Effects of oral rehydration and external cooling on physiology, perception, and performance in hot, dry climates.

Only limited research evaluates possible benefits of combined drinking and external cooling (by pouring cold water over the body) during exercise. Therefore, this study examined cold water drinking and external cooling on physiological, perceptual, and performance variables in hot, dry environments. Ten male runners completed four trials of walking 90 min at 30% VO(2max) followed by running a 5-km time trial in 33 ± 1 °C and 30 ± 4% relative humidity. Trials examined no intervention (CON), oral rehydration (OR), external cooling (EC), and oral rehydration plus external cooling (OR + EC). Investigators measured rectal temperature, skin temperatures, heart rate, thirst, thermal sensation, and ratings of perceived exertion (RPE). Oral rehydration (OR and OR + EC) significantly lowered heart rate (P < 0.001) and thirst (P < 0.001) compared with nondrinking (CON and EC) during low-intensity exercise. External cooling (EC and OR + EC) significantly reduced chest and thigh temperature (P < 0.001), thermal sensation (P < 0.001), and RPE (P = 0.041) compared with non-external cooling (CON and OR) during low-intensity exercise. Performance exhibited no differences (CON = 23.86 ± 4.57 min, OR = 22.74 ± 3.20 min, EC = 22.96 ± 3.11 min, OR + EC = 22.64 ± 3.73 min, P = 0.379). Independent of OR, pouring cold water on the body benefited skin temperature, thermal sensation, and RPE during low-intensity exercise in hot, dry conditions but failed to influence high-intensity performance.

An assessment of cinacalcet HCl effects on bone histology in dialysis patients with secondary hyperparathyroidism.

AIMS: Cinacalcet lowers plasma parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism (sHPT), but the bone histologic response has not been described. This prospective, double-blind, placebo-controlled trial assessed the effects of cinacalcet on bone histology and serum markers of bone metabolism in dialysis patients with sHPT. METHODS: Patients with intact PTH (iPTH) > or = 300 pg/ml were randomly assigned 2:1 to receive cinacalcet or placebo with concurrent vitamin D and/or phosphate binder therapy. Cinacalcet (30 - 180 mg/day) was used to achieve iPTH levels < or = 200 pg/ml. Bone biopsies were performed before and after one year of treatment. RESULTS: Baseline and end-of-study data were available from 32 patients (19 cinacalcet, 13 placebo). Baseline bone turnover was elevated in 27, reduced in 3 and normal in 2 patients. Serum bone-specific alkaline phosphatase (BSAP) and N-telopeptide (NTx) were elevated. Cinacalcet treatment decreased PTH and diminished activation frequency, bone formation rate/bone surface, and fibrosis surface/bone surface. Adynamic bone was observed in three patients receiving cinacalcet; in two of these, PTH levels were persistently low (< 100 pg/ml). The histomorphometric parameter changes in bone corresponded to PTH, BSAP and NTx reductions. Bone mineralization parameters remained normal. CONCLUSIONS: Treatment with cinacalcet lowered PTH and reduced bone turnover and tissue fibrosis among most dialysis patients with biochemical evidence of sHPT.

Mechanomyographic responses of the superficial quadriceps femoris muscles to incremental isometric muscle actions.

The purpose of this study was to compare the composite and individual relationships for mechanomyographic (MMG) amplitude vs. torque during incremental isometric muscle actions. Ten women and six men (mean age +/- SD = 21.8 +/- 1.6 y) performed isometric leg extension muscle actions at 10-100% of peak isometric torque. Accelerometers were placed over the superficial quadriceps femoris muscles to detect the MMG signals. Polynomial regression analyses were used to determine the composite and individual patterns for MMG amplitude vs. isometric torque. The results indicated that the composite MMG amplitude vs. isometric torque relationships for all subjects combined were quadratic for the vastus lateralis and vastus medialis, and linear for the rectus femoris. The results of the individual analyses for the vastus lateralis revealed that the best fit model was linear for six subjects, quadratic for five subjects, cubic for three subjects, while two subjects exhibited no significant relationship. For the rectus femoris, eight subjects demonstrated linear patterns, six were quadratic, and two were cubic. For the vastus medialis, six subjects demonstrated linear patterns, four were quadratic, four were cubic, and two demonstrated no significant relationship. Examination of the patterns between muscles for each individual subject demonstrated that twelve of the sixteen subjects demonstrated different patterns for MMG amplitude vs. isometric torque for at least two of the three muscles examined. The results indicated there were differences in the patterns of responses for the composite MMG amplitude vs. isometric torque relationships for the three muscles. Furthermore, individual patterns for MMG amplitude frequently differed from the composite patterns, as well as between muscles. The results suggested that, in addition to using composite results of MMG responses, individual subject responses should be examined. Furthermore, caution should be used in generalizing the MMG responses of the quadriceps femoris muscles when examining a single muscle.

