First Hour Of Infusion Research Articles

Low Dose Rituximab Efficiently Clears Circulating CLL Cells and Maintains Sensitivity to Antibody Dependent Cellular Phagocytosis (ADCP)

Introduction: We have recently shown that high frequency (2 x week) low dose (50 mg)(HFLD) rituximab (RTX) and acalabrutinib is highly effective initial therapy for patients (n=38) with progressive CLL (ClinicalTrials.gov NCT03788291, PMID:36689726). The first dose of 50 mg of IV rituximab administered at 25 mg/h decreased the median circulating CLL cell count by 84% from pre-treatment baseline at 1h with no further decrease in the count during the remainder of the infusion (PMID:37003030). During the first hour of infusion, median CLL cell membrane CD20 levels decreased to 65% of baseline and were 41% of baseline at the end of the infusion. Median serum rituximab concentration was 2 mcg/ml at 1h and 10 mcg/ml at the end of the infusion. Median complement (CH50) concentration decreased to 91% of baseline at 1 h and to 81% of baseline at the end of the infusion. The cessation of clearance of CLL cells from the circulation within 1h of starting rituximab therapy is thus unlikely to be caused by low rituximab levels, decreased CLL cell CD20 expression or low serum complement levels. We and others have previously shown that ADCP is the primary mechanism of clearance of anti-CD20 mAb opsonized B cells in both humans and mice. We hypothesized that clearance of circulating CLL cells decreases because residual circulating CLL cells are resistant to mAb induced ADCP. To test this hypothesis, we measured in vitro ADCP sensitivity of CLL cells sampled from patients before and after rituximab treatment. Methods: Blood specimens were collected from 13 patients prior to starting therapy (C1D1_pre), 1h after start of IV rituximab infusion (C1D1_1h), at end of rituximab infusion (C1D1_post), and 48 h after initiation of therapy (C1D3_pre). Sensitivity of circulating CLL cells to in vitro ADCP was measured using live cell time-lapse high-content microscopy imaging of phagocytosis of CLL cells by human monocyte derived macrophages (hMDM) as previously described (PMID:32005699). Phagocytosis was quantified using a void index and sensitivity of samples was compared using the area under the curve of the 2h void index plot (AUC). Experiments were done in triplicate with co-cultures of hMDM and CLL cells without mAb as controls. Rituximab (10 mcg/ml) was used to test CD20 mAb mediated ADCP and alemtuzumab (10 mcg/ml) to test non-CD20 mediated ADCP. Results: Figure (median and 95% confidence intervals) shows that neither rituximab nor alemtuzumab induced ex-vivo ADCP as measured by median void index AUC was significantly altered by prior in vivo exposure of CLL cells to rituximab (Wilcoxon Match-Paired Sign test; all p>0.05). Discussion: The rapid decrease in circulating CLL cells induced by IV rituximab occurred only within the first hour after initiation of mAb infusion. Our measurements show that serum rituximab and complement concentrations and CLL cell membrane CD20 levels should be adequate to support additional CLL cell clearance after 1h. We now demonstrate that residual circulating CLL cells remain sensitive to in vitro ADCP by both rituximab and alemtuzumab. This suggests that despite reduced levels of surface antigen, circulating cells remain sensitive to mAb mediated clearance. Alternative explanations for the limited clearance of circulating CLL cells include: 1. Saturation of the limited cytotoxic capacity of the innate immune effector cells (Kupffer cells and splenic macrophages) compatible with our previously reported data on finite macrophage ADCP capacity (PMID:32556153); 2. Mobilization of CLL cells from lymphoid tissue; and 3. Temporary sequestration of rituximab opsonized CLL cells in tissue (e.g. spleen or lungs), which is unlikely given the observed decrease in lymph node size following initiation of therapy. Ongoing research is testing these hypotheses.

Do Federal Price Transparency Regulations Neglect Oncology Patients?

