Cholesterol-lowering effects of psyllium hydrophilic mucilloid for hypercholesterolemic men.

The effect of psyllium hydrophilic mucilloid on serum cholesterol levels was investigated in 26 men with mild to moderate hypercholesterolemia (range of cholesterol level, 4.86 to 8.12 mmol/L [188 to 314 mg/dL]) in a double-blind, placebo-controlled parallel study. Following a two-week baseline period, subjects were treated for eight weeks with 3.4 g of psyllium or cellulose placebo at mealtimes (three doses per day). All subjects maintained their usual diets, which provided less than 300 mg of cholesterol per day and approximately 20% of energy from protein, 40% from carbohydrate, and 40% from fat. Eight weeks of treatment with psyllium reduced serum total cholesterol levels by 14.8%, low-density lipoprotein (LDL) cholesterol by 20.2%, and the ratio of LDL cholesterol to high-density lipoprotein cholesterol by 14.8% relative to baseline values. The reductions in total cholesterol and LDL cholesterol became progressively larger with time, and this trend appeared to be continuing at the eighth week. Psyllium treatment did not affect body weight, blood pressure, or serum levels of high-density lipoprotein cholesterol, triglycerides, glucose, iron, or zinc. No significant changes in serum lipid levels, body weight, blood pressure, or other serum parameters were observed with placebo treatment. Subject adherence to psyllium treatment was excellent, and no adverse effects were observed. Results of this study show that psyllium is an effective and well-tolerated therapy for mild to moderate hypercholesterolemia.

Effects of increasing doses of 1 alpha-hydroxyvitamin D2 on calcium homeostasis in postmenopausal osteopenic women.

This study is the first reported administration of 1 alpha-hydroxyvitamin D2 (1 alpha-OHD2) to human subjects. A total of 15 postmenopausal osteopenic women were given increasing oral doses of 1 alpha-OHD2, beginning with a low dose of 0.5 microgram/day. In 15 subjects, the doses were raised at weekly intervals to 1.0, 2.0, 4.0, and 5.0 micrograms/day, and in 5 of these subjects, the dose was further increased to 8.0 or 10.0 micrograms/day. Mean urine calcium +/- SEM showed a dose-related increase from 134 +/- 17 mg/24 h on 0.5 microgram/day to 198 +/- 21 mg/24 h on 4.0 micrograms/day (p < 0.05) and to 241 +/- 35 mg/24 h on 5.0 micrograms/day (p < 0.05). No subjects had hypercalciuria (> 350 mg/24 h, the upper limit of the laboratory normal range) at doses less than 5.0 micrograms/day; 5 subjects had hypercalciuria at or above 5.0 micrograms/day (3 at 5.0 micrograms/day, 1 at 8.0 micrograms/day, and 1 at 10.0 micrograms/day). Mean serum calcium increased slightly on the 4.0 micrograms dose only (p < 0.05) but remained well within the normal range. Mean creatinine clearance and BUN, used as measures of renal function, showed no significant changes. Routine blood and urine assays also showed no significant changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism of 1 alpha-hydroxyvitamin D2 to activated dihydroxyvitamin D 2 metabolites decreases endogenous 1 alpha, 25-dihydroxyvitamin D 3 in rats and monkeys.

The vitamin D analog 1 alpha-hydroxyvitamin D2 (1 alpha-OHD2) is under development for the treatment of secondary hyperparathyroidism and metabolic bone disease. This analog is metabolized in vivo to the natural active dihydroxylated metabolite of vitamin D2, 1 alpha,25-dihydroxyvitamin D2 [1 alpha,25-(OH)2D2]. To study the metabolism of this analog, an assay involving HPLC separation and purification of metabolites followed by RRA with the vitamin D receptor was developed to quantitate the active metabolites of the analog and the endogenous active metabolite of vitamin D3, 1 alpha,25-(OH)2D3, from the same blood sample. This assay was used to determine blood levels of active dihydroxylated vitamin D compounds in rats and monkeys treated with oral 1 alpha-OHD2. As the circulating 1 alpha,25-(OH)2D2 level increased dose dependently in these rats and monkeys, a concomitant decrease in the endogenous 1 alpha,25-(OH)2D3 was observed. In rats orally administered more than 2.5 micrograms 1 alpha-OHD2/kg.day, a second active metabolite of 1 alpha-OHD2, 1 alpha,24-(OH)2D2, was detected in concentrations similar to those of 1 alpha,25-(OH)2D2. These results indicate that the regulatory control of endogenous vitamin D metabolism as well as analog metabolism must be considered when assessing the therapeutic potential of a vitamin D analog.

