New Diagnostic Criteria for the Localization of Insulinomas with the Selective Arterial Calcium Injection Test: Decision Tree Analysis.

PURPOSE: To explore optimal diagnostic criteria for localizing insulinomas with the selective arterial calcium injection (SACI) test using decision tree analysis. MATERIALS AND METHODS: A retrospective study included 86 vessels of 18 patients (5 men, 13 women; mean age 67 y; range, 49-73 y) with insulinomas who underwent SACI test between June 2007 and May 2016. Of 27 insulinomas, 7 were found in the head, 13 in the body, and 7 in the tail of the pancreas. Two patients had multiple tumors. To identify optimal diagnostic criteria, decision tree analysis was performed, and sensitivity, specificity, and accuracy of the conventional and the proposed new diagnostic criteria (plasma insulin concentration after calcium injection [ICpost] > 2.0 × plasma insulin concentration before calcium injection [ICpre]) were compared. RESULTS: The proposed new diagnostic criteria for insulinoma obtained by decision tree analysis were (i) ICpost > 2.7 × ICpre and maximum insulin concentration > 60.3 µIU/mL or (ii) ICpost > 2.7 × ICpre and maximum insulin concentration < 60.3 µIU/mL with ICpre being ≥ 7.5 µIU/mL. Sensitivity, specificity, and accuracy of the new criteria for the SACI test were 100%, 91.4%, and 94.2; sensitivity, specificity, and accuracy of conventional criteria were 100%, 69.0%, and 79.1%. CONCLUSIONS: New diagnostic criteria for localization of insulinomas with the SACI test yielded higher diagnostic performance than conventional criteria.

Expert Panel Recommendations for the Identification and Management of Hyperkalemia and Role of Patiromer in Patients with Chronic Kidney Disease and Heart Failure.

Virtual panel meetings were conducted among 7 physicians, all of whom are independent experts, including 3 nephrologists, 2 cardiologists, and 2 emergency medicine physicians (the panel). The panel met with the purpose of discussing the current treatment landscape, treatment challenges, economic impact, and gaps in care for patients with hyperkalemia that is associated with heart failure and chronic kidney disease. The stated goal of the panel discussion was to develop practical solutions in the identification and management of hyperkalemia in this patient population. The panel noted that hyperkalemia is a serious condition that can lead to life-threatening complications, yet the treatment paradigm for hyperkalemia has remained without major advances for approximately 50 years, until the approval of patiromer. A number of issues still exist in the management of this patient population, including the lack of uniform treatment guidelines and consensus regarding the approach to treatment. As part of its effort, the panel developed an algorithm, the Proposed Diagnostic Algorithm for Hyperkalemia Treatment in the Acute Care Setting/Chronic Care. The panel agreed that patiromer appears to be a viable option for the management of hyperkalemia in patients with chronic kidney disease and/or heart failure and in patients who experience chronic hyperkalemia. DISCLOSURES: This panel discussion was funded by Relypsa and facilitated by Magellan Rx Management. Rafique is a principal investigator for Relypsa and serves as a consultant for Instrumentation Laboratory, Magellan Health, Relypsa, and ZS-Pharma. Butler serves as consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, CardioCell, Janssen, Merck, Novartis, Relypsa, and ZS-Pharma. Lopes and Farnum are employed by Magellan Rx Management. Rafique designed the management protocol for this panel discussion and contributed to the writing and editing of this report document. The other authors report no conflicting interests. Relypsa is the manufacturer of Veltassa (patiromer).

Comparative assessment of calcitonin stimulation test using calcium gluconate and pentagastrin and the usefulness of procalcitonin basic and post-stimulation concentrations in the diagnosis of patients after surgery for medullary.