<h3>Purpose/Objective(s)</h3> Financial toxicity is far more prevalent in oncology than in general patient populations and is associated with inferior quality of life and health outcomes. In 2021, the US Centers for Medicare and Medicaid Services (CMS) required all hospitals to publish "shoppable," payer-negotiated prices for ≥ 300 services of which 70 (including specialty care such as joint and cataract surgery) were specified, but oncology price inclusion was optional. National Cancer Institute (NCI)-designated centers are referral sites for cancer care, but the rate at which they choose to report prices for radiation therapy (RT) or systemic therapy is unknown. We predicted that the proportion of NCI-designated cancer centers reporting RT and infusion prices would lag behind their general rate of compliance with publication of shoppable prices. <h3>Materials/Methods</h3> 63 clinical NCI-designated cancer centers were identified. On February 1, 2021, (1 month after regulations took effect), online shoppable price lists and lengthy "chargemaster" documents containing prices for every offered service were identified through search terms such as "price transparency" or "price estimate." These tools were queried for the Current Procedural Terminology (CPT) codes 77385 and 96413 corresponding to the charge per fraction for simple intensity modulated radiation therapy (IMRT) and the first hour of infusion of systemic therapy, respectively. Search terms such as "radiation," "radiotherapy," "IMRT", "chemotherapy," and "infusion" were also used. Primary endpoints were the rate of reporting of shoppable prices for IMRT and infusion. Secondary endpoints were the rate of publication of shoppable prices and the rate of reporting any RT service. Descriptive statistics including proportions and frequency counts were performed. <h3>Results</h3> The price transparency webpages for all 63 institutions were easily identified. 52 (83%) listed shoppable prices in any format including 49 (78%) user-friendly web-based tools and 3 downloadable documents. 9 (17%) and 8 (15%) centers listed prices for IMRT and infusion, respectively, in their shoppable tools, and 20 (38%) listed at least one RT price. When also including negotiated prices found in chargemaster documents, 20 (32%), 23 (37%), and 31 (49%) of the 63 centers listed negotiated IMRT, infusion, and any RT prices, respectively. <h3>Conclusion</h3> Although 83% of NCI-cancer centers are compliant with mandates to report shoppable prices, almost 1 in 5 are noncompliant. Furthermore, less than 1 in 5 report negotiated RT and systemic therapy prices in shoppable tools. Oncology price reporting rates rise when considering chargemaster data, but these documents are opaque and patients may not know they exist. Policy changes such as mandatory RT and infusion price reporting should be considered to mitigate financial burden by improving patient access to reliable oncology price information.

Relationship between norepinephrine dose, tachycardia and outcome in septic shock: A multicentre evaluation

PurposeSeptic shock is associated with massive release of endogenous catecholamines. Adrenergic agents may exacerbate catecholamine toxicity and contribute to poor outcomes. We sought to determine whether an association existed between tachycardia and mortality in septic shock patients requiring norepinephrine for more than 6 h despite adequate volume resuscitation. Materials and methodsMulticentre retrospective observational study on 730 adult patients in septic shock consecutively admitted to eight European ICUs between 2011 and 2013. Three timepoints were selected: T1 (first hour of infusion of norepinephrine), Tpeak (time of highest dose during the first 24 h of treatment), and T24 (24-h post-T1). Binary logistic regression models were constructed for the three time-points. ResultsOverall ICU mortality was 38.4%. Mortality was higher in those requiring high-dose (≥0.3 mcg/kg/min) versus low-dose (<0.3 mcg/kg/min) norepinephrine at T1 (53.4% vs 30.6%; p < 0.001) and T24 (61.4% vs 20.4%; p < 0.0001). Patients requiring high-dose with concurrent tachycardia had higher mortality at T1; in the low-dose group tachycardia was not associated with mortality. Resolving tachycardia (from T1 to T24) was associated with lower mortality compared to patients where tachycardia persisted (27.8% vs 46.4%; p = 0.001). ConclusionsUse of high-dose norepinephrine and concurrent tachycardia are associated with poor outcomes in septic shock.