Comparison of Fourier and wavelet transform procedures for examining mechanomyographic and electromyographic frequency versus isokinetic torque relationships.

The purpose of this study was to compare the isokinetic torque-related patterns for mechanomyographic (MMG) and electromyographic (EMG) center frequency [wavelet center frequency (CF), mean power frequency (MPF), and median frequency (MDF)] determined by the fast Fourier transform (FFT) and discrete wavelet transform (DWT). Ten adults [mean +/- SD age = 22.0 +/- 3.4 yrs] performed submaximal to maximal, isokinetic muscle actions of the biceps brachii on a Cybex II dynamometer. For both MMG and EMG, the CF, MPF, and MDF values were intercorrelated at (r = 0.91-0.98). Quadratic models provided the best fit for the absolute and normalized CF, MPF, and MDF versus isokinetic torque relationships for MMG (R2 = 0.67-0.83) and EMG (R2 = 0.72-0.90). The similarities among the CF, MPF, and MDF patterns suggested that Fourier or wavelet transform procedures can be used to examine the patterns of MMG and EMG responses during dynamic muscle actions.

The acute effects of static stretching on peak torque, mean power output, electromyography, and mechanomyography.

The purpose of this study was to examine the acute effects of static stretching on peak torque (PT), the joint angle at PT, mean power output (MP), electromyographic (EMG) amplitude, and mechanomyographic (MMG) amplitude of the vastus lateralis (VL) and rectus femoris (RF) muscles during maximal, voluntary concentric isokinetic leg extensions at 60 and 240 degrees x s(-1) of the stretched and unstretched limbs. Twenty-one volunteers [mean age (SD) 21.5 (1.3) years] performed maximal, voluntary concentric isokinetic leg extensions for the dominant and non-dominant limbs at 60 and 240 degrees x s(-1). Surface EMG (muVrms) and MMG (mVrms) signals were recorded from the VL and RF muscles during the isokinetic tests. PT (Nm), the joint angle at PT, and MP (W) were calculated by a dynamometer. Following the initial isokinetic tests, the dominant leg extensors were stretched using four static stretching exercises. After the stretching, the isokinetic tests were repeated. PT decreased (P< or =0.05) from pre- to post-stretching for the stretched limb at 60 and 240 degrees x s(-1) and for the unstretched limb at 60 degrees x s(-1). EMG amplitude of the VL and RF also decreased (P< or =0.05) from pre- to post-stretching for the stretched and unstretched limbs. There were no stretching-induced changes (P>0.05) for the joint angle at PT, MP, or MMG amplitude. These findings indicated stretching-induced decreases in force production and muscle activation. The decreases in PT and EMG amplitude for the unstretched limb suggested that the stretching-induced decreases may be due to a central nervous system inhibitory mechanism.

Mechanomyographic and electromyographic amplitude and frequency responses during fatiguing isokinetic muscle actions of the biceps brachii.