OBJECTIVES: The aim of the study was to compare the calcitonin (CT) stimulation tests with tests of calcium gluconate (CaG) and pentagastrin (PG), their tolerance and usefulness of PCT in the patients' diagnosis with active Medullary thyroid cancer (MCT) after thyroidectomy. METHODS: CT was marked in serum by the immunosorbent sandwich test. PCT was marked by the immunosorbent sandwich test, with the final reading of fluorenscence. PG was given intravenously at a dose of 0.5 mg/kg body weight for 10 seconds. CaG was also given by intravenous injection at a dose of 2.5 mg of elemental Ca/kg body weight at a rate of 5ml/min, for minimum 3 minutes. Blood was taken at the 0 minute, the 3 and 5 minute after getting the stimulating substances. RESULTS: The post-stimulation CT concentration in the 3 and 5 minute of the CaG test vs PG is significantly higher compared to the baseline. The maximal stimulation of the CT is in the 3 minute, but higher concentrations occurred using the CaG. CONCLUSION: The results of the study suggest a similar diagnostic value of the tests with CaG compared to the PG as stimulants. In the present study we noticed a trend of basic and post-stimulation concentrations of PCT to increase in the tests with PG and CaG which correspond with the elevated concentrations of CT.

Assessment and clinical course of hypocalcemia in critical illness.

INTRODUCTION: Hypocalcemia is common in critically ill patients. However, its clinical course during the early days of admission and the role of calcium supplementation remain uncertain, and the assessment of calcium status is inconsistent. We aimed to establish the course of hypocalcemia during the early days of critical illness in relation to mortality and to assess the impact of calcium supplementation on calcium normalization and mortality. METHODS: Data were collected on 1,038 admissions to the critical care units of a tertiary care hospital. One gram of calcium gluconate was administered intravenously once daily to patients with adjusted calcium (AdjCa)<2.2 mmol/L. Demographic and outcome data were compared in normocalcemic (ionized calcium, iCa, 1.1-1.3 mmol/L) and mildly and severely hypocalcemic patients (iCa 0.9-1.1 mmol/L and <0.9 mmol/L, respectively). The change in iCa concentrations was monitored during the first four days of admission and comparisons between groups were made using Repeated Measures ANOVA. Comparisons of normalization and outcome were made between hypocalcemic patients who did and did not receive calcium replacement according to the local protocol. The suitability of AdjCa to predict low iCa was determined by analyzing sensitivity, specificity and receiver operating characteristic (ROC) curves. Multivariate logistic regression was performed to determine associations of other electrolyte derangements with hypocalcemia. RESULTS: 55.2% of patients were hypocalcemic on admission; 6.2% severely so. Severely hypocalcemic patients required critical care for longer (P=0.001) compared to normocalcemic or mildly hypocalcemic patients, but there was no difference in mortality between groups (P=0.48). iCa levels normalized within four days in most, with no difference in normalization between those who died and survived (P=0.35). Severely hypocalcemic patients who failed to normalize their iCa by day 4 had double the mortality (38% vs. 19%, P=0.15). Neither iCa normalization nor survival were superior in hypocalcemic patients receiving supplementation on admission. AdjCa<2.2 mmol/L had a sensitivity of 78.2% and specificity of 63.3% for predicting iCa<1.1 mmol/L. Low magnesium, sodium and albumin were independently associated with hypocalcemia on admission. CONCLUSIONS: Hypocalcemia usually normalizes within the first four days after admission to ICU and failure to normalize in severely hypocalcemic patients may be associated with increased mortality. Calcium replacement appears not to improve normalization or mortality. AdjCa is not a good surrogate of iCa in an ICU setting.

Cost-effectiveness analysis regarding postoperative administration of vitamin-D and calcium after thyroidectomy to prevent hypocalcaemia / Análisis de costo-efectividad de la administración postoperatoria de Vitamina D y calcio después de tiroidectomía para la prevención de la hipo calcemia

Objective Hypocalcaemia is a frequently arising complication following total thyroidectomy. Routine postoperative prophylactic administration of vitamin D or metabolites and calcium reduce the incidence of symptomatic hypocalcaemia; this article reports evaluating its cost-effectiveness in Colombia. Methods Meta-analysis was used for comparing the administration of vitamin D or metabolites to oral calcium or no treatment at all in patients following total thyroidectomy and a cost-effectiveness analysis was designed based on a decision-tree model with local costs. Results The OR value for the comparison between calcitriol and calcium compared to no treatment and to exclusive calcium treatment groups was 0.32 (0.13-0.79 95 %CI) and 0.31 (0.14-0.70 95 %CI), respectively. The most cost-effective strategy was vitamin D or metabolites and calcium administration, having a US $0.05 incremental cost-effectiveness ratio. Conclusion Prophylactic treatment of hypocalcaemia with vitamin D or metabolites + calcium or calcium alone is a cost-effective strategy.

