Fuller Albright and our current understanding of calcium and phosphorus regulation and primary hyperparathyroidism.

The major contributions of Fuller Albright to our understanding of calcium and phosphorus regulation and primary hyperparathyroidism are highlighted. Albright was the first investigator to initiate a systematic study of mineral metabolism. With resources limited to the measurement of serum calcium and phosphorus and the infusion of parathyroid extract, Albright used balance studies to establish a framework for our understanding of calcium and phosphorus regulation and primary hyperparathyroidism. Albright was the first to show that the etiology of primary hyperparathyroidism could be from either an adenoma or hyperplasia of the parathyroid glands and stone disease was a separate manifestation of primary hyperparathyroidism. Albright also showed that: 1) a renal threshold for calcium excretion was present in hypoparathyroid patients; 2) correction of hypocalcemia in hypoparathyroid patients with vitamin D had a phosphaturic action; 3) renal failure reduced the intestinal absorption of calcium in primary hyperparathyroidism; 4) the ''hungry bone'' syndrome developed after parathyroidectomy in severe primary hyperparathyroidism; and 5) a target organ can fail to respond to a hormone. He also suggested that a malignant tumor could be responsible for ectopic hormone production. Finally, our review integrates the observations of Albright with our current knowledge of calcium regulation and disorders.

Quantitative analysis of ES-285, an investigational marine anticancer drug, in human, mouse, rat, and dog plasma using coupled liquid chromatography and tandem mass spectrometry.

A method was developed for the quantitative analysis of the novel anticancer agent ES-285 (spisulosine; free base) in human, mouse, rat, and dog plasma using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry in order to support pre-clinical and clinical studies with the drug. Sample preparation was carried out by protein precipitation with acetonitrile, containing isotopically labeled (d(3)) ES-285 as internal standard. Aliquots of 10 micro l of the supernatant were injected directly on to an Inertsil ODS-3 column (50 x 2.0 mm i.d., 5 micro m). Elution was carried out using methanol-10 mM ammonium formate (pH 4) in water (80 : 20, v/v) pumped at a flow-rate of 0.2 ml min(-1) with a run time of 8 min. Multiple reaction monitoring chromatograms obtained on an API365 triple-quadrupole mass spectrometer were used for quantification. The lower limit of quantitation (LLOQ) was 10 ng ml(-1) in human, mouse, rat, and dog plasma and the linear dynamic range extended to 500 ng ml(-1). A full validation of the method was performed in human plasma, and partial validations were performed in mouse, rat and dog plasma. Accuracies and precisions were <20% at the LLOQ concentration and <15% for all other concentrations in all matrices. ES-285 was stable during all steps of the assay. Thus far this method has been used successfully to analyze over 500 samples in pre-clinical trials, and will be implemented in the planned clinical phase I studies.

Predictors of glycemic control and short-term adverse outcomes in youth with type 1 diabetes.

OBJECTIVES: To examine predictors of glycemic control and to assess how glycemic control affects the incidence of short-term adverse outcomes in a pediatric population with type 1 diabetes. STUDY DESIGN: Three hundred youth, aged 7 to 16 years, with type 1 diabetes who were receiving diabetes specialty care were followed up prospectively for 1 year. Treatment plans and frequency of adverse outcomes were ascertained by questionnaires and medical record review. Incidence rates of adverse outcomes were compared among 3 strata of the population, representing tertiles of baseline glycosylated hemoglobin (HbA1c). RESULTS: Blood glucose monitoring frequency was the sole modifiable predictor of HbA1c (P <.0001). Overall incidence rate of hospitalization was 13 per 100 person-years, more than 3 times the rate in the general pediatric population and significantly higher in the upper HbA1c tertile compared with the other strata (P =.001). Rate of emergency department use was 29 per 100 person-years and did not differ significantly among tertiles. Incidence of severe hypoglycemia was 62 per 100 person-years and notably high even in those with poorest glycemic control. CONCLUSION: Despite improvements in diabetes care, the incidence of short-term adverse events in children with type 1 diabetes remains high, particularly in those with poorest glycemic control.