The purpose of this investigation was to examine the mechanomyographic (MMG) and electromyographic (EMG) amplitude and mean power frequency (MPF) patterns during fatiguing isokinetic muscle actions of the biceps brachii. Ten adults [three women (mean +/- SD age = 20 +/- 2 yrs) and seven men (mean +/- SD age = 23 +/- 3 yrs) ] volunteered to perform 50 consecutive maximal, concentric isokinetic muscle actions of the biceps brachii at 180 degrees x s(-1). The percent decline (mean +/- SD) in isokinetic peak torque (PT) was 70 +/- 17% and polynomial regression analyses indicated a cubic relationship (R2 = 0.994) between PT and repetition number. Both MMG amplitude and MMG MPF decreased linearly (r2 = 0. 774 and 0.238, respectively) across repetitions. The results for EMG amplitude demonstrated a cubic (R2 = 0.707) pattern across repetitions, where EMG amplitude increased during repetitions 1-20, remained stable during repetitions 20-40, and increased during repetitions 40-50. There was a quadratic (R2 = 0. 939) reduction in EMG MPF throughout the test. The decreases in MMG amplitude and MMG MPF may have been due to de-recruitment of fast fatiguing motor units, a reduction in muscular compliance, or the effects of "muscle wisdom." The results for EMG amplitude may have reflected nonmaximal efforts by the subjects and/or peripheral fatigue. The factor(s) determining the decrease in EMG MPF are unclear, although a reduction in muscle fiber action potential conduction velocity may have been partially responsible.

Mechanomyographic time and frequency domain responses of the vastus medialis muscle during submaximal to maximal isometric and isokinetic muscle actions.

The purpose of this study was to examine the patterns for the mechanomyographic (MMG) amplitude and mean power frequency (MPF) versus torque relationships during isometric and isokinetic muscle actions. Ten adults (mean age +/- SD = 22 +/- 1 y) volunteered to perform isometric and isokinetic leg extension muscle actions at 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100% of peak torque on a Cybex II dynamometer. A piezoelectric crystal contact sensor was placed on the vastus medialis to detect the MMG signal. Regression analyses indicated that for the isometric muscle actions, the relationships for MMG amplitude (R2 = 0.998) and MPF (R2 = 0.987) versus torque were cubic. For the isokinetic muscle actions, the relationships for MMG amplitude (r2 = 0.927) and MPF (r2 = 0.769) versus torque were linear. The different patterns for MMG amplitude and frequency may reflect differences in the motor control strategies that modulate torque production for isometric versus dynamic muscle actions.

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.

Effect of intensive glycemic control on microalbuminuria in type 2 diabetes. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes Feasibility Trial Investigators.

OBJECTIVE: Microalbuminuria can reflect the progress of microvascular complications and may be predictive of macrovascular disease in type 2 diabetes. The effect of intensive glycemic control on microalbuminuria in patients in the U.S. who have had type 2 diabetes for several years has not previously been evaluated. RESEARCH DESIGN AND METHODS: We randomly assigned 153 male patients to either intensive treatment (INT) (goal HbA(1c) 7.1%) or to standard treatment (ST) (goal HbA(1c) 9.1%; P = 0.001), and data were obtained during a 2-year period. Mean duration of known diabetes was 8 years, mean age of the patients was 60 years, and patients were well matched at baseline. We obtained 3-h urine samples for each patient at baseline and annually and defined microalbuminuria as an albumin:creatinine ratio of 0.03-0.30. All patients were treated with insulin and received instructions regarding diet and exercise. Hypertension and dyslipidemia were treated with similar goals in each group. RESULTS: A total of 38% of patients had microalbuminuria at entry and were evenly assigned to both treatment groups. INT retarded the progression of microalbuminuria during the 2-year period: the changes in albumin:creatinine ratio from baseline to 2 years of INT versus ST were 0.045 vs. 0.141, respectively (P = 0.046). Retardation of progressive urinary albumin excretion was most pronounced in those patients who entered the study with microalbuminuria and were randomized to INT. Patients entering with microalbuminuria had a deterioration in creatinine clearance at 2 years regardless of the intensity of glycemic control. In the group entering without microalbuminuria, the subgroup receiving ST had a lower percentage of patients with a macrovascular event (17%) than the subgroup receiving INT (36%) (P = 0.03). Use of ACE inhibitors or calcium-channel blockers was similarly distributed among the groups. CONCLUSIONS: Intensive glycemic control retards microalbuminuria in patients who have had type 2 diabetes for several years but may not lessen the progressive deterioration of glomerular function. Increases in macrovascular event rates in the subgroup entering without albuminuria who received INT remain unexplained but could reflect early worsening, as observed with microvascular disease in the Diabetes Control and Complications Trial.

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.

A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism.