Role of Luteinizing Hormone in Changes in Concentrations of Progesterone and Luteal Blood Flow During the Hours of a Simulated Pulse of 13,14-Dihydro-15-Keto-Prostaglandin F2alpha (PGFM) in Heifers

A bolus treatment (e.g., 25 mg) of prostaglandin F(2alpha) (PGF) in the study of luteolysis in cattle results in dubious interpretations. Therefore, in experiment 1 of the present study, a 13,14-dihydro-15-keto-PGF (PGFM) pulse was simulated by incremental intrauterine (IU) infusion of PGF for 2.7 h on Day 14 postovulation. Concentrations of PGFM during the first hour of infusion and at the maximum were not different between simulated (n = 7) and spontaneous (n = 7) pulses. In experiment 2, four groups (n = 6 per group) were treated at Minute 0 (beginning of infusion) as follows: saline (infused IU), PGF (infused IU), acyline/saline, and acyline/PGF. Two hours before Minute 0, each heifer was given flunixin meglumine to inhibit endogenous PGF secretion, and heifers in the acyline/saline and acyline/PGF groups were given acyline to inhibit luteinizing hormone (LH). Plasma progesterone concentrations were similar among groups during Minutes 0 to 60, with no indication of an initial transient progesterone increase in the two PGF groups. Progesterone began to decrease in the PGF groups at Minute 60 and to rebound at Minute 135 after the PGFM peak at Minute 120. The rebound was complete in association with an increase in LH in the PGF group, but it was not complete when LH was inhibited in the acyline/PGF group. Luteal blood flow increased during PGF infusion in the two PGF groups and remained elevated for approximately 2 h after the PGFM peak in the PGF group but not in the acyline/PGF group. Novel findings were that an initial transient increase in progesterone did not occur with the simulated PGFM pulse and that LH stimulated a progesterone rebound and maintained the elevated luteal blood flow after the PGFM peak.

Feasibility of infusion pumps for continuous spinal administration of local anesthetics in post‐operative pain therapy

For completion of perioperative care and for general ethical considerations, any intraoperatively used catheter technique should be utilizable for post-operative pain therapy. Continuous spinal anesthesia (CSA) is an established form of local anesthetic application. However, for its use in post-operative therapy, infusion pumps are required that are technically able to deliver low rates and are distinctive in design to avoid possible pump or medication swaps. Because of a lack of devices specifically designed for CSA, we investigated the potential deployability of infusion pumps for post-operative pain therapy via CSA microcatheters, which were originally designed and approved for different applications. The accuracy of infusion rates of three different pumps was measured in a liquor model environment. Furthermore, we investigated safety and user-friendliness by interviewing 30 anesthesiologists and 15 pain nurses. Except for the first hour of infusion, all pumps provided comparable and adequate flow profiles. However, interviews revealed significant risk factors for all pumps in terms of swapping devices, lines or medications and misprogramming the units. All pumps tested were technically able to deliver accurate flow rates; however, because the non-CSA-specific design involves the risk of medication overdosage and syringe swaps, none of the systems tested can be recommended for routine use in post-operative CSA, irrespective of the fact that it was an off-label application anyway. Therefore, to ensure patient safety, continuous spinal administration of local anesthetics via microcatheters is a questionable method of post-operative pain therapy as long as non-specific pumps are used.

The Impact of Insulin Adsorption onto the Infusion Sets in the Adult Intensive Care Unit

