High-dose Calcium Research Articles

Cell-associated magnesium and QT dispersion in hemodialysis patients

Background: Impaired magnesium (Mg) homeostasis has been implicated in a variety of cardiovascular disturbances, including ventricular arrhythmias and changes in the interval between the onset of wave Q to the end of wave T (QT interval) on electrocardiogram. Cardiac arrhythmias are common in patients on hemodialysis therapy. Methods: We investigated the relationship between QT interval corrected for heart rate (QTc) dispersion and Mg content in peripheral blood mononuclear cells (PBMC) of chronic hemodialysis patients treated with high-dose calcium carbonate providing Mg in excess (group I; n = 18) or low-dose calcium carbonate and smaller Mg load (group II; n = 13). Results: Mean Mg content in PBMC of group I patients (27.9 ± 4.2 [SD] μmol/L/mg protein) was significantly greater than in group II patients (10.4 ± 4.1 μmol/L/mg protein; P < 0.05) and greater in both groups than in healthy control subjects (2.75 ± 0.6 μmol/L/mg protein; P < 0.05). Mean QTc dispersion was significantly longer (74.6 ± 21.4 milliseconds) in group I than group II (37.8 ± 13.1 milliseconds; P < 0.02) and longer in both groups than in controls (27.3 ± 9.6 milliseconds; P < 0.05). After dialysis, in both groups of patients, cell-associated Mg (c-a Mg) levels and QTc dispersion were significantly greater (P < 0.05) than before dialysis started. One week after stopping calcium carbonate treatment, group 1 patients showed significant reductions in predialytic c-a Mg levels (to 19.5 ± 9.8 μmol/L/mg protein; P < 0.05) and QTc dispersions (to 48.9 ± 23.7 milliseconds; P < 0.05). Plasma Mg and other electrolyte concentrations prior to and during hemodialysis did not correlate with QTc dispersion. Conclusion: Prolongation of QTc dispersion in patients on chronic hemodialysis therapy could be, at least in part, a consequence of increased concentrations of c-a Mg resulting from excess daily Mg intake. Am J Kidney Dis 41:196-202. © 2003 by the National Kidney Foundation, Inc.

Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure

Pulmonary hypertension (PHT) is mainly explained by four underlying pathophysiological phenomena: 1. Vasoconstriction, 2. reduction of pulmonary vascular bed, 3. reduction in vessel elasticity, and 4. obliteration of the vessel lumen by thrombotic material and subsequent cellular alterations of the vessel wall (vascular remodeling). Chronic right heart load is thus a consequence of increased pulmonary pressure and vascular resistance. Main targets of advanced therapeutic strategies are therefore first: resolution of chronically increased vascular tone by smooth muscle cell relaxation (vasodilators), second: reversal of vascular remodeling and third: prevention from pulmonary embolization and/or in-situ thrombosis (chronic anticoagulation). Long term administration of high dose calcium channel blockers (though operative only in a minority of 10 - 15 % of all patients), prostanoids (eg. prostacyclin, iloprost), and the recently approved unselective oral endothelin antagonist bosentan are regarded as established medical therapies for treatment of chronic PHT. However, applicability of these substances can be limited by potentially serious adverse events and/or necessity for elaborate parenteral application. Recent data are indicative for a strong pulmonary vasodilative potency of the selective phosphodiesterase-5 (PDE5) inhibitor sildenafil. Smaller clinical studies and numerous case reports underline the good tolerability of this orally applied substance in various form of PHT. Based on these encouraging results, the simple availability, and the low costs (in comparison to "established therapies") of the drug, sildenafil is currently widely used in an "off-label" indication for treatment of PHT. Controlled randomized studies have to confirm the current findings, before general recommendations regarding the use of sildenafil for treatment of PHT can be made.

The role of the vitamin D receptor in regulating vitamin D metabolism: a study of vitamin D-dependent rickets, type II.