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.

Elimination of cocaine and metabolites in plasma, saliva, and urine following repeated oral administration to human volunteers.

Chronic administration of lipophilic drugs can result in accumulation and prolonged elimination during abstinence. It has been suggested that cocaine and/or metabolites can be detected in saliva and urine for an extended period following long-term, high-dose administration. The effects of chronic oral cocaine administration in healthy volunteer subjects with a history of cocaine abuse were investigated. Subjects were housed on a closed clinical ward and were administered oral cocaine in up to 16 daily sessions. In each session, volunteers received five equal doses of oral cocaine with 1 h between doses. Across sessions, cocaine was administered in ascending doses from an initial dose of 100 mg (500 mg/day) up to 400 mg (2 g/day), increasing by 25 mg/dose/session (125 mg/session). Participation in the study was terminated if cardiovascular safety parameters were exceeded. Plasma and saliva specimens were collected periodically during the dosing sessions and during the one-week withdrawal phase at the end of the study. All urine specimens were collected throughout the entire study. Specimens were analyzed for cocaine and metabolites by solid-phase extraction followed by gas chromatographic-mass spectrometric analysis in the SIM mode. The limit of detection for each analyte was approximately 1 ng/mL. The analytes measured included benzoylecgonine (BZE), ecgonine methyl ester, cocaine, benzoylnorecgonine, norcocaine, m- and p-hydroxycocaine, and m- and p-hydroxybenzoylecgonine. Noncompartmental analysis was employed for the determination of plasma and saliva pharmacokinetic parameters. Urinary elimination half-lives for cocaine and metabolites were determined by constructing ARE (amount remaining to be excreted) plots. Two phases of urinary elimination of cocaine and metabolites were observed. An initial elimination phase was observed during withdrawal that was similar to the elimination pattern observed after acute dosing. The mean (N = 6) plasma, saliva, and urine cocaine elimination half-lives were 1.5 +/- 0.1 h, 1.2 +/- 0.2 h, and 4.1 +/- 0.9 h, respectively. For three subjects, the mean cocaine urinary elimination half-life for the terminal phase was 19.0 +/- 4.2 h. There was some difficulty in determining if a terminal elimination phase for cocaine was present for the remaining three subjects because of interference by high concentrations of BZE. A terminal elimination phase was also observed for cocaine metabolites with half-life estimates ranging from 14.6 to 52.4 h. These terminal elimination half-lives greatly exceeded previous estimates from studies of acute cocaine administration. These data suggest that cocaine accumulates in the body with chronic use resulting in a prolonged terminal elimination phase for cocaine and metabolites.

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.

Intermittent positive inotrope infusion in the management of end-stage, low-output heart failure.

The US Food and Drug Administration (FDA) has approved the use of the parenteral positive inotropes (dobutamine and milrinone) for short-term treatment of patients with acute, decompensated heart failure (HF). Despite the limited approved indication, parenteral, positive inotropes have been used clinically for long-term therapy to support the circulation as a bridge to transplant among patients waiting for an organ donor. The increasing number of patients with HF who are ineligible for transplant and the inadequate supply of donor organs have generated interest in the use of intermittent, parenteral positive inotropes for palliative therapy in patients with end-stage HF. Efforts by some clinicians to provide optimal symptomatic relief while controlling health care costs have produced a number of HF clinics that provide intermittent, parenteral inotropic therapy as a component of HF therapy. This article reviews the evidence for and against intermittent infusion of these agents in the ongoing care of people with end-stage HF who are not candidates for transplant. The available evidence indicates that intermittent positive inotropic infusion is associated with fewer HF symptoms, increased functional status, reduced health care costs, but also with increased mortality.

Lethal combination of tramadol and multiple drugs affecting serotonin.