BACKGROUND: The calcimimetic agent R-568 lowers plasma parathyroid hormone (PTH) levels in hemodialysis patients with mild secondary hyperparathyroidism, but its efficacy in those with more severe secondary hyperparathyroidism has not been studied. METHODS: Twenty-one patients undergoing hemodialysis three times per week with plasma PTH levels between 300 and 1200 pg/mL were randomly assigned to 15 days of treatment with either 100 mg of R-568 (N = 16) or placebo (N = 5). Plasma PTH and blood ionized calcium levels were measured at intervals of up to 24 hours after oral doses on days 1, 2, 3, 5, 8, 11, 12, and 15. RESULTS: Pretreatment PTH levels were 599 +/- 105 (mean +/- SE) and 600 +/- 90 pg/mL in subjects given R-568 or placebo, respectively, and values on the first day of treatment did not change in those given placebo. In contrast, PTH levels fell by 66 +/- 5%, 78 +/- 3%, and 70 +/- 3% at one, two, and four hours, respectively, after initial doses of R-568, remaining below pretreatment values for 24 hours. Blood ionized calcium levels also decreased after the first dose of R-568 but did not change in patients given placebo. Despite lower ionized calcium concentrations on both the second and third days of treatment, predose PTH levels were 422 +/- 70 and 443 +/- 105 pg/mL, respectively, in patients given R-568, and values fell each day by more than 50% two hours after drug administration. Predose PTH levels declined progressively over the first nine days of treatment with R-568 and remained below pretreatment levels for the duration of study. Serum total and blood ionized calcium concentrations decreased from pretreatment levels in patients given R-568, whereas values were unchanged in those given placebo. Blood ionized calcium levels fell below 1.0 mmol/L in 7 of 16 patients receiving R-568; five patients withdrew from study after developing symptoms of hypocalcemia, whereas three completed treatment after the dose of R-568 was reduced. CONCLUSIONS: The calcimimetic R-568 rapidly and markedly lowers plasma PTH levels in patients with secondary hyperparathyroidism caused by end-stage renal disease.

Calcimimetic agents and the calcium-sensing receptor.

Blood ionized extracellular calcium is closely regulated. To accomplish this, a hormone-like receptor that is responsive to extracellular ionized calcium regulates both the secretion of parathyroid hormone and the excretion of urinary calcium (as well as other cellular processes). Several hereditary disorders have mutations that cause either loss or gain of function of the calcium-sensing receptor, and alterations of the calcium-sensing receptor may play a role in both primary and secondary hyperparathyroidism. Calcimimetics are agents that act to make the calcium-sensing receptor more sensitive to extracellular ionized calcium; thereby they suppress the secretion of parathyroid hormone. Early trials in animal models of secondary hyperparathyroidism and in patients with primary hyperparathyroidism or with uremic secondary hyperparathyroidism have shown that the first generation calcimimetic, R-568, effectively lowers parathyroid hormone levels and is well tolerated.

Calcium-sensing receptor and calcimimetic agents.

Recognizing the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism greatly improves our understanding of calcium homeostasis. The biology of the low affinity, G-protein-coupled CaR and the effects of its activation in various tissues are reviewed. Physiological roles include regulation of parathyroid hormone (PTH) secretion by small changes in ionized calcium (Ca2+) and control of urinary calcium excretion with small changes in blood Ca2+. The CaR also affects the renal handling of sodium, magnesium and water. Mutations affecting the CaR that make it either less or more sensitive to Ca2+ cause various clinical disorders; heterozygotes of mutations causing the CaR to be less sensitive to extracellular Ca2+ cause familial hypocalciuric hypercalcemia, while the homozygous form results in severe infantile hyperparathyroidism. Mutations causing increased sensitivity of the CaR to extracellular Ca2+ produce hereditary forms of hypoparathyroidism. Disorders, such as primary and secondary hyperparathyroidism, may exhibit acquired abnormalities of the CaR. Calcimimetic drugs, which amplify the sensitivity of the CaR to Ca2+, can suppress PTH levels, leading to a fall in blood Ca2+. Experiences with this agent in patients with secondary and primary hyperparathyroidism and parathyroid carcinoma are summarized. In animals and humans with hyperparathyroidism, this agent produces a dose-dependent fall in PTH and blood Ca2+, with larger doses causing more sustained effects. The treatment has been short-term except for one patient followed for more than 600 days for parathyroid carcinoma; nonetheless the drug did not cause major side-effects and appears to be safe. Further long-term controlled studies are needed with calcimimetic agents of this type.