In vitro studies and animal experiments suggest that the production of 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] and 24,25-(OH)(2)D is reciprocally controlled by 1,25-(OH)(2)D. To investigate the role of the vitamin D receptor (VDR) in controlling vitamin D metabolism in humans, we studied 10 patients with vitamin D-dependent rickets type II due to a defective VDR. After a period of high dose calcium therapy, 7 of the patients had normal serum calcium, phosphorus, alkaline phosphatase, and plasma PTH levels (PTH-N), and 3 showed increased serum alkaline phosphatase and plasma PTH (PTH-H). Serum calcium, phosphorus, alkaline phosphatase, PTH, vitamin D metabolites, urinary calcium/creatinine, and renal phosphate threshold concentration were compared with unaffected family members that comprised the control group. Vitamin D metabolites were measured before and after an oral load of 50,000 U/m(2) cholecalciferol. Compared with the control group, 1,25-(OH)(2)D levels were significantly higher and 24,25-(OH)(2)D levels were lower in the PTH-N group and even more so in the PTH-H group. 1alpha-Hydroxylase (1-OHase) and 24-OHase activities were estimated by the product/substrate ratio. In the PTH-N group, 1-OHase activity was higher and 24-OHase activity was lower than in controls. In the PTH-H group, 1-OHase activity was even higher, probably due to an additive effect of PTH. Thus, 1,25-(OH)(2)D-liganded VDR is a major control mechanism for vitamin D metabolism, and PTH exerts an additive effect. Assessment of the influence of 1,25-(OH)(2)D shows reciprocal control of enzyme activity in man, suppressing 1-OHase and stimulating 24-OHase activity.

Calcium neutralizes fluoride bioavailability in a lethal model of fluoride poisoning.

Acute systemic fluoride poisoning can result in systemic hypocalcemia, cardiac dysrhythmias, and cardiovascular collapse. Topical and intraarterial therapy with calcium or magnesium salts reduces dermal injury from fluoride burns. The mechanism of these therapies is to bind and inactivate the fluoride ion. The purpose of this study is to evaluate the effect of calcium and magnesium to decrease the bioavailability of fluoride in a lethal model of fluoride poisoning. In preliminary studies, we determined that fluoride 3.6 mM/kg intraperitoneally in the form of sodium fluoride was uniformly and rapidly fatal in a mouse model. Using this fluoride dose, we performed a controlled, randomized, blinded study of low- and high-dose calcium chloride (1.8 and 3.6 mM/kg intraperitoneally, respectively) and magnesium sulfate (3.6 mM/kg intraperitoneally) to decrease the bioavailability of the fluoride ion. After injection with sodium fluoride, animals were immediately treated with injections of sodium chloride (control), calcium chloride (low- or high-dose), or magnesium sulfate. The major outcome was 6-hour survival using a Cox Proportional Hazard model. All untreated animals died within 60 minutes. Using a Cox Proportional Hazard model, each 1.8 mM/kg dose of calcium chloride administered reduced the risk of death by 33%. Magnesium sulfate treatment was not associated with a hazard reduction. Calcium chloride administered simultaneously with sodium fluoride reduces the bioavailability of fluoride poisoning in a mouse model. The equivalent dose of magnesium sulfate does not significantly decrease fluoride bioavailability.

Comparison of efficacy and side effects of combination therapy of angiotensin-converting enzyme inhibitor ( benazepril) with calcium antagonist (either nifedipine or amlodipine) versus high-dose calcium antagonist monotherapy for systemic hypertension