Unique 24-hydroxylated metabolites represent a significant pathway of metabolism of vitamin D2 in humans: 24-hydroxyvitamin D2 and 1,24-dihydroxyvitamin D2 detectable in human serum.

We have produced evidence for a new metabolic pathway for vitamin D2 in humans involving the production of 24-hydroxyvitamin D2 (24OHD2) and 1,24-dihydroxyvitamin D2 [1,24-(OH)2D2]. These metabolites were produced after either a single large dose (10(6) IU) of vitamin D2 or repeated daily doses between 10(3) and 5 x 10(4) IU. We developed assay systems for the metabolites in human serum and showed that in some chronically treated patients, the concentration of 1,24-(OH)2D2 equalled that of 1,25-(OH)2D2 at about 100 pmol/L. The metabolites were identified by high performance liquid chromatography with diode array spectrophotometry for 24OHD2 and by high resolution gas chromatography-mass spectrometry for 1,24-(OH)2D2. We show that 1,24-(OH)2D2 synthesis can be stimulated by PTH, indicating a renal origin for this metabolite and postulate that it is formed from 24OHD2, which may be synthesized in liver. We conclude from this study that vitamin D2 gives rise to two biologically active products, 1,24-(OH)2D2 and 1,25-(OH)2D2, and that 1,24-(OH)2D2 could be an attractive naturally occurring analog of 1,25-(OH)2D3 for clinical use.

Intermittent doxercalciferol (1alpha-hydroxyvitamin D(2)) therapy for secondary hyperparathyroidism.

Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1alpha-hydroxyvitamin D(2) [1alphaD(2)]) suppressed intact parathyroid hormone (iPTH) effectively with minimal increases in serum calcium and phosphorus (P) levels. This modified, double-blinded, controlled trial examined the efficacy and safety of 1alphaD(2) use in 138 hemodialysis patients with moderate to severe secondary hyperparathyroidism by using novel dose titration; 99 patients completed the study. Hemodialysis patients with secondary hyperparathyroidism were enrolled onto this study, consisting of washout (8 weeks), open-label 1alphaD(2) treatment (16 weeks), and randomized, double-blinded treatment with 1alphaD(2) or placebo (8 weeks). Oral 1alphaD(2) was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 +/- 52 [SE] pg/mL) decreased by 20% +/- 3.4% by week 1 (P: < 0.001) and by 55% +/- 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1alphaD(2) treatment. In 80% of the patients, iPTH level decreased by 70%, reaching the target level in 83% of the patients. Grouping patients by entry iPTH level (<600, 600 to 1,200, and >1,200 pg/mL) showed rapid iPTH suppression in the group with the lowest level; greater doses and longer treatment were required in the group with the highest level. During open-label treatment, serum calcium and P levels were 9.2 +/- 0.84 (SD) to 9.7 +/- 1.05 mg/dL and 5.4 +/- 1.10 to 5.9 +/- 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1alphaD(2) than placebo, but P levels did not differ. During double-blinded treatment, 3.26% and 0.46% of serum calcium measurements exceeded 11.2 mg/dL with 1alphaD(2) and placebo, respectively (P: < 0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1alphaD(2) therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia.

Efficacy and side effects of intermittent intravenous and oral doxercalciferol (1alpha-hydroxyvitamin D(2)) in dialysis patients with secondary hyperparathyroidism: a sequential comparison.

