Initial Serum Levels Research Articles

Serum levels of Hsp 72 measured early after trauma correlate with survival.

Experimental studies have shown that hemorrhagic shock is associated with the expression of inducible heat proteins, especially heat shock protein (Hsp) 72, in liver, brain, heart, and kidney. Moreover, induction of Hsp 72 by various stressors before the onset of shock has been associated with the attenuation of organ injury caused by hemorrhage. However, it is not known whether Hsp 72 is expressed after severe trauma in humans. The purpose of this study was therefore to determine whether Hsp 72 could be detected in the serum of patients early after severe trauma and whether serum levels of Hsp 72 might correlate with survival of trauma patients or the severity of the postinjury inflammatory response. Clinical data were collected prospectively over a 3-year period for trauma patients mechanically ventilated for more than 2 days who met the following inclusion criteria: Injury Severity Score > or = 16, and age > 18 years. Physiologic data for quantitative assessment of organ dysfunction were collected for each patient. Hsp 72 and nitrate and nitrite levels were measured in the serum of trauma patients collected at or 12 to 48 hours after the admission to the emergency department. Sixty-seven patients with severe trauma were enrolled in the study. Hsp 72 was detected in the serum of all trauma patients. All patients with high initial serum levels of Hsp 72 (serum levels > 15 ng/mL) survived, whereas 29% of the patients with low Hsp 72 serum levels died from their traumatic injuries (p = 0.01). The overall mortality was 21%, occurring within 5 to 7 days. Patients who died were older (mean age, 54 +/- 15 years) than those who survived (mean age, 36 +/- 15 years) (p < 0.0.05). The cause of death was attributable to head injury in 79%, although the severity of head injury (Abbreviated Injury Scale score) was not statistically different between survivors with high serum values of Hsp 72 and patients who died. There was no correlation between the initial serum Hsp 72 values and the severity of organ dysfunction or clinical indicators of the inflammatory response. Hsp 72 can be detected in the serum of severely traumatized patients within 30 minutes after injury. Elevated initial serum levels of Hsp 72 (serum levels > 15 ng/mL) are associated with survival after severe trauma, but are not related to the incidence or severity of the postinjury inflammatory response or organ dysfunction.

Mechanisms of calcification by vesicles isolated from atherosclerotic rabbit aortas

Although several lines of evidence support the role of calcifiable vesicles in dystrophic vascular calcification, the mechanisms whereby vesicles promote aortic calcification remain incompletely understood. Previous reports indicate that ATP promotes in vitro vesicle calcification. Whether ATP-initiated calcification is simply mediated through increased Pi concentrations or by other unknown mechanisms related to ATP hydrolysis is unclear. To determine whether high Pi levels resulting from ATP hydrolysis may cause Ca×P ion products to surpass the threshold for calcium phosphate precipitation, 3 mM Pi instead of 1 mM ATP was added to calcifying media. The inclusion of 1 mM ATP in calcifying media with an initial serum level of Ca 2+ (1.45 mM) and Pi (2.3 mM) was much more effective in promoting calcification than the addition of 3 mM Pi. The higher effectiveness of ATP over Pi in promoting calcification was consistent throughout various incubation periods and vesicle protein ranges. To minimize the effect of Ca×Pi ion products on calcification, the ion product was kept within the physiological ranges throughout the incubation period by reducing initial Pi or ATP concentrations in calcifying media. At these low levels of ion products, ATP was still more effective than Pi in promoting calcification. Both ATP- and Pi-stimulated calcifications were found to increase with increasing levels of ion products whereas greater effectiveness of ATP over Pi remained unaltered. These observations indicate that ATP hydrolysis may initiate calcification through some mechanisms other than a simple provision of Pi in order to surpass the solubility products. Concanavalin A (Con A) was found to bind to vesicles and to enhance both ATP- and Pi-promoted calcification. Taken together, these observations suggest that ATP hydrolysis, Ca×P ion products, and vesicle-associated carbohydrates are implicated in vesicle-mediated calcification.