The present 2 multicenter studies were designed to evaluate whether patients with essential hypertension derived equal benefits from use of combination therapy with a calcium antagonist and angiotensin-converting enzyme (ACE) inhibitor as from doubling the dose of the calcium antagonist. After a 2-week washout and a 2-week single-blind placebo run-in period, a total of 1,390 patients were treated with either nifedipine 30 mg (study 1) or amlodipine 5 mg (study 2) once daily for 4 weeks. The 1,079 patients whose diastolic blood pressure remained between 95 and 115 mm Hg were randomized to 8 weeks of double-blind therapy with amlodipine 5 mg/benazepril 10 mg, amlodipine 5 mg/benazepril 20 mg, nifedipine 30 mg or nifedipine 60 mg (study 1), and amlodipine 5 mg/benazepril 10 mg, amlodipine 5 mg/benazepril 20 mg, amlodipine 5 mg or amlodipine 10 mg (study 2). Both doses of the calcium antagonist/ACE inhibitor combination therapy lowered diastolic pressure as much as the high dose and significantly better than the lower dose of calcium antagonist monotherapy (with either nifedipine or amlodipine). However, 15% of patients in the nifedipine high-dose monotherapy group and 24% in the amlodipine high-dose monotherapy group presented with some form of edema. In contrast, the incidence of edema was similar for patients treated with both combination therapy and low-dose calcium antagonists. Thus, combination therapy with a calcium antagonist and an ACE inhibitor provides blood pressure control equal to that of high-dose calcium antagonist monotherapy but with significantly fewer dose-dependent adverse experiences such as vasodilatory edema.

Treatment of Secondary Hyperparathyroidism in Hemodialyzed Patients with High-Dose Calcium Carbonate without Vitamin D3 Supplements

Background: Vitamin D compounds are usually indicated for the treatment of secondary hyperparathyroidism in dialysis patients. The possibility to induce a reversal of hyperparathyroidism with calcium supplementation alone is controversial. The present study was conducted to assess if oral calcium carbonate may constitute a therapeutic option for the control of hyperparathyroidism in patients with high PTH concentrations at the beginning of the treatment with chronic hemodialysis. Methods: Thirty-one patients with end-stage renal failure with an intact PTH concentration above 250 pg/ml at the beginning of chronic hemodialysis therapy were treated with high doses of calcium carbonate; no patient received either aluminium-containing binders or vitamin D compounds. To minimize hypercalcemia, a calcium dialysate concentration of 2.5 mEq/l was used in all patients. The goal of the study was to reduce the intact PTH concentration to 250 pg/ml with oral calcium carbonate supplements alone. Results: Throughout the first year on hemodialysis treatment, the intact PTH concentration decreased from 538 ± 256 to 251 ± 218 pg/ml (p < 0.001). By the end of the study, the therapeutic objective was achieved in 22 patients (71%) (‘responder’ group). The remaining 9 patients were classified as the ‘treatment failure’ group. The basal intact PTH concentration was not different between both groups (508 ± 235 vs. 612 ± 303 pg/ml, respectively, p = n.s.), but 5 ‘treatment failure’ patients admitted to take a dose of calcium carbonate lower than that prescribed. There were 40 episodes of hyperphosphatemia (11% of all measurements) in 7 of 31 patients, 5 of them belonged to the noncompliance ‘treatment failure’ patients. Only 15 episodes (4% of all measurements) of transient hypercalcemia (range 11.1 – 11.9 mg/dl) were detected in 8 patients. Conclusions: Secondary hyperparathyroidism in hemodialysis patients can often be reverted by oral calcium carbonate alone. But a good adherence to treatment is absolutely necessary.

Vasodilatory edema: synergistic effect of high-dose calcium antagonist/ace inhibitor combination therapy.

Vasodilatory edema: synergistic effect of high-dose calcium antagonist/ace inhibitor combination therapy.

Colocación de stent de Wiktor para el tratamiento de angina vasoespástica: presentación de un caso

A 46-year-old male with a fixed stenosis in the mid-segment of the left anterior descending artery underwent balloon angioplasty. The procedure included the placement of two Wiktor stents because of severe dissection. Five months later he complained of Prinzmetal angina with ST elevation in the anterior wall. A metilergobasine test during the coronary arteriogram showed a discrete, severe spasm on the proximal segment of the left anterior descending artery. Because of a lack of symptomatic improvement with high-dose nitrates and calcium blockers, a Wiktor coronary stent was successfully implanted in the proximal left anterior descending artery, resulting in complete relief of the angina.

