Photon correlation spectroscopy and light absorption measurements have been applied for characterisation of denaturation kinetics and thermal stability of human albumin in solution. The hydrodynamic size of the molecules has been studied as a function of pH, and the denaturation rate of ten different lots of 5% (w/v) human albumin solution has been measured at various temperatures. In the native (pH 7) state, the hydrodynamic molecular diameter was found to 6.3 nm. The molecular size was relatively stable between pH 10 and 5, but increased with decreasing pH to approximately 20 nm at pH 3. The denaturation rate, measured as change in hydrodynamic diameter per min, was strongly dependent on temperature and increased 3-fold per degree in the 73-75 degrees C range. The investigated lots of albumin solution showed large variations in stability at 74 degrees C, with denaturation rates ranging from 10 to 100 nm min-1. The observed thermal stability for the lots investigated was ranked identically with both the employed techniques. In an effort to explain the observed lot to lot variations in denaturation rate, a broad chemical characterisation including determination of free SH content, fatty acid content and composition and metal content, was performed. However, lot to lot variations in these parameters was not found to fully elucidate the observed variations in thermal stability.

Albumins↗

Morning or evening administration of nasal calcitonin? Effects on biochemical markers of bone turnover.

The purpose of this study was to examine the effect of intranasal salmon calcitonin (sCT) administration (200 IE), given either in the morning (8:00) or evening (21:00), on the known circadian variation in biochemical markers of bone turnover. An open, placebo-controlled, randomized, crossover study, with three 24 h studies of blood samples drawn every third hour and urine collected in 3 h aliquots was undertaken. Subjects consisted of nine healthy postmenopausal women, aged 58 +/- 7 years. Urinary CrossLaps (a measure of bone resorption) was measured by ELISA and corrected for creatinine (Cr). Serum osteocalcin (sOC) was measured by radioimmunoassay (RIA). The first 24 h study was performed without intervention. Prior to this control study the participants were randomized to either morning (8:00) or evening (21:00) sCT (200 IE). sCT administrations were given 4-5 days prior to and during the second study. After a washing-out period of 2 weeks the participants were given 200 IE of sCT at the reverse time of the day 5 days prior to and during the third study. At all timepoints, urinary CrossLaps/Cr exhibited a significant (p < 0.001) circadian rhythm with its zenith in early morning and nadir in late afternoon. Both morning and evening administration of sCT significantly decreased the urinary excretion of CrossLaps/Cr approximately 3-6 h after administration with a subsequent rebound effect. sOC did not exhibit a significant circadian variation and was not affected by the calcitonin. The 24 h mean urinary CrossLaps/Cr and sOC remained unchanged. Both morning and evening sCT significantly decreased the urinary excretion of CrossLaps/Cr 3-6 h after administration, with a rebound effect approximately 12 h later. However, the present study does not indicate that neither evening nor twice-daily administration is superior to morning administration.

Administration, Intranasal↗

The response in spinal bone mass to tibolone treatment is related to bone turnover in elderly women.

To determine the ability of bone turnover to predict the response in bone mass during treatment with Tibolone, two biochemical markers of bone metabolism were evaluated [CrossLaps corrected for urinary creatinine (CrossLaps/Cr.) and serum osteocalcin measured in a newly developed assay (N-Mid)]. Data from a 2-year double-blind, randomized trial with 56 completing Tibolone-treated women and 13 placebo-treated women were studied. Bone mineral density in the spine (QDR-1000) and indices of bone turnover were determined every 3 months throughout the study. The response in bone mass was calculated as the percent annual change in bone mineral density from baseline and was determined from a total of nine measurements. The response in bone mass was correlated to prestudy values of CrossLaps/Cr. (r = 0.27; p < 0.05), but was uncorrelated to prestudy values of N-Mid. The changes from baseline of these two markers were significantly correlated with the response in bone mass from the 6 months' time point and throughout the rest of the study, i.e., at 1 year: CrossLaps/Cr.: r = 0.54; p < 0.001, N-Mid: r = 0.49; p < 0.001). The change from baseline in the two markers was clearly more predictive of the response in bone mass than the baseline values of these markers as evaluated in a multiple, linear regression-model. Within 1 year of Tibolone-treatment, measured changes in CrossLaps/Cr. and bone mineral density are at least equally predictive of the true response in bone mass over 2 years. These results indicate a possibility of monitoring Tibolone therapy with biochemical markers of bone turnover, at least on group basis.

Aged↗

Circadian variation in bone resorption is not related to serum cortisol.