The difficulty in achieving tight glycemic control (TGC)1,2 in the adult intensive care unit (ICU) is well documented.3,4 We aimed to explore the impact of insulin adsorption onto infusion sets in the laboratory and to assess retrospectively if higher insulin doses are required after syringe changes in practice in the ICU. Adsorption is reported to occur predominantly during the first hour of infusion, after which binding sites are saturated.5 There is greater insulin recovery with faster flow rates and higher insulin concentration.6 The clinical significance of such adsorption in the ICU setting is uncertain.5 In our study—approved by the local ethics committee—adsorption of insulin onto the giving sets used in our adult ICU was analyzed. The infusion set used was a 50 ml polypropylene syringe (BD Plastipak®) and 1.6 ml/200 cm polyethylene (PE) tubing (Cardinal Health, extension set). In the laboratory, the concentration investigated was 1 U/ml of neutral insulin in sodium chloride 0.9%. The concentrations were determined using a high-performance liquid chromatography method with a Jupitor 300, 5 μm C18, 250 mm × 4.6 mm column (Phenomenex), a mobile phase of 30% acetonitrile and 0.1% TFA in water, and ultraviolet detection at 210 nm. Significant insulin adsorption of 10% occurred during the first hour of an infusion when the infusion rate was 1 ml/h (Figure 1). Our experience suggests that this is a common infusion rate used in intensive insulin therapy. No significant adsorption occurred when the infusion rate was 4 ml/h, although a trend could be seen with solution leaving the PE tubing at the beginning of the time period having a lower insulin concentration, which increased with time. Figure 1. The mean (± standard error) insulin concentration versus time with an infusion rate of 1 U/h. The infusion rates used before and after an infusion set change were investigated for 17 ICU patients known to have been managed with a TGC protocol, aiming for glycemia of 4.4–6.1 mmol/liter, to examine any relationship between the duration of usage of the infusion set and the variation in insulin dosing required. These patients were not prescribed drugs known to affect glucose control, such as inotropes and corticosteroids. In the ICU patients, a significantly higher insulin infusion rate was required after an infusion set change when the infusion rate was 1 ml/h or lower. After an infusion set change, the rate was adjusted upward in 76.5% of cases. In conclusion, we found in the laboratory that less insulin is delivered during the first three hours after an infusion set change, when the infusion rate is 1 ml/h or lower, due to adsorption onto infusion sets. In the ICU, a higher infusion rate was frequently required after an infusion set change when the infusion rate was 1 ml/h or lower. Our results indicate that at low infusion rates, if the syringe and line are not primed, only 90% expected insulin is delivered. The clinical impact of a loss of 0.1 U/h of insulin is questionable, but in practice when syringes were changed, higher rates were frequently required. Further investigation should be undertaken to confirm these findings.

The Effect of Amrinone on Liver Regeneration in Experimental Hepatic Resection Model 1

The phosphodiesterase inhibitors (PDEIs) have been proposed to improve hepatic reperfusion injury and hepatosplanchnic circulation, but the effects of these agents on liver regeneration have not been investigated thoroughly. The aim of this study was to investigate the effect of amrinone, a PDEI, on liver regeneration in rats. Sixty rats were divided into two groups, control and amrinone. Each group was then divided into three groups (n=10). An infusion of amrinone to the study group and of 0.9% NaCl to the control group was performed. Seventy percent liver resection was performed to the rats during the first hour of infusion. The infusion was maintained for 17 h after resection. A total of 18 h infusion was performed. Rats were allowed to survive for 24, 48, and 72 h, and then they were sacrificed. Biochemical, morphological, hematological, and histopathologic measurements and assessments were performed. There were statistically significant differences between the amrinone and control groups in alkaline phosphatase and relative liver weights at 24, 48, and 72 h (P<0.05). There also were statistically significant differences between the groups in AST, bilirubin, and albumine levels at 24 h, ALT and prothrombine time levels at 48 h, and aspartate aminotransferase and alanine aminotransferase levels at 72 h (P<0.05). Hepatic ATP levels, mitotic index, and proliferating cell nuclear antigen labeling index were significantly higher in amrinone group compared with control group at all three time intervals (P<0.05). Amrinone improves both morphological and functional liver regeneration after liver resection.

Stability of Insulin Aspart in Normal Saline Infusion

Aim: To investigate the stability of insulin aspartin sodium chloride 0.9% (normal saline) during storage and continuous IV infusion.Method: Five bags containing insulin 0.1 unit per mL were prepared for each of the four different experimental conditions‐room temperature, 37°C, 2 to 8°C, and within an IV administration set. Insulin was assayed by high pressure liquid chromatography.Results: The insulin concentration fluctuated for 4 hours and then remained within the prescribed range over a 24‐hour period at both room temperature and 37°C. When stored at 2 to 8°C for eight days, the concentration remained stable after one day and was always within the prescribed range. Infusion through an administration set provided a stable concentration after the initial first hour of infusion.Conclusion: Insulin aspart can be produced in batches in normal saline, stored at room temperature or 37°C for 24 hours or in the refrigerator for eight days, and administered without significant change in the prepared concentration.