Survival After a Massive Hydrofluoric Acid Ingestion

Hydrofluoric acid ingestion is known to have a very high mortality rate secondary to the rapid development of hypocalcemia and fatal arrhythmias. A 33-year-old man ingested an estimated dose of hydrofluoric acid 6 times that considered to be lethal. The patient survived with minimal morbidity despite having multiple ventricular fibrillation arrests. His survival is attributed to early, high dose calcium therapy given via the nasogastric and intravenous routes.

Osteoporosis: Prevention, diagnosis, and management

Osteoporosis is a public health scourge that is usually eminently preventable. Some risk factors, such as low calcium intake, vitamin D deficiency, and physical inactivity, are amenable to early interventions that will help maximize peak bone density. Other risk factors subject to modification are cigarette smoking and excessive consumption of protein, caffeine, and alcohol. Hip fractures are the most serious outcome of osteoporosis, with enormous personal and public health consequences. The ongoing Study of Osteoporotic Fractures has identified additional independent predictors of hip fracture risk, including maternal hip fracture, absence of significant weight gain since age 25, height, hyperthyroidism, use of long-acting benzodiazepines or anticonvulsants, spending < 4 hours a day on one's feet, inability to rise from a chair without using one's arms, poor visual depth perception and contrast sensitivity, and tachycardia. In an individual perimenopausal woman, the risk of osteoporotic fracture and the urgency of estrogen replacement therapy can be best estimated on the basis of bone mineral density, as measured by dual-energy x-ray absorptiometry, coupled with the presence or absence of existing fractures and clinical risk factors evident from the history and physical examination. Estrogen, calcitonin, and bisphosphonates have all been proved effective in retarding postmenopausal bone loss and therefore reducing the risk of fracture. The use of sodium fluoride is more controversial, although a recent study has suggested a possible role for slow-release fluoride combined with high-dose calcium supplementation.

Effect of ipriflavone in combination with calcium supplements on bone metabolism in elderly osteoporotic women

Ipriflavone and calcium supplements are used in the treatment of osteoporosis. However, the effect of ipriflavone in combination with high-dose calcium supplements (1 g/day) on bone metabolism in elderly osteoporotic women is still a matter of controversy. Enrolled in this study were 22 women over 70 years of age diagnosed as having involutional osteoporosis. The patients were randomly assigned to treatment with either ipriflavone plus calcium or with calcium supplements only for 6 months. Biochemical markers of bone metabolism and bone mass of the hand were determined at baseline and at 6 months. Serum parathyroid hormone, serum osteocalcin, serum alkaline phosphatase, and the urinary hydroxyproline/creatinine ratio decreased in both groups. These decreases were greater in the “ipriflavone plus calcium supplement” group than in the “calcium supplement only” group. Serum calcitonin increased in the “ipriflavone plus calcium supplement” group. Metacarpal index and metacarpal bone mineral density did not change in either group. These findings suggest that treatment with ipriflavone plus calcium supplements may inhibit bone resorption and modulate bone turnover in elderly osteoporotic women and may be more effective than calcium supplements alone.

Calcium and Vitamin D Nutritional Needs of Elderly Women

Because osteoporosis is irreversible, the most effective approach to reduce morbidity and mortality from this disease is to maximize peak bone mass and minimize bone loss. This presentation reviews the evidence that calcium and vitamin D influence rates of bone loss in postmenopausal women. In the first five or more years after menopause, women lose bone very rapidly. During this period, high dose calcium supplementation modestly reduces cortical loss from long bones but has minimal effect on more trabecular sites such as the spine. In addition, vitamin Dappears to enhance the effectiveness of supplemental calcium. Late postmenopausal women are generally more responsive to added calcium, and those with the lowest dietary calcium intakes benefit the most. In calciumreplete women, supplementation with vitamin D reduces bone loss and fracture incidence. Available evidence indicates that postmenopausal women should consume 1000–1500 mg of calcium and 400 to 800 KI of vitamin D per day to minimize bone loss.