Serum osteocalcin, serum procollagen type I carboxyterminal propeptide (sPICP), and the urinary excretion of pyridinium crosslinks (biochemical markers of bone formation and resorption) all exhibit a circadian variation with a peak during the night. This study was performed to investigate the influence of the endogenous circadian rhythm in cortisol on the biochemical markers of bone turnover. Participants included 11 patients substituted with hydrocortisone due to either hypopituitarism (n = 7) or bilateral adrenalectomy (n = 4). Their daily tablet intake of hydrocortisone was divided in four equal doses in order to abrogate the known circadian variation in cortisol. 24 healthy postmenopausal women served as controls. The study design was performed over 24 h, with blood samples taken every 3 h, and urine collected in 3 h aliquots. Urinary pyridinium crosslinks (Pyr/ Cr, D-Pyr/Cr), serum osteocalcin (sOC), and serum PICP were measured. Patients without a circadian variation in cortisol had normal circadian variation in the urinary excretion of pyridinium crosslinks and sPICP, but no circadian rhythm in serum osteocalcin. We conclude that the etiology of the circadian rhythm in the biochemical markers of bone turnover is still unknown. This study indicates that the circadian variation in sOC can be controlled by the endogenous circadian variation in serum cortisol, whereas this hormone does not control the circadian variation in either the serum PICP or the urinary excretion in pyridinium crosslinks.

Adrenalectomy↗

Development of a monoclonal antibody to urinary degradation products from the C-terminal telopeptide alpha 1 chain of type I collagen. Application in an enzyme immunoassay and comparison to CrossLaps ELISA.

A monoclonal antibody MAbA7 was raised against a synthetic peptide having a sequence (EKAHDGGR) specific for a part of the C-telopeptide alpha 1 chain of type I collagen. MAbA7 was labelled with horseradish peroxide and used in a competitive one-step enzyme-linked immunosorbent assay (ELISA) for measurement of urinary type I collagen degradation products. The assay was technically evaluated and preliminary clinical data are presented. The measuring range was 200-7000 micrograms l-1 with a detection limit of 25 micrograms l-1. Within-run and total CVs were 5.5 and 8.0%, respectively. Analytical recovery averaged 96.6% +/- 5.3 (mean +/- 1SD). Values obtained in the ELISA were highly correlated (r = 0.93) to values obtained by a commercially available assay (CrossLaps ELISA) known to measure urinary degradation products derived from the C-telopeptide of type I collagen reflecting the rate of bone resorption. Investigation of the urinary fragments responsible for the immunological response in the two assays revealed, however, that they are not identical. Values obtained in urine samples from postmenopausal women (n = 108) and patients with Paget's disease (n = 6) increased 43% (p < 0.01) and 28-fold (p < 0.001), respectively, when compared to a premenopausal level (n = 50). A decrease in the urinary concentrations of 67% (p < 0.01) was seen after 6 months in urine samples from postmenopausal women (n = 13) receiving hormone replacement therapy (HRT) compared to a group receiving placebo (n = 9). Likewise, the urinary concentrations decreased 88% (p < 0.001) in early postmenopausal women receiving bisphosphonate therapy (n = 11) for a period of 9 months compared to a group receiving placebo (n = 12). These results suggest that the monoclonal antibody and the new assay may be useful for further investigations of the physiological and clinical importance of type I collagen degradation.

Adult↗

Comparison of the effects of two weeks' intervention with different meal frequencies on glucose metabolism, insulin sensitivity and lipid levels in non-insulin-dependent diabetic patients.

AIMS: To compare the effects of 2 weeks on different meal frequencies on glucose metabolism, lipid levels and 24-hour blood pressure in non-insulin-dependent diabetic subjects. METHODS: Ten non-insulin-dependent diabetic outpatients from Aarhus City participated in a crossover study design. None were treated with insulin. The patients were randomly allocated to two isoenergetic diets either taken as three or eight meals per day for 2 weeks each. At the end of each period, the diurnal blood pressure and the responses to a test meal were measured. Furthermore, a hyperinsulinemic, euglycemic clamp was placed. RESULTS: Both the insulin sensitivity and 24-hour ambulatory blood pressure were similar as were the responses of glucose, insulin and free fatty acids to a carbohydrate-rich test meal at the end of the two diet periods. The HDL-cholesterol level was lowest in response to the 8-meal diet (p = 0.02). CONCLUSION: Increasing meal frequencies in a 2-week treatment period with weight-maintaining diets on an outpatient basis subdued the HDL-cholesterol levels but apparently had no impact on glucose metabolism or diurnal blood pressure in NIDDM subjects. These results give no indications of long-term beneficial effects of increasing the meal frequency in NIDDM patients.