Prognostic impact of Cyfra21-1 and other serum markers in completely resected non-small cell lung cancer

Purpose: The aim of this prospective study was to assess the prognostic impact of serum tumor markers (Cyfra21-1, carcinoembryonic antigen, neuron-specific enolase, squamous cell carcinoma-antigen and TPAcyk) in patients with non-small cell lung cancer (NSCLC) receiving complete resection. Methods: Sixty-seven patients with histologically proven NSCLC and complete resection of stage I–IIIA disease were included. The serum levels of all markers were measured using commercially available immunoassays. Results: With a median follow-up of 86 months for surviving patients, those with initial Cyfra21-1 serum levels higher than 3.57 ng/ml had a significantly worse prognosis ( P=0.014). The remaining serum tumor markers showed no prognostic impact. In a Cox regression model, Cyfra21-1 proved to be an independent prognostic factor for both overall survival and disease-free interval. In addition, Cyfra21-1 sustained as an independent prognostic factor in completely resected stage I/II disease. Conclusions: With a cut-off value of 3.57 ng/ml, Cyfra 21-1 was an independent prognostic factor for survival in NSCLC-patients with complete resection. Further evaluation is needed, particularly in stage I/II disease. When the prognostic impact is confirmed with larger patient numbers this may contribute to the identification of stratification variables for future treatment approaches of NSCLC.

Changes in Serum PBB and PCB Levels over Time among Women of Varying Ages at Exposure

The identification of host factors that are predictors of changes in serum polyhalogenated biphenyl contaminants over time has been a difficult challenge in epidemiologic studies of exposed individuals. Of particular concern are age at exposure, reproductive and lactational histories, and changes in body mass index. Using both cross-sectional and longitudinal approaches, this study examined factors related to high initial serum PBB and PCB levels and changes in these levels over time among women of varying ages at exposure (n=1772; age range<1 to 45 years). In 1973, PBB exposure occurred through consumption of farm products contaminated with PBB added to cattle feed. Exposures to PCBs began in 1941 through PCB-contaminated silo sealant deteriorating into animal feed. The Michigan Department of Public Health began enrolling participants in 1977 and has continued to follow them through annual updates. At enrollment, questionnaires were administered to obtain demographic, lifestyle, and anthropometric measurements, medical/reproductive and occupational histories, and contaminated food consumption patterns. Blood samples were collected for PBB and PCB analysis at enrollment for all participants; additional serum tests were done on a subset of the population during follow-up. Median serum levels at enrollment were 2.0 ppb PBB and 5.0 ppb PCB. A decline in serum PBB level over an interval that ranged from 1 to 146 months (median=31) was observed for 44.6% of the women (median=1.0 ppb), while 12.2% showed an increase (median=1.0 ppb). PCB levels declined in 50.3% of the women (median=3.0 ppb) while 12.2% increased (median=2.0 ppb). Relative to women whose contaminant levels were stable, higher initial serum level was a predictor of decline for both PBB and PCB (OR=1.66, 95% CI 1.52–1.82; OR=3.26, 95% CI 2.58–4.12, respectively); a yearly increase in interval between tests was related to declining PCBs (OR=1.65, 95% CI 1.46–1.87). In addition, age≤10 years at exposure (OR=1.72, 95% CI 1.03–2.86) and residence on a quarantined farm (OR=1.40, 95− CI 1.03–1.90) were predictors of a decrease in PBBs. Factors related to an increase in PBB levels were age≤10 years at exposure (OR=0.30, 95% CI 0.10–0.96) and initial PBB level (OR=1.24, 95% CI 1.15–1.33); and for PCBs, high initial level (OR=1.34, 95% CI 1.17–1.53) and body mass index (OR=1.07, 95% CI 1.01–1.13). One or more live births during the interval between tests were not related to changing levels of either contaminant; breastfeeding data were not available for examination. Early age at exposure appears to be an important predictor of changes in serum PBB levels OVER TIME.