The death of a 36-year-old alcoholic man who died after developing seizure activity while being treated with tramadol, as well as with venlafaxine, trazodone, and quetiapine, all of which interact with the neurotransmitter serotonin, is reported. The decedent, who had a history of chronic back pain, alcoholism, depression, mild hypertensive cardiovascular disease, and gastritis, had just been discharged from the hospital after 4 days of alcohol detoxification treatment. During the admission, no withdrawal seizures were noted. The morning after discharge, a witness observed the decedent exhibiting seizure activity and then collapsing. An autopsy was performed approximately 6 hours after death, and the anatomic findings were consistent with seizure activity and collapse, which included biting injuries of the tongue and soft-tissue injuries of the face. Toxicologic analysis identified tramadol, venlafaxine, promethazine, and acetaminophen in the urine; tramadol (0.70 mg/L) and venlafaxine (0.30 mg/L) in the heart blood, and 0.10 mg of tramadol in 40 ml of submitted stomach contents. No metabolites, such as acetate, acetone, lactate, and pyruvate, were found in the specimens that would be characteristically found in a person with alcohol withdrawal syndrome. The threshold for seizures is lowered by tramadol. In addition, the risk for seizure is enhanced by the concomitant use of tramadol with selective serotonin reuptake inhibitors or neuroleptics, and its use in patients with a recognized risk for seizures, i.e., alcohol withdrawal. The cause of death in this individual was seizure activity complicating therapy for back pain, depression, and alcohol withdrawal syndrome. The data in Adverse Event Reporting System of the Food and Drug Administration from November 1, 1997 to September 8, 1999 was reviewed along with a MEDLINE search from 1966 to the present. This case appears to be the first reported death caused by seizure activity in a patient taking tramadol in combination with drugs that affect serotonin.

Stress produced by gavage administration in the rat.

This research project examined the relationship between gavage administration of various vehicles and induction of the stress response, as defined by increased plasma corticosterone levels, in the rat. In addition, we assessed elicitation of clinical signs of distress and aspiration leading to airway/pulmonary changes. We studied various vehicles used in toxicology studies, including water, corn oil, and 1% methylcellulose/0.2% Tween 80. Male CD rats received a single gavage administration of vehicle, blood was collected 1 h after dosing for measurement of plasma corticosterone, and necropsies were performed 4 h after dosing. Gavage administration of corn oil at. 20 mL/kg, but not 1% methylcellulose/0.2% Tween 80 or water, induced a stress response in a volume-dependent fashion, resulting in elevated plasma corticosterone levels. This response was not due to aspiration, which occurred after administration of. 20 mL/kg of water or 1% methylcellulose/0.2% Tween 80 but not corn oil. Administration of corn oil at 40 mL/kg resulted in plasma corticosterone levels that were elevated for 4 h. The stress response produced by corn oil was not unique to this vehicle but also occurred after gavage administration of sesame, soybean, and peanut oils. Our data indicate that gavage dosing of lipid vehicles induces activation of the stress response, as indicated by increased adrenal output of corticosterone, in a volume-dependent fashion. In conclusion, gavage administration of various vehicles can result in aspiration, pulmonary injury, and/or elicitation of a stress response in a vehicle- and dose volume-dependent fashion. The results of our project suggest that dose volumes for gavage administration in the rat generally should not exceed 10 mL/kg.

Difluoromethylornithine in combination with tamoxifen in female rats: 13-week oral toxicity study.