Intermittent oral 1alpha-hydroxyvitamin D2 is effective and safe for the suppression of secondary hyperparathyroidism in haemodialysis patients. 1alphaD2 Study Group.

Calcitriol and alfacalcidol are useful in suppressing parathyroid hormone (PTH) in haemodialysis patients, but hypercalcaemia and hyperphosphataemia are frequent. The vitamin D analogue, 1alpha-hydroxyvitamin D2 (1alphaD2), has a higher therapeutic index in animal models. Previously, 1alphaD2, 4 microg/day or 4 microg/haemodialysis, lowered iPTH to the target range in 87.5% of 24 haemodialysis patients with moderate to severe secondary hyperparathyroidism (plasma iPTH, 359-1521 pg/ml). The incidences of hypercalcaemia (serum Ca>2.8 mM) or hyperphosphataemia (serum P>2.23 mM) were low. Later, 10 of these patients were re-treated with 1alphaD2, initial dose, 10 microg, thrice weekly with haemodialysis. The iPTH was suppressed as readily, and there was no greater incidence of hypercalcaemia and hyperphosphataemia. Based on these data, a large, multicentre study is ongoing in California and Tennessee/Mississippi, using 1alphaD2 in haemodialysis patients with iPTH >400 pg/ml. In this and the earlier studies, only calcium-based phosphate binders were used to control serum phosphorus. The initial dose, 10 microg thrice weekly with haemodialysis, is adjusted to maintain a target iPTH within the range of 150-300 microg/ml; the final dose range is 2.5-20 microg per haemodialysis. The protocol includes 8 weeks of wash-out with no vitamin D, 16 weeks of open label treatment period with 1alphaD2, and finally 8 weeks of randomized double blinded treatment with either continued 1alphaD2 or placebo. Forty two patients from California and 38 from Tennessee/Mississippi have completed 16 weeks of open label treatment. In California, iPTH declined from 832+/-95 pg/ml at baseline to 222+/-71 pg/ml at the nadir and to 477+/-117 pg/ml at week 16 of the treatment. In Tennessee/Mississippi, the iPTH declined from 977+/-65 pg/ml to 286+/-42 pg/ml at the lowest point and to 493+/-79 at the end of the treatment. Plasma iPTH reached or fell below the target range in 84% of the 80 patients completing open treatment. Asymptomatic hypercalcaemia (serum Ca>2.8 mM) increased from 0.3 episodes/100 weeks during wash-out to 3.6 episodes/100 treated weeks in California and from 0 to 3.7 episodes in Tennessee/Mississippi. In California and Tennessee, the episodes of hyperphosphataemia (serum P>2.2 mM) increased from 5.0 and 5.0 episodes per 100 patient/week during wash-out to 10.1 and 10.9 episodes/100 treatment weeks, respectively, with 1alphaD2 treatment. There were no adverse events in association with 1alphaD2 treatment. Thus, oral 1alphaD2 is safe and highly effective for the treatment of secondary hyperparathyroidism.

Prevention of metabolic bone disease in the pre-end-stage renal disease setting.