Serum Levels of Interleukins (IL)-4, IL-5, IL-13, and Interferon-γ in Acute Asthma

T-cell activation and alteration of cytokine levels are involved in the pathogenesis of bronchial asthma. However, the profile of circulating T-lymphocyte subsets and related cytokines during acute asthmatic attacks is still unclear. We hypothesized that serum levels of interleukin (IL)-4, IL-5, and IL-13 would be increased, whereas IFN-γ would be decreased in acute asthma. The subjects enrolled in this study included 58 acute asthmatics, 22 asymptomatic asthmatics, and 10 healthy controls. Serum levels of IL-4, IL-5, IL-13, and IFN-γ were measured using a sandwich enzyme-linked immunosorbent assay. We correlated serum levels of IL-4, IL-5, IL-13, and IFN-γ with initial forced expiratory volume in 1 sec (FEV1). Compared with control subjects, acute asthmatics had significantly increased levels of circulating IL-4 (p < 0.001), IL-5 (p < 0.001), and IL-13 (p < 0.001), although the differences were of borderline significance in serum IFN-γ (p = 0.069). There were also significant differences in the circulating levels of IL-4, IL-5, and IL-13 between acute asthmatics and asymptomatic asthmatics. There was no significant association between initial FEV1 and serum levels of IL-4 or IL-13, however, among acute asthmatics, a lower initial FEV1 was associated with higher IL-5 and/or lower IFN-γ levels. Our results suggest that serum levels of IL-4, IL-5, and IL-13 may be elevated in acute asthma, and that higher levels of IL-5 and/or lower levels of IFN-γ are associated with severe airway obstruction.

Evaluation of S-100b as a specific marker for neuronal damage due to minor head trauma.

Management of patients with minor head trauma (MHT) continues to be debated in the literature. Measurement of S-100b in serum has been introduced into the discussion as an additional screening tool for intracerebral injuries because routine cranial computed tomography (CCT) of a large number of patients causes logistic difficulties, and the neurologic examination is often impaired by a high frequency of coincidental intoxication. The aim of our study was to determine the diagnostic value of measuring S-100b in the serum of MHT patients to identify risk groups. Additional validity should be aquired by a comparison with plasma levels of polymorphonuclear neutrophil (PMN) elastase an established general trauma marker. A series of 52 patients with MHT were included in the prospective study. At admission the patients underwent a routine CCT scan to detect intracerebral lesions, and blood samples were drawn to investigate circulating levels of S-100b and PMN elastase. For comparison, data for a positive control group of 10 severe head trauma patients (initial Glasgow Coma Scale score < 8) and for a negative control group with 20 healthy volunteers were obtained. The interval between MHT and admission to our hospital was 73.4 +/- 47.0 minutes. The initial S-100b serum levels of MHT patients were 0.470 +/- 0.099 ng/ml, those of the positive control group were 7.16 +/- 3.77 ng/ml, and those of the negative control group were 0.05 +/- 0.01 ng/ml. Relevant pathologic CCT scans were detected in 28.8% of MHT patients; one patient of that group was subjected to immediate surgical intervention (1.9%). At a cut-off point of 0.1 ng/ml, the sensitivity of positive S-100b levels reached 100% and the specificity 40.5%. Plasma levels of PMN elastase reached 60.52 +/- 10.75 ng/ml in the MHT group, 66.4 +/- 14.92 ng/ml in the severely head-injured group, and 23.26 +/- 1.53 ng/ml in the negative control group. Serum levels of S-100b seem to be a highly sensitive but not very specific marker for isolated neurotrauma. Measurement of this parameter may be helpful as an additional screening tool to identify high risk groups in the cohort of MHT patients.

A new serologic index for low-grade non-Hodgkin's lymphoma based on initial CA125 and LDH serum levels

Serum CA125 (sCA125) was recently reported to be of clinical value in the staging and follow-up of patients with non-Hodgkin's lymphoma (NHL). This report aims to investigate the prognostic value of a new serologic index combining sCA125 and LDH serum levels. One hundred thirty-seven patients were studied, sixty-three with histologically proven low-grade NHL, and seventy-four with a high-grade subtype. sCA125 and LDH levels were elevated in more than one third of patients. sCA125 was more frequently increased than LDH in low-grade NHL. In this group, complete remission (CR) was achieved in 87, 45, and 0% (P = <2 x 10(-6)) of patients with normal sCA125 and LDH serum levels (Low-risk group), one parameter increased (Intermediate-risk group), and increased sCA125 and LDH serum levels (high-risk group), respectively. The estimated five-year overall survival was 97%, 67% and 22% for low, intermediate, and high-risk groups, respectively. This combination was the only parameter predictive of RFS and OS in multivariate analysis (P < 0.0001). In this study the combination of s-LDH and sCA125 levels (normal vs. abnormal) was found to be an important prognostic factor in low-grade lymphoma and may be used in the selection of appropriate therapeutic approaches for individual patients.