Randomized, Double-Blinded, Placebo-Controlled Study of Effect of Wheat Bran Fiber and Calcium on Fecal Bile Acids in Patients With Resected Adenomatous Colon Polyps

Ongoing epidemiologic and nutritional studies suggest that colorectal carcinogenesis is consistent with complex interactions between genetic susceptibility and environmental and dietary factors. Among the dietary components found to reduce colon cancer risk are high intakes of dietary fiber and calcium. We designed and conducted a randomized, double-blinded, placebo-controlled trial involving supplementation of the customary dietary intake with fiber and calcium and measurements of fecal bile acids to examine the potential mechanisms by which added dietary interventions might reduce colorectal cancer risk. In a randomized, double-blinded, phase II study, we used a factorial design to measure the effects of dietary wheat bran fiber (2.0 or 13.5 g/day) in the form of cereal and supplemental calcium carbonate (250 or 1500 mg/day elemental calcium) taken as a tablet on fecal bile acid concentrations and excretion rates. Measurements were made at base-line randomization (i.e., after a 3-month placebo run-in period using 2.0 g wheat bran fiber plus 250 mg calcium carbonate) and after 3 and 9 months on treatment in a randomly selected 52-patient subsample of the 95 fully assessable study participants who had a history of colon adenoma resection. Concentrations of fecal bile acids, total, primary (i.e., chenodeoxycholic and cholic), and secondary (i.e., deoxycholic, lithocholic, and ursodeoxycholic), were measured in 72-hour stool samples by gas-liquid chromatography. All P values resulted from two-sided tests. All geometric mean fecal bile acid concentrations and excretion rates were lower at 9 months than at 0 months or 3 months on treatment in the high-dose fiber, high-dose calcium, and high-dose fiber/high-dose calcium treatment groups. The high-dose fiber effect at 9 months of supplementation was statistically significant with respect to virtually all geometric mean fecal bile acid concentrations and excretion rates. For example at 9 months versus 0 months, high-dose fiber supplementation caused a reduction in fecal concentrations of total bile acids (52% reduction; P = .001) and deoxycholic acid (48% reduction; P = .003). High-dose calcium supplementation also had a significant, but lower, effect at 9 months versus 0 months on the geometric mean total bile acid (35% reduction; P = .044) and deoxycholic fecal bile acid (36% reduction; P = .052) concentrations. High-dose wheat bran fiber and calcium carbonate supplements given for 9 months are associated with statistically significant reductions in both total and secondary fecal bile acid concentrations and excretion rates in patients with resected colon adenomas. This study supports the hypothesis that one of the important ways in which a high intake of wheat bran fiber and calcium may reduce the risk of colorectal neoplasia and cancer is by reduction of the concentrations of fecal bile acids. Phase III studies of these agents in the prevention of adenoma recurrence are necessary to confirm this hypothesis and have now been initiated at multiple institutions.

Calcitriol-resistant rickets due to vitamin D receptor defects

Calcitriol-resistant rickets (CRR) is an autosomal recessive disease due to a defect in the vitamin D receptor (VDR) or a site distal to it. The main characteristics are extreme rickets, with growth attenuation, osteomalacia, secondary hyperparathyroidism, severe dental caries, and alopecia. Serum studies reveal hypocalcemia, hypophosphatemia, very high calcitriol, and increased alkaline phosphatase levels. The clinical and chemical abnormalities do not respond to therapy with high-dose vitamin D, indicating target organ unresponsiveness. Eleven different mutations in the gene-encoding VDR have thus far been reported. They affect either the C-terminal ligand-binding region or the N-terminal DNA binding zinc-fingers sequences, with mutation hot spots identified at conserved sequences among the steroid-thyroid receptors superfamily. These result in impaired calcitriol binding to target organs, signified in vitro as failure of fibroblasts to bind [ 3H]calcitriol or to respond to calcitriol by 24-hydroxylase activity enhancement. Receptor studies and mutational analyses are used for prenatal diagnosis of CRR. Therapy with high-dose calcium overcomes the VDR defect, normalizes serum calcium, and maintains bone remodeling and mineral apposition. These responses to therapy have interesting implications upon our understanding of the potential role of calcium alone and that of vitamin D in bone physiology. Like other hormone-resistant diseases, CRR, with its various mutations, provides the opportunity for investigating the nature of vitamin D and of VDR physiology, which has been only partially explored to date.