Most reports on the effectiveness and side effects of oral versus parenteral calcitriol or alfacalcidol in hemodialysis patients with secondary hyperparathyroidism show no advantage of parenteral treatment. The efficacy and safety of intravenous doxercalciferol (1alphaD(2)) were studied in hemodialysis patients with secondary hyperparathyroidism (plasma intact parathyroid hormone [iPTH]: range, 266 to 3,644 pg/mL; median, 707 pg/mL). These results were compared with those of a previous trial using intermittent oral 1alphaD(2); the same 70 patients were entered onto both trials, and 64 patients completed both trials per protocol. Twelve weeks of open-label treatment in both trials were preceded by identical 8-week washout periods. Degrees of iPTH suppression from baseline were similar in the two trials, with iPTH level reductions less than 50% in 89% and 78% of patients during oral and intravenous treatment, respectively. Grouping patients according to entry iPTH levels (<750 and >/=750 pg/mL) showed similar but more rapid iPTH suppression in the low-iPTH groups, whereas longer treatment and larger doses were required by the high-iPTH groups. Highest serum calcium levels averaged 9.82 +/- 0.14 and 9.67 +/- 0.11 mg/dL during oral and intravenous 1alphaD(2) treatment, respectively (P: = not significant [NS]). Prevalences of serum calcium levels greater than 11.2 mg/dL during oral and intravenous treatment were 3.62% and 0.86% of calcium measurements, respectively (P: < 0.001). Highest serum phosphorus levels during oral and intravenous treatment averaged 5.82 +/- 0.21 and 5.60 +/- 0.21 mg/dL, respectively (P: = NS). The percentage of increments in serum phosphorus levels during oral treatment exceeded that during intravenous treatment during 5 of 12 treatment weeks. Thus, intermittent oral and intravenous therapy with 1alphaD(2) reduced iPTH levels effectively and similarly, hypercalcemia was less frequent, and serum phosphorus levels increased less during intravenous than oral 1alphaD(2) therapy, suggesting that intravenous 1alphaD(2) therapy may be advantageous in patients prone to hypercalcemia or hyperphosphatemia.

Pharmacokinetics and systemic effect on calcium homeostasis of 1 alpha,24-dihydroxyvitamin D2 in rats. Comparison with 1 alpha,25-dihydroxyvitamin D2, calcitriol, and calcipotriol.

1 alpha,24-Dihydroxyvitamin D2 (1 alpha,24(OH)2D2) is a metabolite of 1 alpha-hydroxyvitamin D2 (1 alpha-OH-D2), a prodrug in development as a treatment for secondary hyperparathyroidism occurring in end stage renal disease. This prodrug has a broader therapeutic index than the corresponding vitamin D3 analogue, possibly because hepatic metabolism of 1 alpha-OH-D2 shifts at higher dose levels from 1 alpha,25-dihydroxyvitamin D2 (1 alpha,25(OH)2D2) to 1 alpha,24(OH)2D2. In this report, we present the pharmacokinetics of 1 alpha,24(OH)2D2 and its systemic effects on serum and urine calcium in rats. These properties were compared with those of 1 alpha,25(OH)2D2, calcitriol, the active metabolite of endogenous vitamin D3, and calcipotriol, a vitamin D analogue noted for its rapid clearance and minimal effect on calcium homeostasis. Comparison of the blood concentration curves from time zero to infinity indicated that 1 alpha,24(OH)2D2 had about one-fifth the systemic exposure of 1 alpha,25(OH)2D2 or calcitriol, but almost 30 times that of calcipotriol. The oral bioavailabilities and circulating half-lives of 1 alpha,24(OH)2D2 and calcitriol were similar, whereas those of calcipotriol were much less. In vitamin D-deficient rats, oral doses of 1 alpha,25(OH)2D2 and calcitriol produced similar dose-dependent increases in serum calcium, whereas an oral dose 30 times greater was required for 1 alpha,24(OH)2D2 to produce a similar response. Dose-response curves generated after oral and subcutaneous administration of 1 alpha,24(OH)2D2, calcitriol, and calcipotriol to normal rats indicated that 1 alpha,24(OH)2D2 increases serum and urine calcium to a much lesser extent than calcitriol, and to a slightly greater extent than calcipotriol. These properties of 1 alpha,24(OH)2D2 suggest that production of this metabolite from 1 alpha-OH-D2 contributes to the lowered toxicity of 1 alpha-OH-D2 and indicate that 1 alpha,24(OH)2D2 contributes to the lowered toxicity of 1 alpha-OH-D2 and indicate that 1 alpha,24(OH)2D2 itself has therapeutic potential.

Anti-proliferative activity and target cell catabolism of the vitamin D analog 1 alpha,24(S)-(OH)2D2 in normal and immortalized human epidermal cells.