Evaluation of Orntide microspheres in a rat animal model and correlation to in vitro release profiles.

Orntide acetate, a novel luteinizing hormone-releasing hormone (LHRH) antagonist, was prepared and evaluated in vivo in 30-day and 120-day sustained delivery formulations using a rat animal model. Orntide poly(d,l-lactide-co-glycolide) (PLGA) and poly(d,l- lactide) (PLA) microspheres were prepared by a dispersion method and administered subcutaneously in a liquid vehicle to rats at 2.2 mg Orntide/kg of body weight (30-day forms) or 8.8 mg Orntide/kg (120-day forms). Serum levels of Orntide and testosterone were monitored by radioimmunoassays, and a dose-response study at 4 doses (3, 2.25, 1.5, and 1.75 mg Orntide/kg) was conducted to determine the effective dose of Orntide. Microspheres with diameters between 3.9 and 14 micron were prepared. The onset and duration of testosterone suppression varied for different microsphere formulations and were influenced both by polymer properties and by microsphere characteristics. Microspheres prepared with 50:50 and 75:25 copolymers effectively sustained peptide release for 14 to 28 days, whereas an 85:15 copolymer and the PLA microspheres extended the pharmacological response for more than 120 days. Increase in drug load generally accelerated peptide release from the microspheres, resulting in higher initial serum levels of Orntide and shorter duration of the release. In general, apparent release was faster in vivo than under in vitro conditions. Orntide microspheres effectively suppressed testosterone in rats, providing rapid onset of release and extended periods of chemical castration. Testosterone suppression occurred immediately after microsphere administration without the initial elevation seen with LHRH superagonists.

Succinylcholine-Induced Hyperkalemia in Patients with Renal Failure: An Old Question Revisited

Succinylcholine-Induced Hyperkalemia in Patients with Renal Failure: An Old Question Revisited

Significance of serum pro-gastrin-releasing peptide as a predictor of relapse of small cell lung cancer: comparative evaluation with neuron-specific enolase and carcinoembryonic antigen

Neuron-specific enolase (NSE) and carcinoembryonic antigen (CEA) have been reported to be useful markers for staging, monitoring treatment, and predicting relapse in patients with small cell lung cancer (SCLC). Recently, pro-gastrin-releasing peptide (Pro-GRP) became available as a sensitive, specific, and reliable tumor marker for patients with SCLC. The aim of this study is to determine the most useful tumor marker to detect the relapse of SCLC. Furthermore, we analyzed the relationship between tumor markers at relapse and survival from relapse or response to salvage chemotherapy. Medical records were reviewed to obtain serum levels of Pro-GRP, NSE, and CEA before and after the initial chemotherapy, and at relapse. Consecutive 66 patients with SCLC, with an objective response and confirmed relapse treated at the National Cancer Center Hospital East, were analyzed in this study. The percentages of patients whose tumor marker level were elevated before treatment, decreased after the treatment, and increased again at relapse were 67% (95% CI, 55–78) for Pro-GRP, 20% (10–29) for NSE, and 38% (26–50) for CEA. Multivariate analysis indicated that poor performance status before initial treatment and elevated serum levels of lactate dehydrogenase at relapse were poor prognostic factors for patients with recurrent SCLC ( P<0.005). None of the serum levels of Pro-GRP, NSE, and CEA at relapse was a significant prognostic factor and associated with an objective response to salvage chemotherapy. The present study demonstrated that serum levels of Pro-GRP reflect the disease course of patients with SCLC most accurately.

S-100 serum levels and outcome after severe head injury.