Objetivos La hipo calcemia es la complicación más frecuente después de tiroidectomía. La administración profiláctica de vitamina D o metabolitos y calcio reduce la incidencia de hipocalcémia sintomática. Se evalúa su costo-efectividad en Colombia. Materiales y métodos Utilizamos la información de un meta-análisis que comparó la administración de vitamina D o metabolitos contra calcio no tratamiento en pacientes llevados a tiroidectomía total y diseñamos un análisis de costo-efectividad basados en un modelos de decisiones con costos locales. Resultados El valor del OR para la comparación entre calcitriol y calcio comparado con no tratamiento o calcio exclusivo fue de 0.32 (95 % IC, 0.13- 0.79) y 0.31 (95 % IC, 0.14-0.70), respectivamente. La estrategia más costo-efectiva fue la administración de vitamina D o metabolitos y calcio, con una relación de costo-efectividad incremental de US $0.05. Conclusiones El tratamiento profiláctico de la hipo calcemia con vitamina D o metabolitos y calcio o calcio exclusivo después de tiroidectomía total es una estrategia costo-efectiva.

Stability assessment of o/w parenteral nutrition emulsions in the presence of high glucose and calcium concentrations.

The purpose of the present study was to examine how the colloid stability features of o/w parenteral nutrition emulsions made with SMOFlipid (lipid emulsion based on soybean oil, medium chain triglycerides, olive oil and fish oil) will change in the presence of high concentration of calcium and glucose if usual micronutrients are also present, according to the needs of the clinical nutrition patient. Particle size analysis, zeta potential, dynamic surface tension measurements and light microscopic screening were carried out to evaluate the possible changes in the kinetic stability of the emulsions. Our results indicate that the higher glucose concentration of 15 or 20% could not compensate the emulsion-destabilizing effect of higher (5 mM) calcium concentration even in the presence of a modern fat emulsion. Therefore calcium demand of undernourished patient requiring 5 mM or higher final Ca²âº content in nutrient solution should be supplemented in another way.

Cost-effectiveness analysis regarding postoperative administration of vitamin-D and calcium after thyroidectomy to prevent hypocalcaemia.

OBJECTIVE: Hypocalcaemia is a frequently arising complication following total thyroidectomy. Routine postoperative prophylactic administration of vitamin D or metabolites and calcium reduce the incidence of symptomatic hypocalcaemia; this article reports evaluating its cost-effectiveness in Colombia. METHODS: Meta-analysis was used for comparing the administration of vitamin D or metabolites to oral calcium or no treatment at all in patients following total thyroidectomy and a cost-effectiveness analysis was designed based on a decision-tree model with local costs. RESULTS: The OR value for the comparison between calcitriol and calcium compared to no treatment and to exclusive calcium treatment groups was 0.32 (0.13-0.79 95 %CI) and 0.31 (0.14-0.70 95 %CI), respectively. The most cost-effective strategy was vitamin D or metabolites and calcium administration, having a US $0.05 incremental cost-effectiveness ratio. CONCLUSION: Prophylactic treatment of hypocalcaemia with vitamin D or metabolites + calcium or calcium alone is a cost-effective strategy.

[Assessment of the protective effect of calcium-magnesium infusion and glutathione on oxaliplatin-induced neurotoxicity].