Modulation of 5-Fluorouracil with High-Dose Leucovorin Calcium: Activity in Ovarian Cancer and Correlation with CA-125 Levels

The purpose of this study was to estimate the response rate, response duration, and survival of patients with advanced ovarian cancer treated with a 132-hr continuous infusion of high-dose calcium leucovorin in combination with five consecutive daily bolus doses of 5-fluorouracil (5-FU) and to correlate changes in CA-125 levels with clinical and radiologic assessment of disease progression. Forty-six heavily pretreated patients [median number of previous chemotherapy regimens, 2.5 (range 1-7)] with advanced ovarian cancer received 132-hr continuous infusions of calcium leucovorin (500 mg/m 2/day) for 5 1 2 days, with daily bolus doses of 5-FU (370 mg/m 2/day) for 5 days beginning 24 hr after initiation of the calcium leucovorin. Twenty-three patients had clinically measurable disease and 23 had evaluable disease; CA-125 levels were performed prior to each treatment course and after the final course of therapy. One of 42 patients had a partial response to combination chemotherapy (duration, 8.9 months); 16/42 had stable disease [median duration, 4.9 months (range, 2.4-9.0 months)]. Toxicity of combination therapy included mild myelosuppression and stomatitis, similar to previously reported toxicity profiles for the 5-FU and calcium leucovorin combinations. Sensitivity of CA-125 levels as a single indicator of disease progression was 55%. The combination of infusional high-dose calcium leucovorin and 5-FU has little activity in refractory ovarian cancer. CA-125 levels incorrectly predict clinical disease activity in about one-third of cases and should not be the sole criterion for determination of clinical response when evaluating chemotherapeutic efficacy in heavily pretreated patients.

A comparison of the effects of oestrogen/progestogen, high-dose oral calcium, intermittent cyclic etidronate and an ADFR regime on calcium kinetics and bone mass in postmenopausal women with spinal osteoporosis

The effects of four different treatments for osteoporosis were compared in a prospective, randomized, 3-year study in 74 postmenopausal women with spinal crush fracture osteoporosis. Patients were randomly assigned to cyclic oestrogen/progestogen therapy (group 1, n = 20), a daily oral calcium dose of 2 g (group 2, n = 17), intermittent cyclic etidronate therapy (group 3, n = 19), or an ADFR treatment with triiodothyronine as activator and etidronate as depressor (group 4, n = 18). Spine and forearm bone mineral content was measured before entry and every 30 weeks. Combined calcium balance and 47Ca kinetic studies were performed before and after 1 and 3 years of treatment. Bone turnover, estimated by serum alkaline phosphatase and renal hydroxyproline excretion, decreased in all four groups during the first half of the treatment period but remained reduced during the second half in groups 1 and 3 only. Group 1 had a significantly positive calcium balance after 60 weeks of treatment. After 150 weeks, the positive effect on calcium balance was significant and greater in groups 1 and 3 than in the other groups. This was achieved by a greater reduction in resorption rate in group 1 at week 60 and in groups 1 and 3 at week 150 as compared with the other groups. Only group 1 had a significant increase in spinal bone mass while a decrease in bone mass at the distal forearm was observed in the etidronate-treated group. We conclude that treatment of postmenopausal osteoporosis with oestrogen/progestogen for 3 years results in net spinal bone gain and a positive effect on calcium balance slightly better than that of intermittent etidronate. These effects were inferior in the groups receiving a large calcium supplementation or the ADFR group where no change in calcium balance or bone mass was found.