S-100B a protein of astroglial cells is described as a marker for neuronal damage. Reliable outcome prediction from severe head injury is still unresolved. Clinical scores like the Glasgow Coma Score (GCS) and diagnostic scores like the Marshall CT Classification (MCTC) are well established and investigated, but there are still some concerns about these tools. The aim of this study was to investigate the predictive value of the initial serum level of S-100B. 44 patients with severe head injury (GCS < 9) were included. Blood samples were drawn within 1 to 6 hours of injury. After a period of 11 months their outcome was correlated using the Glasgow Outcome Scale. Patients with good outcome had significantly lower serum concentrations of S-100 on admission (0.96 microgram/l versus 5.5 micrograms/l mean, p < 0.0001). In addition patients with a S-100 serum level below 2 micrograms/l showed a significant better rating on the GOS at follow-up (4 points versus 1.8 points mean, p < 0.0001). With this cut-off line it was possible to predict longterm outcome with a sensitivity of 75% and specitivity of 82%. The serum level of S-100B calculated with one to six hours of a severe head injury is a useful additional outcome predictor.

Pediatric Case of Accidental Oral Overdose of Methotrexate

Methotrexate is a chemotherapy antimetabolite, folic acid antagonist, that inhibits the enzyme dihydrofolate reductase resulting in decreased levels of tetrahydrofolate in the cells. This in turn blocks synthesis of thymidylate, a nucleotide necessary for DNA synthesis. It is readily absorbed from the gastrointestinal tract. Toxicity from overdose can affect multiple organ systems including bone marrow, liver, intestinal tract, kidneys, lungs, skin, and blood vessels, resulting in death in severe cases. Methotrexate is widely used to treat neoplastic disease, dermatologic disorders (psoriasis), and rheumatologic disorders (severe rheumatoid arthritis). As its indications for use increase, more accidental overdoses can be expected. We present the treatment and clinical course of one such case, that of a 2-year-old who accidentally took her grandmother’s arthritis pills. Her initial serum level was 10 times greater than that needed to cause toxicity. She was treated with gastric lavage, activated charcoal, leucovorin rescue, and ICU admission. Her clinical course was unremarkable, and the only evidence of toxicity was a mild elevation in a liver-associated enzyme that resolved without any clinical sequela. Leucovorin at a dose equal to or greater than the possible ingestion should be given as soon as possible in methotrexate overdoses. [Gibbon BN, Manthey DE: Pediatric case of accidental oral overdose of methotrexate. Ann Emerg Med July 1999;34:98-100.]

Long acting injectable oxytetracycline-liposphere formulations

Oxytetracycline (OTC) was encapsulated in a liposphere delivery system composed of OTC, solid triglyceride, phospholipid, buffer solution and preservatives. The formulation is an injectable microdispersion containing 8–20 wt% OTC with an average particle of size of 30 μ. The in vitro t 1 2 release of OTC was in the range of 28 h. Serum OTC concentration after a single intramuscular injection of OTC-liposphere formulation in turkeys showed an effective extended release for 3–5 days as compared to about 1 day for the commercial OTC solution (Dabicycline, 10 wt% in acidic solution). A mixture of OTC in lipospheres and OTC solution in a 4:3 volume ratio resulted in initial high OTC serum levels that lasted for 5 days. The biodegradability of the formulation was demonstrated by observing the injection site for up to 28 days after injection. The blank formulation was readily eliminated from the site and no signs of residuals were observed 28 days after injection. OTC loaded formulations based on trilaurin were also degraded but at slower rate than the blank formulation that might be a result of the hydrophobicity of OTC which retards hydrolysis and biological elimination.

SOLUBLE C-ERBB-2 (P185) IN BREAST-CANCER PATIENTS IN RELATION TO PROGNOSIS

Serum levels of P185-HER-2 were measured in 137 breast cancer patients and in 40 controls. The patients were divided into 4 groups: group A - 40 newly diagnosed patients; group B - 57 patients on long-term follow-up without active disease; group C - 26 patients with metastatic disease and group D - 5 patients with locally advanced inoperable tumors. The median level in controls was 4.8 U/l. The median P185 serum levels in groups C and D were significantly higher compared to groups A and B. In group C 60% and in group D 100% of patients had baseline elevated levels of serum P185 (>5 U/l) compared to 28% in groups A and B. Of the 14 patients in group A with elevated baseline levels of serum P185, 6 (43%) developed metastasis during the 24-month follow-up period. On serial measurements during follow-up in 23 patients of group A, 3 relapsed and the P185 level increased. In group C, serial measurements in patients with elevated baseline levels of P185 correlated with clinical response to therapy. These data suggest that serum levels of P185 are elevated in patients with metastatic disease. High initial P185 serum levels in new patients may have prognostic significance. Serial measurements of P185 in asymptomatic patients may help in monitoring disease state. In metastatic patients, serial P185 determination may be of benefit in assessing response to therapy.