OBJECTIVE: To assess the efficacy of calcium-magnesium (Ca/Mg) infusion and glutathione (GSH) for preventing the neurotoxicity induced by oxaliplatin. METHODS: This is a randomized, double blind, placebo controlled clinical trail. The patients receiving FOLFOX4 chemotherapy for their solid tumor were randomized to receive Ca/Mg, GSH or normal saline with chemotherapy simultaneously. The incidence and severity of oxaliplatin-induced neurotoxicity were observed. The ECOG performance status was recorded and compared among the 3 groups. RESULTS: Ninety-three patients admitted in our department from Mar 2006 to Dec 2007 were entered into this study, including 29 patients in the Ca/Mg group, 33 in the GSH group and 31 in the chemotherapy alone group. The incidences of acute neurotoxicity were 82.8%, 90.9% and 93.5%, respectively. At the third cycle, the incidences of grade 1-2 chronic neurotoxicity were 37.9%, 48.5% and 42.0%, respectively. No grade 3 neuropathy was observed. After 6 cycles, the incidence of grade 1-2 neuropathy was increased to 68.2%, 88.9% and 85.2%, respectively. A lower percentage was observed in Ca/Mg arm without a statistically significant difference, and grade 3 neuropathy occurred in 5 patients. After 9 cycles, the incidence of grade 1-2 neuropathy was increased to 81.3%, 90.0% and 92.9%, respectively. Grade 3 neuropathy occurred in another 2 patients. No statistically significant difference was observed among the 3 arms. Changes of patient's ECOG score after chemotherapy were similar. CONCLUSION: This study didn't provide evidence that Ca/Mg infusion and GSH can prevent the oxaliplatin-induced neurotoxicity.

Early hospital readmission was less likely for hemodialysis patients from facilities with longer median length of stay in the DOPPS study.

The length of hospital stay is considered to influence hospital readmission in general. The Dialysis Outcomes and Practice Patterns Study (DOPPS), an international prospective observational study undertaken to establish a relationship between facility practices and dialysis outcomes, started in 1996. Results suggest that the duration of hospital stay is significantly correlated with the probability of early readmission in dialysis patients. Thus, early hospital readmission was observed to be less likely for hemodialysis patients from facilities with longer median length of stay. The lengths of hospital stay for hemodialysis patients differed in the three continents studied. Although socioeconomic pressures may drive the lengths of hospital stay, the duration of hospitalization should be determined keeping in mind the safety of clinical course for each disease. In this forum, a 47-year-old female hemodialysis patient with severe secondary hyperparathyroidism, who had been treated with hemodialysis for 21 years, was hospitalized with severe clinical symptoms. Although the clinical symptoms disappeared 10 days after total parathyroidectomy with autotransplantation, severe hypocalcemia persisted despite large amounts of intravenous calcium gluconate. This patient was hospitalized for a long duration owing to the large calcium deficit in her body. Had the length of her hospital stay been shortened, either she could have needed rehospitalization or her condition could have worsened.

[Life threatening hyperkalemia: the value of the electrocardiogram]. / Levensbedreigende hyperkaliëmie: de waarde van het elektrocardiogram.

In two men, aged 19 and 64, with chronic renal insufficiency and subacute symptoms of malaise and weakness of the leg muscles, broad QRS complexes were seen in the ECG. The younger patient developed an asystole and resuscitation was unsuccessful. His blood potassium level was found to be 8.3 mmol/l. The older patient recovered after administration of calcium gluconate. His blood potassium level was found to be 8.5 mmol/l. An 80-year-old woman who was taking various drugs because of heart failure also complained of muscle weakness. Her blood potassium level was 7.2 mmol/l and her ECG showed narrow complexes. She recovered without calcium gluconate after a change in medication. Hyperkalemia is a potentially life-threatening electrolyte disorder that may require immediate treatment. The changes in the ECG, especially widening of the QRS complexes, are the most important clues to the severity of the hyperkalemia. A treatment protocol based on ECG changes may reduce the mortality in these patients.

Assessment of selective arterial calcium stimulation and hepatic venous sampling to localize insulin-secreting tumours.