Modulation of the feeding response of lactating dairy cows to peripheral insulin administration with or without a glucose supply.

The aim of this study was to determine the effect of physiological amounts of insulin without glucoprivation on food intake of dairy cows. Four multiparous Holstein cows at 150 days post-partum were allocated to the treatments, consisting of a 4 h intravenous infusion of: 1) control (saline); 2) insulin (3.41 micrograms/kg); 3) glucose (2.75 mmol/kg); and 4) insulin plus glucose (same dosage). A complete diet was offered ad libitum and the intake behaviour was continuously recorded. The plasma insulin was only slightly increased during the insulin treatment, but the treatments including glucose increased it more. The insulin treatment increased dry matter intake during infusion (+12%; P < 0.07), but the increase was offset during the following 4 h. In contrast, dry matter intake was slightly decreased by insulin during the first hour of infusion (-8%; P < 0.03) when the insulin-induced hypoglycemia was prevented by a concomitant infusion of glucose. The insulin-induced glucoprivation stimulated food intake, whereas glucose availability had no obvious satiating effect in dairy cows.

Effect of an NK1 receptor antagonist (CP-99,994) on hypertonic saline-induced bronchoconstriction and cough in male asthmatic subjects.

To investigate the role of NK1 receptors in the pathogenesis of bronchoconstriction and cough in asthma, we performed a randomized, double-blind, crossover study on the effects of a selective non-peptide tachykinin NK1 receptor antagonist (CP-99,994) on baseline measures of lung function and on hypertonic saline-induced bronchoconstriction and cough in 14 male subjects with mild asthma. CP-99,994 (250 micrograms/2 hours) and placebo were administered intravenously in 2-h infusions during consecutive visits 5 to 7 d apart. Specific airway resistance (SRaw) was measured and spirometry was performed at baseline and at 35 and 60 min. Next, hypertonic saline challenge was performed by delivering 10 breaths of saline of increasing concentration (0.9 to 7% in 1% increments at 5-min intervals) via an ultrasonic nebulizer until SRaw increased from baseline by 200% or 20 units, whichever was greater. Throughout the challenge cough was counted from a taped record made from two microphones placed close to the subject's larynx. We found that CP-99,994 did not significantly affect SRaw or spirometric measures of lung function during the first hour of infusion. Although CP-99,994 infusion markedly attenuated the bronchoconstrictor response to the saline challenge in two subjects, it did not significantly decrease the area under curves obtained for SRaw and cough during saline challenge for the group as a whole (p = 0.9 for SRaw;p = 0.8 for cough). We conclude that administration of 250 micrograms/kg of CP-99,994 over 2 h does not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in subjects with mild asthma and does not have acute bronchodilator activity in these subjects.

Effect of ICV infusion of CRF on blood pressure and adrenal steroids in rabbits

The effect of prolonged, 22 h long, intracerebroventricular (i.c.v.) infusion of corticotropin-releasing hormone (CRF) on plasma cortisol, corticosterone and electrolyte concentrations, mean arterial blood pressure (MAP) and heart rate (HR) were investigated in conscious rabbits. During i.c.v. infusion of CRF, 1 and 3 μ/h, at a rate of 17 μl/h, plasma cortisol and corticosterone concentrations rose to the level noted after ACTH stimulation in rabbits. Plasma [Na] did not change, but plasma [K] was reduced and plasma osmolality increased during the infusion of CRF, 3 μ/h. MAP and HR, recorded continuously during i.c.v. infusion of CRF, changed only with the higher dose of CRF: MAP was elevated during the first 5 h of infusion, and then returned to the control level. HR was lower than control at the end of the first hour of infusion and again between 9 and 15 h of infusion. The prolonged rise of CRF concentration in the brain induced a sustained rise in circulating adrenal steroid hormones. MAP did not increase to the level noted after bolus i.c.v. injection of CRF and the rise in MAP was not sustained.