Pharmacokinetic studies of vitamin D analogues: relationship to vitamin D binding protein (DBP)

Vitamin D(3), 25-hydroxyvitamin D(3) (25OHD(3)) and 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)) bind to the vitamin D binding protein (DBP) in the serum. During the development of synthetic vitamin D analogues, it has been shown that the majority of analogues bind to DBP with a low affinity. This modifies their biological activitiesin vitro compared to 1α,25(OH)(2)D(3), since binding to DBP decreases the cellular uptake and access to the vitamin D receptor. It is therefore important to elucidate the possible role played by the binding or lack of binding to DBPin vivo. We have investigated the relationship between the binding affinity for human DBP and the serum level and serum half-life (t(1/2)) in rats of a series of new vitamin D analogues. The binding affinity for DBP was determined by displacement of(3)H-1,25(OH)(2)D(3) from DBP attached to Affi-Gel 10. The serum levels in rats following a single intravenous dose were assessed by HPLC and the serum half-life was determined for each analogue. In the group of vitamin D analogues which showed a low or no affinity for DBP, we have identified compounds with a short t(1/2) and compounds with a long t(1/2), all characterized by low initial serum levels. Compounds with a long t(1/2) were also found in the group with a high affinity for DBP, and they were easily identifiable by their high initial serum level. These results showed that the initial serum level of vitamin D analogues correlated with the affinity for DBP, but that there seemed to be no correlation with the metabolic rate as reflected by measurement of the serum half-life of the analogues.

Trough serum vancomycin levels predict the relapse of gram-positive peritonitis in peritoneal dialysis patients

We reviewed 31 episodes of gram-positive peritonitis that occurred in our peritoneal dialysis population between 1990 and 1993 in an attempt to identify the risk factor(s) for peritonitis relapse. All patients were treated with 4 weekly doses of intravenous vancomycin. Vancomycin doses no. 1 and 2 were based on body weight (15 mg/kg with a 1-g minimum); vancomycin doses no. 3 and 4 were adjusted in an attempt to maintain the trough serum vancomycin level at greater than 12 mg/L. Nine peritonitis episodes complicated by a relapse were identified. Peritonitis episodes preceding a relapse were similar to relapse-free episodes with respect to patient age, diabetes, peritoneal dialysis modality, duration of peritoneal dialysis treatment, residual urea clearance, peritoneal fluid cell count, causative organism, and weekly vancomycin dose. However, cumulative 4-week mean trough vancomycin levels were consistently lower during peritonitis episodes preceding a relapse (7.8 ± 0.6 mg/L during relapse-prone episodes v 13.7 ± 0.9 mg/L during relapse-free episodes; P = 0.0004). Furthermore, relapses developed during nine of 14 peritonitis episodes demonstrating a 4-week mean trough vancomycin level less than 12 mg/L compared with zero of 17 episodes with a 4-week trough level greater than 12 mg/L ( P < 0.05). The detection of a low initial 7-day trough vancomycin level also was a useful marker for subsequent peritonitis relapse. In 13 peritonitis episodes associated with an initial trough level less than 9 mg/L, nine were complicated by a relapse. The mean trough vancomycin level persisted below 9 mg/L over the final 3 weeks of therapy in all nine relapse-prone episodes as opposed to only one of four relapse-free episodes. All peritonitis relapses were treated successfully with 4 weeks of intravenous vancomycin therapy. This coincided with a significantly higher 4-week mean trough vancomycin level during treatment of the relapses (14.7 ± 0.7 mg/L during the relapse v 7.8 ± 0.6 mg/L immediately preceding the relapse; P < 0.05) despite similar mean weekly vancomycin dosages during both periods (19.4 ± 1.0 mg/kg during the relapse v 17.8 ± 1.2 mg/kg prior to the relapse; P = NS). In patients with uncomplicated peritoneal dialysis-related gram-positive peritonitis treated with weekly intravenous vancomycin, we conclude that (1) a suboptimal trough serum vancomycin level (cumulative 4-week trough serum vancomycin level <12 mg/L or an initial 7-day trough serum level <9 mg/L) is the only clinical parameter that identified peritonitis episodes at risk for relapse, and that (2) on detection of a suboptimal initial trough level (<9 mg/L), prevention of a subsequent peritonitis relapse may be possible if adequate trough vancomycin levels (>9 mg/L and preferably >12 mg/L) can be maintained for the remainder of therapy.