OBJECTIVE: Non-invasive localization modalities such as ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) often fail to localize insulinomas smaller than 2 cm in diameter. Recent studies have shown that the selective arterial stimulation and hepatic venous sampling (ASVS) technique using intra-arterial calcium as the insulin secretagogue facilitates the regionalization of such occult insulinomas. This study assesses the sensitivity of ASVS in localizing insulin-secreting tumours. SUBJECTS AND METHODS: Eleven consecutive patients (8 women), aged 29-82 years, were studied over the past 4 years at our hospital. Hyperinsulinaemic hypoglycaemia due to an insulin-secreting tumour was proven in all patients. Calcium gluconate (0.025 mEq/kg body weight) was injected directly into the arteries supplying the pancreas and the liver. Insulin levels were measured in samples taken from the right hepatic vein before and 30, 60 and 120 s after each injection. The ASVS technique was performed in all 11 patients; the results were compared with the surgical findings in 10 patients and the autopsy findings in 1 case. The ASVS results were also compared with the findings of other, previously performed imaging modalities. RESULTS: ASVS correctly localized 4 insulin-secreting tumours to the head, 3 to the body, 1 to the tail, 2 to the tail or body of the pancreas and 1 to the liver. Thus, the sensitivity was 100% (11/11) whereas other localization techniques were less sensitive: 7/11 tumours were detected by angiography, 4/8 by endosonography, 3/8 by CT and 1/6 by MRI. Insulinomas (confirmed by histological examination), sized 4-25 mm, were found in 10 patients. All were cured by selective surgery and remained free of hypoglycaemia over the next 1-4 years of follow-up. An insulin-secreting neuroendocrine tumour in the liver was documented in 1 case at autopsy. CONCLUSIONS: Arterial stimulation and hepatic venous sampling is a very sensitive technique for preoperative localization of insulin-producing tumours. It can help to plan minimally invasive surgery and to select an appropriate strategy for patients suffering from malignant tumours in others.

Topical treatments for hydrofluoric acid dermal burns. Further assessment of efficacy using an experimental piq model.

Several topical treatments for hydrofluoric acid dermal burns (Zephiran, calcium acetate and magnesium hydroxide antacid soaks, and calcium gluconate gel) were assessed for efficacy in a pig model. Gross appearance and histopathology of treated and untreated burn sites were evaluated. For superficial burns, Zephiran was most effective; calcium acetate, magnesium hydroxide antacid, and calcium gluconate gel were less effective. For deep burns, gross observations showed that calcium acetate and Zephiran were most efficacious, whereas histopathology indicated comparable efficacy of Zephiran, calcium acetate, and calcium gluconate gel for all skin layers. Magnesium hydroxide antacid demonstrated efficacy only for the subdermis. The clinically beneficial effects of both Zephiran and calcium gluconate gel were affirmed. Although results suggest that calcium acetate and magnesium-containing antacids may be beneficial for human hydrofluoric acid dermal burns, these are not established clinical treatments.

Evaluation of four animal models of intrarenal calcium deposition and assessment of the influence of dietary supplementation with essential fatty acids on calcification.

Firstly, to determine a satisfactory animal model for induction of intrarenal calcification, a study of four previously described animal models of intrarenal calcification was carried out which showed that intraperitoneal injection of 10% calcium gluconate into female Sprague-Dawley rats was most effective. We then investigated the hypothesis that dietary supplementation with essential fatty acids could reduce the intrarenal calcification developing as a result of intraperitoneal calcium injection. Using a combination of fish oil and evening primrose oil, we demonstrated a significant difference in renal parenchymal calcification, which was 940 +/- 240 micrograms Ca/g dry weight renal parenchyma in unsupplemented animals and 320-370 +/- 55-65 micrograms Ca/g dry weight renal parenchyma in supplemented animals (means +/- SEM, P < 0.005). It was also demonstrated that there was synergism between eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA): dietary supplementation with a combined oil preparation containing 27 mg/ml EPA and 67 mg/ml GLA mixed as 2% with food was as effective as oils containing either 400 mg/ml EPA or 80 mg/ml GLA mixed as 4% of food.

Direct in vivo assessment of parathyroid hormone-calcium relationship curve in renal patients.