Blood Glucose↗

Tibolone: influence on markers of cardiovascular disease.

Tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties relieves climacteric symptoms and prevents postmenopausal bone loss. The influence of tibolone treatment on coagulation, fibrinolysis, and lipid metabolism was investigated in 91 healthy late postmenopausal women. They were randomly assigned in a double-blind, placebo-controlled 2-year study to receive either tibolone 1.25 mg (n = 36, 29 completed) or 2.5 mg (n = 35, 28 completed) or placebo (n = 20, 13 completed). The biochemical markers of lipid metabolism, fibrinolysis, and coagulation were measured every 3 months. In both tibolone groups a similar (approximately 30%) decrease in high density lipoprotein cholesterol and a corresponding lowering of apolipoprotein A-1 (P < 0.001) was detected. Also serum total cholesterol and triglycerides were reduced (approximately 15%; P < 0.01), whereas low density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) were unaffected by tibolone. The two dose levels of tibolone resulted in a similar, marked lowering (approximately 30%) of tissue plasminogen activator and plasminogen activator inhibitor activity as compared with placebo (P < 0.001). Plasminogen increased (approximately 15%; P < 0.001) in both groups. Fibrinogen was lowered (P < 0.01) in the low-dose group, and antithrombin III remained unchanged. The overall effect on hemostatic factors of the present doses of tibolone in healthy, late postmenopausal women tends towards increased fibrinolysis and unchanged coagulation. This may be beneficial and might theoretically counterbalance the potentially negative effect of the decrease in high density lipoprotein cholesterol.

Aged↗

Measurement of bone degradation products in serum using antibodies reactive with an isomerized form of an 8 amino acid sequence of the C-telopeptide of type I collagen.

An enzyme-linked immunosorbent assay for measuring type I collagen degradation products in serum (S-ELISA) was developed. The assay uses a high affinity polyclonal antibody which reacts with an isomerized form of an 8 amino acid sequence of the C-telopeptides of type I collagen (EKAHD-beta-GGR). Cross-reactivity to a nonisomerized synthetic peptide form of the 8 amino acid sequence is less than 0.2%. Values obtained in a group of premenopausal women (age, 33.3 +/- 3.11 years) were 69 +/- 24 ng/ml(n = 22). In a group of early postmenopausal women (age, 51.8 +/- 1.88 years) values obtained were 125 +/- 43 ng/ml (n = 46), which represents an increase of 81% (p < 0.001). Values found in untreated patients with Paget's disease were 234 +/- 95 ng/ml (n = 15), and for primary hyperparathyroidism we found 335 +/- 82 ng/ml (n = 10). Intravenous administration of a bisphosphonate (Pamidronate) to Paget's disease patients for 3 days was reflected in the S-ELISA by a decrease in the values of 55% when compared with values before treatment (n = 15). Following treatment with another bisphosphonate (Alendronate) for 6 months, values were decreased to 48 +/- 19 ng/ml (n = 12), which corresponds to a 62% decrease. Clinical results presented in this context support that the assay is a sensitive and specific index of bone resorption. It may, therefore, prove useful in the follow up of treatment of patients with metabolic bone diseases and in the clinical investigation of osteoporosis.

Adult↗

Comparison of a carbohydrate-rich diet and diets rich in stearic or palmitic acid in NIDDM patients. Effects on lipids, glycemic control, and diurnal blood pressure.