PURPOSE: Cancer chemoprevention is the use of pharmacologic or natural agents to inhibit the development of cancer. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the biosynthesis of polyamines. DFMO has demonstrated chemopreventive efficacy in animal models of tumorigenesis. Tamoxifen (TAM) is currently used for treatment of estrogen receptor-positive breast carcinoma and has demonstrated efficacy in chemoprevention of breast cancer in women at high risk for the disease. The administration of tamoxifen with DFMO is being considered for development by the National Cancer Institute as a potential drug regimen for the chemoprevention of breast carcinoma. METHODS: The toxicity of DFMO in combination with TAM was evaluated in female rats following 13 weeks of daily administration by gavage. Dose groups were vehicle control, DFMO (1000 mg/kg per day), low TAM (0.25 mg/kg per day), high TAM (2.5 mg/kg per day), low combination (1000 + 0.25) and high combination (1000 + 2.5). RESULTS: No mortalities occurred in the study. Clinical signs of toxicity were limited to dermal lesions consisting of scab formation and abrasions produced by DFMO. Administration of either DFMO or TAM resulted in decreased body weight gains, with coadministration having an additive effect. Serum albumin, total protein, cholesterol and triglyceride levels were decreased in all drug-treated dose groups, although histologic evidence of liver lesions were not seen. TAM resulted in increased numbers of red blood cells, whereas DFMO produced a slightly anemic response. DFMO produced lesions in the small intestine consisting of necrosis of crypt epithelium and crypt microabscess, which were enhanced by TAM coadministration. Administration of TAM resulted in histologic changes in the ovaries, fallopian tube, vagina, cervix and uterus, indicating that inhibition of ovulation and reproductive cycle arrest in the proestrus stage had occurred. Coadministration with DFMO did not affect the changes to the reproductive system induced by TAM. CONCLUSIONS: Coadministration of DFMO with tamoxifen did not result in toxicity unique to the combination drug regimen, but rather toxicity resulted from administration of each drug. Under the conditions of the study, the overall toxicity produced by dual administration of DFMO with tamoxifen was additive with respect to the toxicity associated with each agent alone.

Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits.

DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg).

Thirteen-week oral toxicity study of difluoromethylornithine in combination with tamoxifen citrate in female dogs.

PURPOSE: Cancer chemoprevention is the use of pharmacologic or natural agents to inhibit the development of cancer. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the biosynthesis of polyamines. DFMO has demonstrated chemopreventive efficacy in animal models of tumorigenesis. Tamoxifen (TAM), a nonsteroidal antiestrogen, is approved for use in the treatment of estrogen receptor-positive breast carcinoma and has demonstrated efficacy in chemoprevention of breast cancer in women at high risk for the disease. The administration of TAM with DFMO is being considered for development by the National Cancer Institute as a potential drug regimen for the chemoprevention of breast carcinoma. METHODS: The toxicity of DFMO in combination with TAM was evaluated in female Beagle dogs following 13 weeks of daily oral administration by capsule. Dose levels in milligrams per kilogram body weight per day were: 0 (vehicle control), 100 DFMO, 0.1 TAM, 1.0 TAM, 0.1 TAM + 100 DFMO and 1.0 TAM + 100 DFMO. RESULTS: No mortalities occurred. Diarrhea was produced by TAM and vaginal discharge, due to reproductive tract lesions, was produced by both DFMO and TAM, either alone or in combination. DFMO decreased reticulocyte counts and TAM increased counts of mature neutrophils. DFMO alone resulted in lesions to the intestines and ovaries, and cornified epithelium of vagina and cervix. TAM produced cornified epithelium of vagina and cervix, and numerous lesions in the ovaries, fallopian tube, uterus, cervix and vagina which were likely due to an estrogen agonist effect. Coadministration of DFMO increased the incidence and/or severity of these reproductive tract lesions. Each compound alone produced ovarian atrophy, and antral follicles and corpora lutea were completely absent in the 1.0 TAM + 100 DFMO group. CONCLUSIONS: Coadministration of DFMO and TAM resulted in additive toxicity involving the female reproductive system.

Determination of phenethylamine, a phenethyl isothiocyanate marker, in dog plasma using solid-phase extraction and gas chromatography-mass spectrometry with chemical ionization.

Phenethyl isothiocyanate is unstable in aqueous media and at low pH, and rapidly degrades to phenethylamine. Concentrations of phenethylamine, a phenethyl isothiocyanate marker, in dog plasma, were determined utilizing solid-phase extraction and gas chromatography-mass spectrometry with chemical ionization using acetone as the reagent gas. Deuterated d5-amphetamine was used as an internal standard. After extraction, phenethylamine and d5-amphetamine were derivatized using MBHFBA. Ions monitored for d5-amphetamine were m/z 337 and 338; and for phenethylamine were m/z 318 and 319. Precision and accuracy were studied using control solutions prepared in naive dog plasma (80 and 300 ng/ml). Intra-day variability was determined using six replicates of each control solution analyzed on a single day. The relative standard deviation for the 80 ng/ml control was 12.9% and for the 300 ng/ml it was 12.1%. Relative accuracy was 10.9% for the low control and -4.1% for the high control. Inter-day variability was determined over a 6-day period. For the 80 and 300 ng/ml control solutions, the relative standard deviations were 15.8 and 9.1%, respectively, and relative accuracy values were 10.1 and -5.2%, respectively. Standard curves were prepared in naive dog plasma and were linear over the range of phenethylamine assayed (10-500 ng/ml). The results of this study indicate that the proposed method is simple, precise, accurate and sensitive enough for analysis of large numbers of plasma samples.