Secondary hyperparathyroidism (SHP) is a well documented finding even in the early stages of chronic renal failure (CRF). A sigmoidal relationship, fitting a four parameter model, links PTH secretion rate and calcium concentration changes. To our knowledge, PTH secretory parameters have only been studied in uremic patients who are in dialysis treatment. As a result of these studies, a possible role for derangement in setpoint values (that is, the serum calcium concentration corresponding to the mid-range value on the sigmoidal curve) has been suggested in the pathogenesis of SHP in CRF. Our study was undertaken to gain insight into the calcium-PTH relationship curve in the first course of CRF and to assess whether a change in any of the secretory parameters is related to the beginning of SHP. We studied 27 male renal patients with a variable degree of renal function (creatinine clearance 12 to 164 ml/min) and 9 control subjects. In all patients and controls the following parameters were evaluated: (1) basal 1,25(OH)2 vitamin D, 25(OH)vitamin D, calcitonin (CT), intact PTH; (2) GFR by Cr51EDTA clearance; (3) the sigmoidal PTH-ionized calcium relation curve, by means of a hypocalcemic stimulating test (Na2-EDTA 37 mg/kg body weight/2 hr) and a hypercalcemic test (Ca gluconate giving 8 mg/kg of body weight/2 hr of Ca element), performed on two consecutive days.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo assessment of left atrial contractile performance in normal and pathological conditions using a time-varying elastance model.

BACKGROUND: Contractile function of the ex vivo, isolated left atrium (LA) has been described by a time-varying elastance, but this atrial chamber property has not been shown in vivo. METHODS AND RESULTS: Instantaneous LA pressure-volume (P-V) relations were studied in 12 anesthetized, autonomically blocked, atrially paced dogs. LA volume was calculated from orthogonal sonomicrometer pairs using a cast-validated formula. Data were collected during increases in LA pressure produced by a phenylephrine bolus (200 to 400 micrograms IV). Isochronal P-V points from 5 beats, representing a wide range of atrial pressures, were fitted by linear regression analysis (range of R2, .92 to .99). There were significant time-dependent increases in the slopes [E(t)] and small but statistically insignificant decreases in the volume axis intercepts [VO(t)] of the instantaneous LA P-V relations during atrial contraction; maximal elastance (Emax) occurred 29 +/- 16 milliseconds before atrial end systole (minimal LA volume). Emax was not significantly different than the slopes of either the nonisochronal end-systolic P-V relation (Ees) or the nonisochronal maximal P-to-V relation (EmaxPV): 5.5 +/- 2.8, 4.3 +/- 1.5, and 5.4 +/- 4.2 mm Hg/mL, respectively. In 7 dogs, data were collected both before and after a rapid infusion of calcium gluconate (1 to 2 g IV). Emax increased significantly with a calcium-induced increase in inotropic state (4.5 +/- 1.6 to 5.7 +/- 1.8 mm Hg/mL, P < .01), but the volume axis intercept was unchanged (3.6 +/- 0.7 versus 3.4 +/- 1.9, P = NS). In 4 additional dogs with heart failure (mean LA pressure, 26 +/- 6 mm Hg) produced by 3 weeks of rapid right ventricular pacing, LA stroke volume was significantly greater than and elastance determinations were similar to those of normal dogs. However, the effects of calcium infusion on LA function were attenuated in these animals. CONCLUSIONS: We conclude that (1) in the intact heart, LA contraction may be approximated by time-varying elastance with time-dependent changes in E(t) and that (2) LA systolic P-V relations using either the nonisochronal maximum P-to-V ratio or end systole may be useful as an estimate of Emax, are highly linear and sensitive to calcium-induced changes in inotropic state, and may be useful in identifying LA chamber adaptation to chronic hemodynamic loads.

Hydrofluoric acid dermal burns. An assessment of treatment efficacy using an experimental pig model.