The methods for preventing hyperparathyroid bone disease, the major variety of renal osteodystrophy, from developing in patients with renal impairment are reviewed. With far-advanced chronic renal failure (creatinine clearance [CCr] < 15 to 20 ml/min), when many of these patients are seen by nephrologists, the use of diets very low in protein, and hence also very low in phosphorus content, combined with calcium-containing phosphate binders, have been shown to lower serum intact PTH levels and improve the osseous pathology. However, the degree of dietary restriction required to achieve success may be quite difficult to follow by most patients encountered in clinical practice. In less-advanced renal insufficiency (CCr, 25 to 60 ml/min), the active vitamin D sterols calcitriol or alfacalcidol [1 alpha-hydroxyvitamin D3] have been shown to ameliorate the skeletal lesions of renal osteodystrophy. The results of six double-blind, placebo-controlled studies and five major open-labeled studies with calcitriol or alfacalcidol are reviewed. Skeletal biopsies were improved and sometimes normalized by using calcitriol or alfacalcidol in daily doses of 0.25 to 0.5 microgram/d, and the incidence of hypercalcemia was quite low with these doses. When the dosage was increased in one study, there was a higher incidence of hypercalcemia. Improved bone mineral density of the spine and hip was reported after 1 yr in calcitriol-treated patients compared with results in the placebo group. Another report documented more favorable intact PTH suppression with intermittent dosing of 2.0 micrograms given either once or three times weekly compared with daily dosing (0.5 microgram/d); there was no rise of serum Ca over the 3-mo trial with any protcol. Other data support the greater likelihood of having normal bone if treatment is initiated when CCr exceeds 25 ml/min. There was no risk of more rapid progression of renal insufficiency in any of the studies reviewed, which include 242 patients who were given an active vitamin D sterol. One trial that used a calcitriol dose of 0.5 microgram/d noted a fall in CCr and a rise in serum creatinine, but true GFR (inulin clearance) did not change. A calcitriol-induced reduction of tubular creatinine secretion is suggested. The risk of inducing low bone turnover (adynamic bone) seems to be quite low with 10.4% of alfacalcidol-treated patients versus 6.5% of placebo developing this "lesion" after 2 yr. Despite the lack of Food and Drug Administration approval for use of these sterols in the predialysis state, evidence is compelling that: there are benefits in retarding the development or progression of metabolic bone disease; there is minimal risk, providing that low doses are used; and there is close monitoring of serum Ca, P, and creatinine. The optimal benefits may be obtained if this treatment is started early in the course of renal insufficiency (CCr in the range of 25 to 60 ml/min).

Effective suppression of parathyroid hormone by 1 alpha-hydroxy-vitamin D2 in hemodialysis patients with moderate to severe secondary hyperparathyroidism.

Calcitriol, as used for treating secondary hyperparathyroidism, has a low therapeutic index. The safety and efficacy of the vitamin D analog, 1 alpha (OH)-vitamin D2, (1 alpha D2), which has less toxicity in animals than 1 alpha (OH)-vitamin D3, was tested in a multicenter study of 24 hemodialysis patients with secondary hyperparathyroidism [serum intact (i) PTH > 400 pg/ml]. Calcium-based phosphate binders alone were used to maintain serum phosphorus < or = 6.9 mg/dl. After eight weeks without calcitriol (washout), oral 1 alpha D2, 4 micrograms/day or 4 micrograms thrice weekly, was started, with the dose adjusted over 12 weeks to maintain serum iPTH between 130 and 250 pg/ml. Pre-treatment serum iPTH fell from 672 +/- 70 pg/ml (SEM) to 289 +/- 36 after treatment (P < 0.05). The maximal decrease in serum iPTH was 48 to 96%, with 87.5% of patients reaching target iPTH levels. The final dose of 1 alpha D2 average 14.2 micrograms/week. Pre-treatment serum calcium rose modestly from 8.8 +/- 0.2 mg/dl to 9.5 +/0 0.2 after treatment (P < 0.001). Only once did modest hypercalcemia (serum Ca > 11.2 mg/dl) necessitate stopping treatment. Neither the average serum P level, the incidence of hyperphosphatemia, nor the dose of phosphate binders changed from washout to treatment. Thus, oral 1 alpha D2 is highly efficacious in suppressing secondary hyperparathyroidism in hemodialysis patients and is safe despite exclusive use of calcium-based phosphate-binders. Future studies should clarify the optimal dosage regimen.

1 alpha-Hydroxy-vitamin D2: a new look at an 'old' compound.