Short-term effects of somatostatin analogue (SMS 201–995) on left ventricular function in healthy persons: A scintigraphic study

Since somatostatin has been reported to have a negative inotropic and chronotropic effect on atria and positive inotropic effect on ventricle, present study was designed to investigate the acute effects of somatostatin analogue SMS 201-995 infusion on the left ventricular function in healthy volunteers. After labeling the autologous red blood cells with 750-1000 MBq 99mTc-pertechnetate, ECG-gated radionuclide ventriculography was performed. Using Fourier analysis of the left ventricular time-activity curve, ejection fraction (EF), peak ejection rate (PER), peak filling rate (PFR), time to end-systole (TES) and normalized TES/T values were calculated. Study group consisted of 12 healthy volunteers. Somatostatin analogue SMS 201-995 infusion was given at a rate of 100 micrograms/h during 2h. Baseline, 1st, 2nd h and 4th h imagings were done using the same protocol. Simultaneously heart rate and blood pressure were recorded. The difference between parameters was tested using Kruskall-Wallis test. The mean heart rate, systolic and diastolic blood pressures and did not show any statistically significant change during the somatostatin analogue infusion and 2h later in comparison to baseline values. The mean PER and PFR had a slight decrease at the first hour of infusion, but the change was not significant. However, the significant correlation of PER values with heart rate, EF and TES observed at baseline study were disappeared during the infusion. These results indicate that somatostatin analogue infusion does not appear to change the left ventricular systolic and diastolic function in healthy persons significantly.

Role of platelet activating factor in pathogenesis of acute pancreatitis in rats.

The importance of platelet activating factor in acute pancreatitis was examined by determining the tissue content of endogenous platelet activating factor and the protective effects of TCV-309, a highly selective platelet activating factor blocker, against caerulein induced pancreatitis in rats. Infusion of caerulein (10 micrograms/kg/h) for five hours resulted in about 70% increase in pancreatic weight, 22% rise in protein content, 50% reduction in tissue blood flow, nine fold increase in tissue level of platelet activating factor and 165% rise in plasma amylase as well as histological evidence of acute pancreatitis. Such infusion of caerulein in chronic pancreatic fistula rats caused a marked increase in protein output from basal secretion of 10 mg/30 minutes to 40 mg/30 minutes in the first hour of infusion followed by a decline in protein output to 15-20 mg/30 minutes in the following hours of the experiment. Exogenous platelet activating factor (50 micrograms/kg) injected ip produced similar alterations in weight, protein content, blood flow, and histology of the pancreas but the increment in serum amylase was significantly smaller and pancreatic secretion was reduced below the basal level. TCV-309 (50 micrograms/kg) given ip before caerulein or platelet activating factor administration significantly reduced the biochemical and morphological alterations caused by caerulein and abolished those induced by exogenous platelet activating factor. These results indicate that platelet activating factor plays an important role in the pathogenesis of acute pancreatitis probably by reducing the blood flow and increasing vascular permeability in the pancreas.

Differential baroreceptor reflex modulation by centrally infused angiotensin peptides.

The present study was designed to investigate the effect of intracerebroventricular (icv) and intravenous (iv) infusion of angiotensin (ANG)-(1-7), ANG III, and ANG II on the baroreceptor control of heart rate (BHR) in conscious rats. Reflex changes in HR were elicited by bolus iv injection of either phenylephrine or sodium nitroprusside before and within 1 and 3 h of icv infusion of ANG II (n = 10), ANG III (n = 9), ANG-(1-7) (n = 9), or saline (n = 9) at a rate of 3 nmol.7.5 microliter-1.h-1. In another group of animals (n = 23), iv infusion of the same amount of ANG peptides was carried out at a rate of 0.7 ml/h. The average ratio of changes in HR in beats per minute and changes in mean arterial pressure (MAP, mmHg) was used as an index of BHR sensitivity. ANG II and ANG III produced a significant increase in the basal levels of MAP, but only during the first hour of infusion (iv or icv). No significant changes in baseline HR were observed. ANG-(1-7) and saline infusion did not change basal levels of HR or MAP (iv or icv). ANG II (iv and icv) and ANG III (icv) caused a significant decrease in the BHR sensitivity for reflex bradycardia. In contrast, icv infusion of ANG-(1-7) induced a significant increase in BHR sensitivity for reflex bradycardia (-3.0 +/- 0.3, 1 h, and -2.8 +/- 0.1 beats.min-1.mmHg-1, 3 h vs. -2.1 +/- 0.2 beats.min-1.mmHg-1, before infusion).(ABSTRACT TRUNCATED AT 250 WORDS)