Low dialysate calcium in continuous ambulatory peritoneal dialysis: A randomized controlled multicenter trial

Hypercalcemia is a common complication in continuous ambulatory peritoneal dialysis (CAPD) patients treated with calcium-containing phosphate binders and using the standard dialysate calcium concentration of 3.5 mEg/L (SCa). Lowering the dialysate calcium was proposed to overcome this problem. The current randomized controlled multicenter study was designed to investigate efficiency and safety of a low calcium dialysate (2.00 mEq/L; LCa) compared with SCa (3.5 mEq/L) in CAPD patients. After an 8-week run-in period, 103 stable CAPD patients, 68 men, 35 women, aged 54.5 years (range, 20 to 77)) were randomly allotted to treatment with either LCa or SCa. All patients received calcium carbonate as oral phosphate binder to achieve serum phosphate levels < 6.2 mg/dL. If persistent hypercalcemia arose, CaCO 3 was replaced by AI(OH) 3 until normocalcemia was achieved. All patients received 0.25 μg calcitriol/d. Parameters monitored included total and ionized serum calcium, serum phosphate, phosphate binder intake, incidence of hypercalcemia, serum aluminium, intact parathyroid hormone (1,84PTH), osteocalcin, alkaline phosphatase, bone mineral density and hand skeletal x-ray. Primary end points were (a) number of hypercalcemic episodes, (b) tolerated doses of calcium-containing phosphate binders, and (c) 1,84PTH. After 6 months of therapy, total and ionized calcium were lower in LCa patients (total Ca:9.6 v 10.08 mEq/L, P = 0.005; iCa: 4.76 v 5.15 mg/dL; P = 0.013). In the LCa group, siginificantly fewer episodes of hypercalcemia were recorded (total S-calcium > 10.8 mg/dL: LCa 24 v SCa 86 episodes; P < 0.005). Use of LCa permitted the administration of more CaCO 3 (mean daily tablet number: LCa, 5.9 v SCa, 4.2; P < 0.05). More AI(OH) 3 was required in the SCa group (2.0 v 0.7 tablets/d per patient; P < 0.01). Control of serum phosphate was comparable, and initial and final serum levels did not differ between the groups. 1,84 PTH levels were within the desired range in the LCa group (medians: start of run-in, 15 pmol/L; start of therapy, 15.5 pmol/L; wk 24, 14 pmol/L), whereas in the SCa group, 1,84 PTH declined to the normal range (start of run-in, 15 pmol/L; start of therapy, 9.2; wk 24, 7.05 pmol/L; normal, 1 to 6 pmol/L). No radiologic signs of renal osteodystrophy or demineralization of the bones were observed with LCa. Adverse events were rare, with the exception of peritonitis. The frequency of peritonitis episodes and exit-site infections was similar, however, in LCa and SCa patients. In conclusion, this randomized controlled multicenter study in a large number of CAPD patients documents significantly better tolerance of calcium-containing phosphate binders with no adverse effects on PTH levels or other end points after 6 months of treatment when dialysate calcium concentration is lowered to 2.0 mEq/L.