Calcitriol is effective in suppressing PTH levels in haemodialysis patients with hyperparathyroidism but has a low therapeutic index. There is a search for other vitamin D sterols that suppress PTH but cause less hypercalcaemia. We review evidence that 1 alpha-hydroxy-vitamin D2 (1 alpha-D2) may be an effective and safer alternative to calcitriol. In vitamin D-deficient rats, 1 alpha-D2 is equipotent to 1 alpha-D3, which is converted to calcitriol before it acts; but, in normal rats, 1 alpha-D2 is much less toxic at high doses. In osteopenia models, either steroid-induced or following ovariectomy, 1 alpha-D2 is equal to or more effective than 1 alpha-D3 in preventing bone loss but causes less hypercalciuria. Studies in osteoporotic women reveal minimal hypercalciuria with 1 alpha-D2 at doses up to 4 micrograms/day, data suggesting greater safety than reported with calcitriol or 1 alpha-D3. Preliminary data in haemodialysis patients with secondary hyperparathyroidism demonstrate the efficacy of 1 alpha-D2 in suppressing PTH levels with minimal untoward effects on serum Ca and no effects on serum P. Taken together, these observations suggest that 1 alpha-D2 deserves strong consideration as a therapeutic agent for secondary hyperparathyroidism associated with end-stage renal disease.

Symptomatic hypercalcemia in a diabetic patient undergoing continuous ambulatory peritoneal dialysis: value of bone biopsy in the diagnosis and management.

An elderly man with diabetes mellitus and end-stage renal disease managed with continuous ambulatory peritoneal dialysis (CAPD) was hospitalized with peripheral vascular insufficiency; he developed hypercalcemia and became mentally obtunded. Lowering dialysate Ca from 3.5 mEq/L to 2.5 mEq/L, stopping calcium acetate, and ultimately hemodialysis with calcium-free dialysate did not lead to reversal of the hypercalcemia or improvement of his symptoms. The intact parathyroid hormone PTH level was 187 pg/mL, a value rarely associated with significant osteitis fibrosa. A search for other causes of hypercalcemia was unrevealing, and a iliac crest bone biopsy was done. The latter showed osteitis fibrosa, and the patient underwent parathyroidectomy. The hypercalcemia reversed quickly, and his mental symptoms slowly improved. The discussion reviews the probable causes of hypercalcemia in diabetic patient undergoing CAPD with 3.5 mEq/L dialysate calcium and using calcium-containing phosphate binders, with hyperparathyroidism certainly not the usual cause. The reason for the occurrence of significant hyperparathyroidism in the face of only modest elevation of PTH is considered. The value of bone biopsy in resolution of this problem is apparent.

Effects of sucralfate and ranitidine on aluminum concentrations in elderly volunteers.

Elevated aluminum concentrations have been implicated in several disease states in the elderly. We examined the effects of sucralfate, a basic aluminum salt of sucrose sulfate, and ranitidine, administered individually and in combination, on plasma and urine aluminum concentrations in the elderly in a prospective, randomized, three-arm crossover study. Subjects were 20 healthy volunteers over age 65 years, with no clinically significant comorbidities or recent use of aluminum-containing drugs or histamine (H)2-antagonists. The three regimens were ranitidine 300 mg at bedtime, sucralfate 1 g 4 times/day, and ranitidine 300 mg at bedtime plus sucralfate 1 g 4 times/day, administered for 4 weeks, with a washout period of at least 1 week between regimens. Plasma and urine aluminum concentrations were measured on days 0, 1, 7, 14, and 28 of each regimen. After 28 days, mean plasma aluminum concentrations were significantly higher in subjects receiving sucralfate alone (8.5 +/- 1.8 micrograms/L) and sucralfate plus ranitidine (5.1 +/- 1.3 micrograms/L) compared with those receiving ranitidine alone (2.4 +/- 0.7 micrograms/L). Urine aluminum concentrations were significantly higher in subjects receiving sucralfate alone (133.2 +/- 32.8 micrograms/g creatinine) and sucralfate plus ranitidine (148.1 +/- 51.9 micrograms/g creatinine) compared with those receiving ranitidine alone (11.0 +/- 3.7 micrograms/g creatinine). There was no significant difference in plasma or urine aluminum concentrations between subjects who received sucralfate alone versus those who received sucralfate plus ranitidine. Sucralfate 4 g/day in elderly subjects produces a significant increase in both plasma and urine aluminum concentrations, compared with ranitidine 300 mg/day. This increase most likely is secondary to gastrointestinal absorption of aluminum in the sucralfate formulation. The clinical relevance of this increase requires further evaluation.