OBJECTIVE: To compare the effects on lipid levels, glycemic control, and diurnal blood pressure of two diets rich in one of the two quantitatively most important saturated fatty acids, stearic and palmitic acid, with a carbohydrate-rich diet in NIDDM patients. RESEARCH DESIGN AND METHODS: A total of 15 NIDDM patients participated in a randomized crossover study with three 3-week diet interventions separated by 2-week washout periods. Patients started with a diet rich in stearic acid (44 E% [percent of total energy] fat [13 E% stearic acid], 40 E% carbohydrate, 15 E% protein), palmitic acid (45 E% fat [16 E% palmitic acid], 40 E% carbohydrate, 15 E% protein), or carbohydrate (29 E% fat, 51 E% carbohydrate, and 18 E% protein), then were shifted to the other two diets in a randomized block design. At the start and end of each intervention period, fasting blood samples were drawn for analysis of lipids and blood glucose. In addition, diurnal blood pressure was measured. RESULTS: At the end of the 3-week interventions, total cholesterol was significantly higher after the palmitic acid-rich diet than after the stearic acid-rich or carbohydrate-rich diets (5.3 +/- 1.3 vs. 5.0 +/- 1.2 and 4.9 +/- 1.2 mmol/l, respectively; P = 0.03). No significant differences in triglyceride, LDL, or HDL cholesterol levels were seen after the three intervention diets. No difference in effects between the diet periods were seen for fructosamine, HbA1c, fasting blood glucose, or diurnal blood pressure. CONCLUSIONS: For the first time, it has been demonstrated that a diet rich in palmitic acid was not as effective in lowering cholesterol levels as carbohydrate-rich and stearic acid-rich diets in NIDDM patients. No deleterious effects were seen on diurnal blood pressure, triglyceride levels, and glycemic control. Development of foods containing stearic acid rather than the more atherogenic saturated fatty acids may allow a wider choice of acceptable foods to NIDDM patients.

Adult↗

Elevated ambulatory blood pressure in microalbuminuric IDDM patients is inversely associated with renal plasma flow. A compensatory mechanism?

OBJECTIVE: To evaluate the relationship between renal function, ambulatory blood pressure (AMBP), and glycemic control in microalbuminuric IDDM patients compared with normoalbuminuric patients. RESEARCH DESIGN AND METHODS: Nineteen male patients (age 33 +/- 6 years) with slight microalbuminuria (UAE 20-70 micrograms/min) were compared with 19 normoalbuminuric (UAE < 15 micrograms/min) age-matched (33 +/- 6 years) male patients. Through constant infusion technique, 125I-iothalamate marked the glomerular filtration rate (GFR), and 131I-hippuran marked effective renal plasma flow (RPF). AMBP was measured by oscillometric technique (Spacelabs 90202). RESULTS: The microalbuminuric group had higher daytime systolic AMBP (132 +/- 11 vs. 125 +/- 7 mmHg, P < 0.05) and a poorer glycemic control (HbA1c 9.5 +/- 1.5 vs. 8.2 +/- 1.3%, P < 0.01). GFR (135 +/- 22 and 135 +/- 17 ml/min) and RPF (598 +/- 112 and 542 +/- 98 ml/min) were similar in the two groups. In the microalbuminuric group, daytime systolic AMBP was inversely correlated to both RPF (r = -0.77, P < 0.005) and GFR (r = -0.53, P = 0.02). HbA1c and GFR correlated positively in the microalbuminuric group (r = 0.47, P < 0.04). In contrast, the normoalbuminuric patients exhibited no such associations. CONCLUSIONS: IDDM patients with moderate microalbuminuria have elevated AMBP and a strong negative association between AMBP and RPF. This leaves several possibilities of interpretation. Primary blood pressure increase (of unknown origin) may induce morphological changes leading to reduction in renal function. Alternatively, blood pressure increase early in the course of incipient nephropathy may represent a compensatory mechanism, initially aiming at preservation of renal function, but later becoming maladaptive.

Adult↗

Impact of combined hormone replacement therapy on serum lipid metabolism: new aspects.

The objective of this study was to evaluate the impact of combined estrogen-progestogen therapy on low density lipoprotein (LDL) particle size (determined by the LDL cholesterol/apolipoprotein B ratio). The prospective study was carried out on 139 healthy Danish early postmenopausal women. The subjects were randomized to placebo or to 2 mg estradiol valerate equivalents, either sequentially combined with 75 micrograms levonorgestrel, 10 mg medroxyprogesterone acetate (MPA), or 150 micrograms desogestrel, or continuously combined with 1 mg cyproterone acetate. LDL particle size was calculated before treatment and at nine-well-defined times during the subsequent 84 days. LDL particle size was reduced by all four treatments. This change was statistically significant for estradiol valerate combined with levonorgestrel and MPA (6.2 +/- 2.7% and 5.6 +/- 2.1% (mean +/- SEM), respectively; p < 0.05 for both, placebo-corrected). Estradiol valerate combined with MPA induced cyclic (progestogen-minus estrogen-related values) decreases (-6.3 +/- 2.6%; p < 0.05), and with levonorgestrel there were cyclic increases (5.1 +/- 2.7%; p = 0.067) in LDL particle size (placebo-corrected). In conclusion, combined estrogen-progestogen therapy causes a decrease in LDL particle size. A cyclic variation in LDL cholesterol/apolipoprotein B ratio was observed during sequential treatment.

Apolipoproteins B↗