Vitamin D analogs represent valuable new agents for the suppression of proliferation of a variety of cell types, including those of the skin. One such analog is the vitamin D2 metabolite, 1 alpha,24(S)-dihydroxyvitamin D2, which binds strongly to the vitamin D receptor and induces vitamin D-dependent gene expression in vitro. In the work described here, we studied the anti-proliferative activity and target cell metabolism of 1 alpha,24(S)-dihydroxyvitamin D2 in cells of human epidermal origin. We found this analog to be equally potent in its anti-proliferative effect to the hormone 1 alpha,25-dihydroxyvitamin D3. Furthermore, 1 alpha,24(S)-dihydroxyvitamin D2 was metabolized by the human keratinocyte cell line HPK1A-ras at a slower rate than either 1 alpha,25-dihydroxyvitamin D3 or calcipotriol, a drug used effectively in the treatment of psoriasis. We characterized the metabolic products of 1 alpha,24(S)-dihydroxyvitamin D2 as a mixture of side-chain truncated and hydroxylated products. The main product was identified by GC-MS and NMR techniques as 1 alpha,24(S),26-trihydroxyvitamin D2. The biological activity of this main product was determined in a vitamin D-dependent, growth-hormone reporter gene expression system to be lower than that of the parent molecule. We conclude from these data that 1 alpha,24(S)-dihydroxyvitamin D2 is a valuable new anti-proliferative agent with a slower rate of catabolism by cells of epidermal origin. Preliminary evidence suggests that the parent molecule, and not its products, is responsible for this biological activity in vitro.

Estimation of the mid-upper arm circumference measurement error.

The mid-upper arm circumference measurement error was estimated in order to assess the usefulness of this measurement for detecting small changes in a patient's arm circumference during hospitalization. In a study having a 3 X 3 X 2 factorial design, 10 trained observers recorded 1,560 measurements from 52 healthy adult subjects selected to represent three factors: sex, age, and weight for height. Each observer obtained three independent measurements from every subject. By analysis of variance, the variation between different observers' measurements of the same subject was estimated with 95% confidence to be less than or equal to 2.8% for men and less than or equal to 3.8% for women. This variation was unaffected by age but decreased with decreasing weight for height in women (p less than .05). Variation between each observer's repeated measurements of the same subject was estimated with 95% confidence to be less than or equal to 1.1% and was unaffected by sex, age, or weight for height. It was concluded that the smallest detectable change in arm circumference is 7.8% for men and 9.8% for women when successive measurements are recorded by different observers. However, arm circumference changes as small as 2.2% can be detected in both men and women when successive measurements are obtained by the same observer.

Evaluating upper arm anthropometric measurements.

Jelliffe's standards for evaluating measurements of mid-upper arm circumference, triceps skinfold thickness, and mid-upper arm muscle circumference of American adults were compared with percentile distributions developed from the first Health and Nutrition Examination Survey (NHANES I). These comparisons show that the standards poorly represent the adult U.S. population. Replacement of the standards with updated sex-specific values is not recommended, as (a) no single value for each arm parameter can be considered as "normal" for men or women of all ages and (b) the expression of arm measurements as percentages of standards is an inappropriate method of evaluation. Instead, measurements should be evaluated by comparison with age- and sex-specific percentile distributions developed from the NHANES I.

Alternate approaches to a UMLS.

A scheme for the continuing development of Meta-1, a taxonomy of medical subjects based; on MeSH and other systems, is described. The objective is a single, structured classification for medical knowledge.

Reference values for arm muscle area, arm fat area, subscapular skinfold thickness, and sum of skinfold thicknesses for American adults.

Reference values for the mid-upper arm muscle area, mid-upper arm fat area, subscapular skinfold thickness, and sum of triceps and subscapular skinfold thicknesses of American adults were developed from data collected by the National Center for Health Statistics during the first National Health and Nutrition Examination Survey, 1971 to 1974. The reference values were compared to other reference values derived from a similarly conducted cross-sectional survey of the American population, the Health Examination Survey of 1960 to 1962. These comparisons revealed that arm muscle area and subscapular skinfold thickness of men and arm muscle area of women continuously increase with aging from 18 to 74 yr; arm fat area and sum of skinfold thicknesses of men increase with aging from 18 to 34 yr but stabilize or decrease with further aging; and arm fat area, subscapular skinfold thickness, and sum of skinfold thicknesses of women increase with aging from 18 to 64 yr but decrease thereafter. As these parameters frequently change more than 20% over the period of a single decade, it is important that age be considered in nutritional evaluations based on anthropometric measurements. Changes in these four parameters with successive generations are also frequently large. Consequently, it is imperative that the reference values used in nutritional assessment protocols be updated at regular intervals.

A new format for the medical record.

Over the centuries, the medical record has become stereotyped. Reconsidering the purpose and organization of this document leads me to propose a four-part format consisting of administrative data, a patient synopsis, a chronological medical record, and a detailed medical record. The patient would be identified only in the administrative data section, leaving the rest of the record available for management, outcome, and cost studies, and protecting the patient's privacy. Adoption of this four-part format would make it easier to locate information in the medical record and would facilitate computerization. If the phraseology could be standardized, the new format would also allow easier data flow from one medical record to another and permit the construction of standardized disease profiles. Data on individual patients could then be compared with standardized profiles to identify deficiencies and redundancies in patient care.