New Therapies for Primary Pulmonary Hypertension

Primary pulmonary hypertension (PPH) is often a fatal disease, with a majority of patients dying within 5 years. 1 Fuster V Steele PM Edwards WD Gersh BJ MeGoon MD Frye RL Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984; 70: 580-587 Crossref PubMed Scopus (917) Google Scholar , 2 Voelkel NF Reeves JT Primary pulmonary hypertension. in: Moser KM Pulmonary vascular diseases. Marcel Dekker, New York1979: 573-628 Google Scholar , 3 D’Alonzo GE Barst RJ Ayres SM Bergofsky EH Brundage BH Detre KM Survival in patients with primary pulmonary hypertension. Ann Intern Med. 1991; 115: 343-349 Crossref PubMed Scopus (3018) Google Scholar It affects mostly young adults in their second to fourth decades 4 Rich S Dantzker DR Ayres SM Bergofsky EH Brundage BH Detre KM et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med. 1987; 107: 216-223 Crossref PubMed Scopus (1744) Google Scholar and follows a progressively downhill course culminating in right ventricular failure. Various forms of vasodilator therapy have been used in the past, 5 Rich S Brundage BH The pharmacologic treatment of primary pulmonary hypertension. in: Bergofsky EH Abnormal pulmonary circulation. Churchill Livingstone, New York1986: 283-311 Google Scholar but a large series of patients would be required to determine their long-term efficacy. Acetylcholine, phentolamine, tolazoline and isoprenaline were initially used with conflicting results. Oral vasodilators such as hydralazine and captopril have also been used with early success, but their long-term use has been disappointing. 6 Hermiller JB Bambach D Thompson MJ Huss P Fontana ME Magorien RD et al. Vasodilators and prostaglandin inhibitors in primary pulmonary hypertension. Ann Intern Med. 1982; 97: 470-489 Crossref Scopus (52) Google Scholar , 7 Rich S Martinez J Lam W Rosen KM Captopril as treatment for patients with pulmonary hypertension: problem of variability in assessing chronic drug treatment. Br Heart J. 1982; 48: 272-277 Crossref PubMed Scopus (47) Google Scholar Recently Rich and Brundage 8 Rich S Brundage BH High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation. 1987; 76: 135-141 Crossref PubMed Scopus (331) Google Scholar have shown sustained hemodynamic, symptomatic, and electrocardiographic improvement associated with the use of high-dose calcium channel blockers 8 Rich S Brundage BH High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation. 1987; 76: 135-141 Crossref PubMed Scopus (331) Google Scholar and have also reported improved survival in a proportion of patients. 9 Rich S Kaufmann E Levy P The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992; 327: 76-81 Crossref PubMed Scopus (1405) Google Scholar Long-term benefit with enhanced survival chance, however, seems to be confined to the group of patients who had a significant vasodilatory responsiveness to acute challenge with oral calcium channel blockers and also had a relatively preserved cardiac output. There remains a large proportion of patients with severe disease who have developed right ventricular dysfunction and are, therefore, not suitable for Ca++ channel blockers and require alternate therapies. Much attention has been placed recently on lung transplantation and novel therapies which combine both vasodilatory and antithrombotic actions.

Cisplatin, Fluorouracil, and Leucovorin: Increased Toxicity Without Improved Response in Squamous Cell Head and Neck Cancer