A slow release formulation for recombinant bovine interferon αI-1

Recombinant bovine interferon- α I 1 (rBoIFN-α) has known antiviral and immunomodulatory effects which have been exploited to reduce clinical disease in a number of clinical situations including bovine respiratory diseases. A slow release rBoIFN-α formulation may be of value to reduce bovine respiratory disease under field conditions by extending the period of protection, and hence improving the prophylactic benefits of rBoIFN-α. In this report, we describe a formulation of rBoIFN-α in sesame oil containing calcium stearate which can successfully sustain the release of rBoIFN-α over an 8-day period. Recombinant bovine IFN-α could be measured in serum for 8 days following treatment with an initial burst of release 6 h after injection. After a single subcutaneous depot injection of 50 mg and 100 mg of rBoIFN-α, initial serum levels reached 12–15 ng/ml and 25 ng/ml respectively. Correlating with this burst of release, there was a decrease in the number of circulating CD4 −CD8 − γδ + T lymphocytes, and a slight neutropenia. No alterations in other cell phenotypes tested (CD4, CD8, CD2, CD6, B cells, monocytes or MHC class II) were observed, nor were there changes in lymphokine activated killer (LAK), natural killer (NK) cell activity, or oxygen radical formation (assessed by reduction of nitroblue tetrazolium). However, despite the rapid and short-lived burst of rBoIFN-α, levels of 2–5 oligoadenylate (2–5 A) synthetase remained elevated for 8 days. The sustained increase of 2–5 A synthetase was not due to the high initial dose released during the burst 6–12 h after injection, since injection of a bioavailable equivalent dose of interferon induced a significant rise in 2–5 A synthetase activity for 4 days only. As 2–5 A synthetase is known to be a correlate of antiviral activity, we propose that this formulation of rBOIFN-α may be one approach to increase the window of protection, leading to more effective prevention of bovine respiratory disease.

Separation of Myocardial Versus Peripheral Effects of Calcium Administration in Normocalcemic and Hypocalcemic States Using Pressure-Volume (Conductance) Relationships

This study used left ventricular pressure-volume (conductance) relationships to separate the effects of calcium administration on myocardial performance and peripheral vasoconstriction in normocalcemic and hypocalcemic states. Hypocalcemia was produced in anesthetized dogs with intravenous citrate-phosphate-dextrose until serum [Ca2+] was ≈0.7 mmol/L. Calcium (CaCl2) bolus (5 mg/kg) was administered during normocalcemia (n = 6) and hypocalcemia (n = 6), and data were collected at 1, 5 and 10 min after CaCl2 administration. During normocalcemia, CaCl2 administration increased [Ca2+] 19% at 1 min and was accompanied by a 47% (P < 0.05) decrease in left ventricular contractility (i.e., end-systolic elastance or Elves) and a 13% (P < 0.05) increase in systemic vascular resistance. At 5 and 10 min, serum [Ca2+] and the hemodynamic variables began to return to the baseline values. During hypocalcemia, Elves decreased 25% (P < 0.05), but after CaCl2 bolus, it increased to baseline levels and remained there during the 10-min period. Hypocalcemia and the CaCl2 bolus did not significantly affect SVR. In conclusion, these studies suggest that the indications for the use of calcium should depend on the initial serum level of ionized calcium. (Anesth Analg 1993;77:250-5)

Intranasal estradiol administration to oophorectomized women

An open, dose-finding study into the effects of a new intranasal 17β-estradiol formulation using dimethyl-β-cyclodextrin as a solubilizer was conducted in nine hysterectomized and oophorectomized patients with symptoms of estrogen deficiency. After nasal delivery of 0.34 mg estradiol in three patients, concentration-time curves of estradiol in serum and its metabolite estrone in plasma were established. High initial estradiol serum levels were found in the order of 5 nmol/1. Estrone/estradiol ratios were below unity, whereas, in contrast, estrone/estradiol ratios after oral administration of estradiol are known to exceed unity. Biological activity, as reflected by suppression of FSH and LH, was manifest. In nine patients symptoms of estrogen deficiency were assessed by a questionnaire. After 3 and 6 months of treatment, a clinically and statistically significant decrease ( P < 0.01) of the total score according to this questionnaire was found compared to the beginning of the study. Thus nasal delivery of estradiol using this cyclodextrin formulation has potential for further clinical evaluation.