A name is not enough.

The body of medical knowledge is so vast, and finding a fact within it is often so difficult and frustrating, that various systems have been proposed to help. reviewing the various approaches reveals some of the difficulties of the retrieval task and why it has not been easy to devise a general approach. The imprecision of medical terminology is a major stumbling block. The development of specialized systems to serve particular medical interests has hampered the wider applicability of many such systems. This article offers eight characteristics for an ideal medical knowledge system. The key is for each medical term to be coded and independently defined, with synonymous terms to be equated through term codes. Any coded term could become the nucleus of a cluster of related, coded terms. The knowledge system would encompass all of medicine, would be in the public domain, and would be independent of hardware and software. While such a system is utopian, consideration of its characteristics can further the development of better interim systems.

Description and advantages of an index-driven medical knowledge base.

In the FRAMEMED system design, the inherent attributes of its concepts are expressed in the hierarchical lists of its 26 Elements (e.g., Agents, Clinical Manifestations, Diseases, Tests, etc.). These concepts, contained in regular structures, are then alphabetized by phrase (and synonym), forming a combined index in which the user may quickly find a concept either alphabetically or hierarchically. Stored in the structures of the index are pointers to four types of knowledge records: 1) Descriptive (definition); 2) Relational (incidental attributes); 3) Conditional (rules); and 4) Procedural (how to). In contrast to the index which is stored in regular structures for rapid access (like relational databases), the knowledge records are stored in free text (variable length) and may include pointers to imaging and audio records. A particular feature of the FRAMEMED system is careful attention to modifiers, an aspect usually not emphasized in other systems. In trying to structure the free text describing a patient encounter, for example, the major concepts such as cough, fever, stiff neck, etc., are relatively easy to code (although a common system has not yet been agreed upon). The devil lies in the modifiers such as 'history of', 'severe,' 'constant,' 'absent,' 'left,' 'abnormal,' etc., particularly when there is concatenation of modifiers modifying modifiers. Our Relational records (in our knowledge base) and our Chronological Medical Records (CMR) in our patient record have the same format, namely, a title, several related items, and a date/author. For example, our disease profile (Relational record) for 'Influenza' might include 'cough,' 'fever,' and 'stiff neck.' The CMR of a particular patient encounter might include the same items. The only differences would be the title (disease name for the disease profile, date for the CMR, and the omission of the redundant date in the date/author line of the CMR). Each related item in either of these records is expressed in a four-part string, namely: 1) Relation; 2) Code; 3) Phrase; and 4) Comment. Modifiers (common ASCII symbols) are structured into each of these parts. For example, if the patient did not have 'cough,' the default '+' in the Relation would be edited to a '-', while 'history of' cough would be '>'. Each Relation can be graded (on a 5-level scale) for both importance and frequency. The Code for a test can carry the result suffix, '+ positive/high,' '-negative/low,' '# abnormal (qualitatively)', or '1 unremarkable/normal.' Topological information, such as '/left,' can be appended to a Code. If the cough is getting worse, its code can have the suffix, '<'. The standardized Phrases associated with the Codes come from the hierarchical lists of the index section described earlier. Phrases are not stored, being rematched to the codes as needed for user display. This practice not only saves memory space but allows a CMR encounter recorded in one language to be displayed in another second language subsequently, requiring only the existence of the hierarchical code/phrase in the second language. A free-text Comment is allowed for any related item in a Relational record or CMR, to allow the doctor to add important nuances such as 'worse on arising' or for a numeric result such as a test result or a thermometer reading. Some structuring can be accommodated in the Comment by introducing symbols such as '> relieved by,' followed by a list containing entries such as 'antacids.' Time can be sturctured through symbol lists such as '@-2 mo' representing '2 months previously.' Because Relational records in the knowledge ase and patient encoutner records in the CMR both display findings in hierarchical order; all similar items (e.g., Agents, Clinical Manifestations, Tests, Procedures, etc.) occur together and in an unique order. (abstract truncated)

Representing medical knowledge: reconciling the present or creating the future?

Modern technology has sparked the creation of computing systems that perform many medically related tasks, but communication between these systems is limited, in part by differences in the terminology used for various purposes and in part by the changing nature of medical concepts. The Unified Medical Language System represents an attempt to find a means of translation between diverse knowledge systems. An alternative, which we propose, is to agree on a knowledge base for the future and make use of present accomplishments in moving toward that goal.