To evaluate the activity and toxicity of the drug combination cisplatin, fluorouracil by continuous infusion, and high-dose oral leucovorin calcium (PFL) as induction chemotherapy in patients with advanced and untreated squamous cell head and neck (SCHN) cancer. Nonrandomized, prospective trial. Referral center (comprehensive cancer center). Twenty-two patients with stage III (n = 7) and IV (n = 15) M0 SCHN cancer of the larynx (n = 13), hypopharynx (n = 7), and oropharynx (n = 2) whose standard treatment would have required total laryngectomy. Three cycles of PFL were administered prior to local-regional therapy (concomitant cisplatin and radiation and/or neck dissection, with total laryngectomy reserved for nonresponse or relapse). Chemotherapy included cisplatin (100 mg/m2) on day 1 by short intravenous infusion; fluorouracil (800 mg/m2) on days 1 through 5 by continuous infusion; and leucovorin (100 mg) every 4 hours by mouth for 30 doses. The PFL combination was administered every 21 days. Clinical response to chemotherapy and observed toxic effects during chemotherapy. Five patients were inevaluable for response, with three early deaths (infection in two and sudden death in one), one cerebrovascular accident, and one patient declining further chemotherapy. Of the remaining 17 patients, 10 had a major response to chemotherapy, but in only five patients (29%) was this complete (95% confidence interval, 8% to 51%). Other significant toxic effects included grade 3 to 4 mucositis in eight patients and grade 3 to 4 neutropenia in 10. While PFL is active in patients with SCHN cancer, we were unable to reproduce the high complete response rates reported by other centers. Its use can be associated with significant toxic effects. We do not recommend the use of PFL for the treatment of patients with SCHN cancer outside the context of a clinical trial until there is further critical assessment of its activity and toxicity.

Benefits and demerits of antihypertensive therapy by high-dose calcium channel blocker in severely hypertensive rats.

This study examined the protective effects of a calcium channel blocker, nisoldipine (NSL), against organ damage secondary to severe hypertension. Severe hypertension was induced in male 7-week-old spontaneously hypertensive rats (n = 21) by heminephrectomy and substitution of 1% NaCl solution for drinking water. They were fed a chow containing 0%, 0.03% (low dose) or 0.1% (high dose) NSL for 12 weeks. The systolic blood pressures after 12 weeks were 228 mmHg in the control group, 201 in the low dose NSL group and 188 in the high dose NSL group. Body weight gain was blunted in the high dose NSL group (at 12 weeks: control 289g; low dose NSL 286; high dose NSL 263, p < 0.04). Although a further reduction in cardiac weight was seen in the high dose NSL rate (low NSL -5.2%, p < 0.05; high NSL -9%, p < 0.01), reductions in aortic thickness did not differ between the 2 doses (low NSL -18%, p < 0.001; high NSL -17%, p < 0.001). Moreover, dose-dependent effects of NSL treatment were absent for such endpoints as plasma creatinine (low NSL -15%, p < 0.04; high NSL -17%, p < 0.05), glomerular filtration rate (low NSL +21%, p < 0.05; high NSL +20%, p < 0.03) and urinary protein excretion (low NSL -22%, p < 0.05; high NSL -29%, p < 0.02). Thus, a high dose calcium channel blocker hampered growth and did not further improve vascular wall thickening or renal injury in severely hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Slow‐release verapamil poisoning

To present three cases of slow-release verapamil poisoning that demonstrate the prolonged absorption of the drug and the role of polyethylene glycol and high-dose calcium in management. Three patients with slow-release verapamil poisoning are presented. An 18-year-old woman took 2.3 g and developed hypotension and bradyarrhythmias 18 hours after ingestion, despite gastric lavage and administration of charcoal at three hours. A 23-year-old woman took 4.8 g and presented two hours later clinically unaffected. A 44-year-old woman presented 24 hours after taking 15-20 g. She had a systolic blood pressure of 50 mmHg, no measurable diastolic blood pressure and bradyarrhythmias. Case 1 responded to administration of 30 g of calcium and fluids intravenously. Case 2 was given polyethylene glycol on admission which resulted in passage of a tablet bezoar and no toxicity. Polyethylene glycol was ineffective in Case 3. She responded initially to high doses of calcium and other treatments, but subsequently died of hypotension and cardiac conduction block 39 hours after the overdose. The severity of poisoning with slow-release verapamil warrants aggressive pre-emptive treatment. Polyethylene glycol should be used routinely irrespective of the clinical state. High doses of calcium may be required to treat conduction block and hypotension.