There currently exist various opinions concerning the best therapy for managing hydrogen fluoride (HF) dermal burns. Previously reported animal studies designed to evaluate the efficacy of certain therapies are not completely convincing. Studies initially were conducted to develop a reliable animal model for assessing efficacy of treatment. Evaluation of several animal species, dosing regimens (HF concentrations, exposure periods), and application techniques showed that the most consistent and reproducible dermal lesions were produced with 38% HF applied to the skin of anesthetized pigs for exposures of 9, 12, or 15 minutes using Hill Top Chamber patches. Using this model, the efficacy of six clinically applicable treatments was assessed by subjectively scoring and statistically analyzing photographic and histopathological data obtained from treated and untreated control lesions. Photographic data analysis ranked treatments with respect to effectiveness as follows: iced Zephiran and 10% calcium acetate soaks--highly effective; 2.5% calcium gluconate gel, 5.0% calcium gluconate injection and iced Hyamine soaks--effective; 10% calcium gluconate injection--ineffective. Histopathological data analysis showed the topical treatments (2.5% calcium gluconate gel, iced Hyamine, or iced Zephiran soaks) to be most effective in reducing superficial epidermal damage, and the 5% calcium gluconate injection or 10% calcium acetate soaks to be beneficial to deeper tissues of the dermis and subdermis. Injection of 10% calcium gluconate was ineffective. This study suggests that the anesthetized pig model has good applicability for assessing efficacy of HF dermal burn therapies. In addition, it indicates that further experimentation with 10% calcium acetate soaks is warranted.

A method for in vivo assessment of calcium slow channel blocking drugs.

A method is described, using the cardioaccelerator response in pithed rats, that distinguishes calcium entry blockers from other agents which have modes of action not involving direct blockade of calcium entry. Diltiazem (0.01-0.3 mg kg-1), verapamil (0.01-0.03 mg kg-1), nifedipine (0.1-1.0 mg kg-1), propranolol (0.003-0.3 mg kg-1), xylazine (0.01-1.0 mg kg-1), alinidine (0.03-1.0 mg kg-1), and, to a lesser extent, lignocaine (0.1-3.0 mg kg-1), reduced stimulation-evoked sustained cardioaccelerator responses in the pithed rat. BRL 34915 (0.3-10.0 mg kg-1) and nicorandil (1.0-10.0 mg kg-1) were without effect in this situation. Infusion of calcium gluconate (1.0 mg min-1) reversed the reduction of the cardioaccelerator responses by nifedipine (1.0 mg kg-1), verapamil (0.3 mg kg-1), and diltiazem (0.3 mg kg-1) but not to propranolol (0.1 mg kg-1), alinidine (0.5 mg kg-1), or xylazine (0.3 mg kg-1). Therefore, calcium gluconate is selective in reversing the effects of calcium slow channel blockers in this model, thereby making it a useful technique for distinguishing these drugs in vivo.

Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response.

We developed methods for identifying beta-adrenergic receptors in human right ventricular endomyocardial biopsy tissue with the radioligand (-)[125I]iodocyanopindolol (ICYP). Specific ICYP binding in a crude, high-yield membrane preparation derived from endomyocardial biopsy tissue was high (specificity greater than 90%), of high affinity (KD around 20 pM), saturable and stereospecific for the (-) vs the (+) isomer of isoproterenol. Subjects with mild-moderate and severe biventricular dysfunction had respective decreases in beta-adrenergic receptor density of 38.2% and 57.7% when normalization methods were averaged, with no significant differences in ICYP dissociation constant. A subgroup of subjects was subdivided by left ventricular ejection fraction (LVEF) into those with mild cardiac dysfunction (LVEF less than 0.50 greater than 0.40) and severe heart failure (LVEF less than 0.20) and given graded sequential infusions of dobutamine and calcium gluconate. Those with severe cardiac dysfunction had marked impairment of the dobutamine dP/dt and stroke work index response, whereas these responses to calcium did not differ in the two groups. These data indicate that in the intact human heart endomyocardial biopsy may be used for direct analysis of beta-adrenergic receptors, heart failure-associated myocardial beta-adrenergic down-regulation begins with mild-moderate ventricular dysfunction, reduction in myocardial beta-receptor density is related to degree of heart failure, and beta-receptor down-regulation is associated with pharmacologically specific impairment of the beta-agonist-mediated contractile response.