In Vivo Administration of Tumor Necrosis Factor- is Associated with Antiviral Activity in Human Peripheral Mononuclear Cells

Tumor necrosis factor-alpha (TNF-alpha) has a spectrum of biologic effects and has been shown to exert antiviral effects in fibroblasts in vitro. The in vivo administration of TNF-alpha (40-160 micrograms/m2 intravenously over 2 hr) and its effects on vesicular stomatitis virus (VSV) replication in peripheral blood mononuclear cells (PBMC) from patients with malignancy was investigated. Blood was obtained before, during, and after infusion. The PBMC were separated and infected with VSV at a multiplicity of infection of 0.005 plaque-forming units/cell and virus yields were determined 72 h later. The TNF-alpha inhibited VSV yields by as much as 99% in a dose-dependent manner with the inhibition initially observed during the first hour of infusion. Despite a rapid reduction in TNF-alpha serum levels, the higher doses still produced antiviral effects 4 hr after the infusion. Sera obtained at identical times had no interferon activity. Human gamma-interferon (25 micrograms/ml) added in vitro augmented the TNF-alpha-induced inhibitory activity in both magnitude and duration. Percentages of lymphocytes and monocytes in peripheral blood were reduced at 4 hr after TNF-alpha administration and the monocyte to lymphocyte ratio was diminished and temporally coincided with the loss of TNF-induced antiviral state. These data suggest that the in vivo administration of TNF has a direct inhibitory activity on VSV replication in human peripheral blood mononuclear cells that was enhanceable by gamma-interferon and possibly monocyte mediated.

Exacerbation of Hyperlactatemia by Infusion of Lactated Ringer's Solution in Dogs With Lymphoma

Blood lactate concentrations and acid-base status of six dogs with lymphoma were compared statistically with those from six healthy control dogs before, during, and after a 6-hour infusion of lactated Ringer's solution (LRS). Blood lactate concentrations in dogs with lymphoma were significantly (P less than 0.05) higher immediately before, and at the 1-, 2-, 4-, and 6-hour time periods after infusion when compared with controls. Blood lactate concentrations increased significantly (P = 0.016) after the first hour of infusion in dogs with lymphoma but did not increase in the control dogs. The increase in blood lactate concentrations over baseline values after 1 hour of LRS infusion was significantly (P = 0.008) greater in dogs with lymphoma when compared with controls. Blood lactate concentrations returned to baseline levels after 2 hours of infusion in dogs with lymphoma, suggesting that dogs with lymphoma have a transient inability to handle increased lactate loads when compared with controls. However, the potential to augment lactate use, clearance, or both is present and does occur over time. Blood gas values were not significantly altered within the lymphoma or control dog groups after 6 hours of LRS infusion. Blood bicarbonate concentrations in dogs with lymphoma were significantly decreased before and after LRS infusion when compared with controls.

Four-Hour Atrial Natriuretic Peptide Infusion in Conscious Rats: Effects on Urinary Volume, Sodium, and Cyclic GMP