Management of chronic heart failure in the outpatient.

Current management of chronic heart failure involves reducing the personal and economic burden through controlling symptoms, reducing hospital admissions, and slowing the progression of ventricular dysfunction. As healthcare providers struggle to control the rising costs of health and illness care while reducing morbidity and mortality rates associated with chronic illness, alternative practice models must be evaluated. This article describes a collaborative practice model designed to improve care of older adults with chronic heart failure. Strengths of the model include the use of evidence-based guidelines for heart failure management and for organization of the practice.

Ability of a phase shift US contrast agent to improve imaging of the main renal arteries.

PURPOSE: To evaluate the ability of a phase shift contrast agent to improve Doppler sonographic imaging of the main renal arteries in cases of suspected renal artery stenosis. MATERIALS AND METHODS: In 25 patients in whom renal artery stenosis was suspected, baseline Doppler sonography was performed followed by two studies performed after blinded administration of contrast material or placebo (saline). Each kidney (n = 45) was evaluated for (a) visualization of the main renal artery on a scale of 0-4, (b) presence of accessory renal arteries, and (c) direct Doppler sonographic findings suggestive of renal artery stenosis. Correlative magnetic resonance angiography was performed in 24 patients, and angiograms were obtained in eight kidneys with stenosis at one or both imaging studies. RESULTS: Contrast enhancement was observed in 23 patients. Enhancement was 8-20 minutes. Renal artery visualization scores improved from a mean of 2.56 and 2.71 on baseline and noncontrast scans, respectively, to 3.69 after administration of contrast material. Contrast-enhanced images depicted seven kidneys with accessory renal arteries not seen at other studies. Two of eight cases of stenosis were seen only with contrast-enhanced sonography. CONCLUSION: Use of the phase shift contrast agent appears to enable a reduction in the number of equivocal findings of renal artery stenosis.

Psychophysiological response to a laboratory challenge in women with and without diagnosed irritable bowel syndrome.

The purpose of this study was to describe and compare physiological variables at baseline and in response to laboratory stress among women diagnosed with irritable bowel syndrome (IBS, n = 26), women with undiagnosed chronic gastrointestinal symptoms consistent with IBS (IBS-NP, n = 24), and asymptomatic women (n = 22). Urine catecholamine levels were measured in the first voided specimen on the morning of testing. Cardiovascular variables were measured at baseline and repeatedly during the Stroop Color-Word Conflict Test (Stroop). Women in the IBS group had higher baseline systolic blood pressure (SBP) than the control group and higher basal urine norepinephrine (NE) levels than the IBS-NP group. Control for activity or body mass reduced the group difference in SBP to nonsignificance but did not affect the observed difference in urine NE. There were no significant differences among the groups in other baseline values or in response to the Stroop. These results suggest that, despite higher basal urine catecholamine levels, cardiovascular reactivity to a cognitive challenge in a laboratory setting is not elevated in women with diagnosed IBS.

Dose-response characteristics of mibefradil, a novel calcium antagonist, in the treatment of essential hypertension.