Atrial natriuretic peptide (ANP) is released from the cardiac atria in response to acute volume loads; when infused acutely ANP causes diuresis and natriuresis. Cyclic GMP (cGMP) appears to be the second messenger for ANP in the kidney. The role that ANP plays in the long-term regulation of salt and water balance is unclear, however, since resistance to ANP's natriuretic and diuretic activity develops during prolonged administration. The purpose of the present study is to examine the relationship between the rate of cGMP excretion in response to ANP and the development of resistance to ANP's diuretic and natriuretic activity. Following a 30-min baseline period of infusion of Ringer's solution conscious rats received ANP at 15 micrograms/kg/hr (n = 6) or Ringer's alone (n = 5) for 240 min. ANP-infused rats had a significant diuresis and natriuresis during the first hour of infusion; urinary cGMP excretion also increased compared to baseline. By 120 min after initiating the infusion in ANP-rats urinary volume and sodium excretion had declined to values not significantly different from those of baseline or control. In contrast, urinary cGMP excretion remained elevated for the duration of the ANP infusion, whether compared to baseline values or the control group. Resistance to the diuretic and natriuretic activity of ANP is not a result of mechanisms that involve cGMP generation.

Effects of acute hypermagnesaemia on intracellular calcium concentration and adrenergic activity.

The effects of acute hypermagnesaemia on intracellular free calcium and adrenergic activity were investigated in six normotensive volunteers given intravenous magnesium sulphate for 3 h. The free calcium concentration in platelets decreased after the first hour of infusion (P less than 0.05), but did not remain significantly depressed after 2 and 3 h of continued infusion. Plasma noradrenaline increased during the infusion (P less than 0.05), with no change in plasma adrenaline. The results demonstrate that the effects of intravenous magnesium sulphate on free intracellular calcium and plasma catecholamines are similar to those described with calcium antagonists.

Monohydroxy bile salt sulfates: Tauro-3β-hydroxy-5-cholenoate-3-sulfate induces intrahepatic cholestasis in rats

The biologic effects of sulfation of tauro-3β-hydroxy-5-cholenoate and of taurolithocholate were compared. Equimolar amounts (100 nmol/min · 100 g body wt) of the following were administered intravenously to male Sprague-Dawley rats over a 180-min period: taurolithocholate, [14C]taurolithocholate-3-sulfate, tauro-3)β3-hydroxy-5-cholenoate, [14C]tauro-3β-hydroxy-5-cholenoate-3-sulfate, its combination with taurocholate, and a saline-albumin solution (control). Sulfation of taurolithocholate and of tauro-3β-hydroxy-5-cholenoate only prevented the cholestatic effect of the former. Bile flow during infusion of [14C]tauro-3β-hydroxy-5-cholenoate-3-sulfate was reduced by 80% at the end of the experiment. A dose-dependent bile flow reduction was demonstrated. Recovery of the administered bile acid was 3% in urine, 13% in serum, 23% in the liver tissue, and 52% in bile, respectively. Excretion of biliary cholesterol and phospholipids was significantly reduced during the first hour of infusion. Coadministration of taurocholate abolished the cholestatic effect and enhanced the renal excretion of the sulfated bile salt. These data suggest that (a) the cholestatic effect of tauro-3β-hydroxy-5-cholenoate-3-sulfate is comparable with or may even exceed the effect of taurolithocholate and (b) although sulfation renders some bile salts more water soluble, it does not prevent the cholestatic effect of all monohydroxy bile salts.

Calcium antagonists and hormone release

Recent in vitro studies have demonstrated that Ca2+ plays an essential role in gonadotrophin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) release. In vivo, we have previously shown that verapamil, a substance known to inhibit calcium entry into cells, is capable of inhibiting basal gonadotrophin release as well as the release of luteinizing hormone and follicle-stimulating hormone (FSH) in response to an iv bolus of GnRH. We have examined the effects of calcium antagonists on the two phases of pituitary LH release in response to constant GnRH infusion in normal subjects. In 6 men, constant infusion of GnRH (0.2 microgram/min x 4 h) resulted in the expected biphasic LH response, with an initial rapid release of LH during the first hour of infusion, followed by a second phase release during the subsequent 3 h. When verapamil (5 mg/h) was infused together with GnRH over a 4 h period, a significant decline of the rapid as well as delayed release of pituitary LH occurred. During the calcium antagonist infusion FSH release was also inhibited, indicating that Ca2+ is also important for the release of this hormone. Our data demonstrate that Ca2+ plays an essential role in the mechanism of GnRH action on both phases of LH release and the release of FSH in normal subjects.