The aim of this study was to determine the dose-response characteristics of the calcium antagonist, mibefradil, and to evaluate its antihypertensive efficacy and safety in varying doses in patients with mild-to-moderate hypertension. Three hundred and three eligible patients were randomized to receive once-daily 6.25-, 12.5-, 25-, 50-, 100-, 150-, or 200-mg mibefradil doses or placebo for 4 weeks. Repeated blood pressure measurements and electrocardiographic recordings were obtained for the 24 h following the last dose of the placebo run-in period and for the first and last doses of randomized treatment. A statistically significant (P < .001 versus placebo) and clinically relevant drop in sitting diastolic blood pressure (SDBP) both at trough and at peak was observed in the 50-, 100-, 150-, and 200-mg mibefradil dose groups (trough placebo-corrected reductions: -4.9, -9.1, -9.9, and -11.9 mm Hg, respectively), with a significant dose-response relationship (P < .001) and high response rates. Trough/peak ratios for the placebo-corrected change from baseline to week 4 in SDBP were >85% for the 50- and 100-mg doses and 68% and 69% for the 150- and 200-mg doses, respectively. The full antihypertensive effect of mibefradil was achieved within 1 week of treatment. Reductions in sitting systolic blood pressure (SSBP) closely paralleled those in SDBP. The antihypertensive effect of mibefradil was associated with a slight dose-dependent decrease in heart rate and increase in the pulse rate (PR) electrocardiographic interval [corrected]. The appropriate therapeutic dose range of mibefradil in the management of mild-to-moderate essential hypertension is 50 to 100 mg.

Evaluation of indapamide 1.25 mg once daily in elderly patients with mild to moderate hypertension.

The objective of this study was to evaluate the safety and efficacy of indapamide 1.25 mg once daily as monotherapy in elderly patients (65 years and older) with mild to moderate essential hypertension. Two hundred and seventy-nine (279) elderly patients were enrolled in a washout period, during which patients received single-blind placebo for 4 weeks. Patients demonstrating supine diastolic pressures between 95 mm Hg and 114 mm Hg at the end of the 4-week placebo washout period were entered into the 8-week double-blind treatment period. Two hundred and four (204) patients qualified for the study and were randomized to the double-blind treatment; 103 patients received indapamide 1.25 mg and 101 patients received placebo for 8 weeks. Overall, 177 patients (92 indapamide and 85 placebo) completed the study. The primary efficacy criterion was the mean change in supine diastolic blood pressure (DBP) from double-blind baseline to the end of 8 weeks of therapy. By week 8 of the double-blind treatment period, indapamide 1.25 mg produced a statistically significant (P = 0.0037) decrease in supine DBP of 8.2 mm Hg compared to a decrease of 5.3 mm Hg produced in the placebo group. Additionally, indapamide 1.25 mg was statistically (P = 0.0028) more effective than placebo in reducing supine systolic BP (SBP) (-10.1 vs -4.2 mm Hg). The incidence of drug-related adverse events during the double-blind treatment period was similar between the two treatment groups. A low dose of indapamide, 1.25 mg, given once daily for 8 weeks was effective as monotherapy with respect to BP reduction in an elderly population with mild to moderate hypertension. Indapamide 1.25 mg was safe and generally well tolerated in this elderly patient population.

A comparison of ethanol concentrations in the occipital lobe and cerebellum.

While many publications have addressed the issue of ethanol concentration in brain tissue as a better indicator of impairment than blood alcohol concentration (BAC), very few have looked at the regional distribution of ethanol in the brain and its possible significance in postmortem sampling. This paper reports on the analysis of occipital pole and cerebellar hemisphere for ethanol in 25/brain samples obtained at autopsy from the brain collection of the National Institutes of Mental Health/Stanley Foundation. When available, these concentrations were compared to BAC. The average ratio of occipital lobe alcohol concentration (OAC) to BAC for cases which also had blood samples (18/24) was 0.9, SD = 0.5, with a range of 0-1.8; the average ratio of cerebellar alcohol concentration (CAC) to BAC for these cases was 0.6, SD = 0.4, range = 0-1.2. When only those cases with a BAC > or = 0.04 g/dl (14/18 cases) were considered, the average OAC/BAC and CAC/BAC ratios were 0.8 (SD = 0.4) and 0.7 (SD = 0.4), respectively. These distribution ratios are well within the ranges reported by other authors and do not significantly differ from each other. The cortical brain region available or selected for postmortem ethanol analysis is probably not critical.

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.