Hr Infusion Research Articles

Toxicity of a 24-Hour Infusion of Gemcitabine in Biliary Tract and Pancreatic Cancer: A Pilot Study

The antitumor activity of gemcitabine is not dose-response related but schedule-dependent. Based on the results of a published phase I study in patients with non-small-cell lung cancer we started a pilot study of a 24-hr infusion of gemcitabine in patients with adenocarcinoma of the pancreas and biliary tract cancer. Twenty-five patients were enrolled and received a 24-hr infusion of gemcitabine once weekly on three consecutive out of 4 weeks. Dose levels of gemcitabine ranged from 100 to 150 mg/m2. One of 13 chemotherapy-naive patients had a partial response. Dose-limiting toxicity (DLT) was thrombocytopenia in pretreated patients and neutropenia in chemotherapy-naive patients. Other toxicities were oral mucositis, fever, flu-like symptoms, and asthenia. Maximum tolerated dose (MTD), especially in pretreated patients, was 100 mg/m2.

Abciximab pharmacodynamics are unaffected by antecedent therapy with other GPIIb/IIIa antagonists in non-human primates.

Tirofiban and eptifibatide are currently approved for the medical stabilization of non-ST segment elevation acute coronary syndromes. In patients undergoing percutaneous coronary intervention (PCI) during infusion of these drugs, conversion to abciximab, which has long term proven clinical efficacy and cost-effectiveness, following PCI may be desirable. The purpose of this study was to determine if the binding or pharmacodynamics of abciximab is affected by a prior infusion of either tirofiban or eptifibatide. In vitro binding experiments were performed to determine if prior exposure to tirofiban or eptifibatide altered the affinity and extent of binding of abciximab to GPIIb/IIIa. For in vivo experiments, cynomolgus monkeys were pretreated with a bolus and 18 hour infusion of saline, tirofiban, or eptifibatide. At the end of the initial treatment, a bolus and 12 hr infusion of abciximab was started without delay. Inhibition of platelet aggregation, GPIIb/IIIa receptor blockade and abciximab pharmacokinetics were measured during and after both infusions. Equilibrium binding of abciximab in vitro was unaffected by tirofiban or eptifibatide. The extent and duration of abciximab inhibition of ex vivo platelet aggregation, receptor blockade, and abciximab pharmacokinetics in monkeys during and after the abciximab infusion were not affected by prior infusion of the animals with tirofiban or eptifibatide. In vitro and in vivo studies revealed that the molecular interaction of abciximab with the platelet GPIIb/IIIa receptor is not altered by immediate prior exposure of platelets to small molecule GPIIb/IIIa antagonists. These preclinical studies suggest that the efficacy of abciximab should not be impaired if it is initiated following termination of therapy with small molecule GPIIb/IIIa antagonists.

Perioperative Stroke Prevention

The definitions of commonly used terms are given in Table 1 (1–8). Stroke has been simply defined as any form of cerebral infarction (2), which includes those attributable to hemorrhage. The latter group is more likely to occur as a complication of specific surgical procedures (e.g., carotid endarterectomy) or the use of anticoagulants and is otherwise rare in the perioperative period (3). Hence, much of the information in this review pertains to ischemic cerebral events.

Association between exogenous atrial natriuretic peptide and hemodynamics in dogs with congestive heart failure produced by experimental mitral regurgitation.

Association between exogenous atrial natriuretic peptide (ANP) and hemodynamic changes was ascertained in 3 dogs with overt congestive heart failure (CHF(+)) and 3 dogs without congestive heart failure (CHF(-)) caused by experimental mitral regurgitation (MR). The hemodynamic measurements were recorded in all dogs during and after 1 hr infusion of ANP at the rate of 0.1 (low dose), 0.5 (medium dose) and 1.0 (high dose) microg/kg/min, respectively. Heart rate, mean arterial pressure, pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance decreased significantly during and after ANP infusion even with low dose in the CHF(+). Stroke volume, stroke volume index and cardiac output in the CHF(+) during and after ANP infusion showed an increasing trend as compared with the CHF(-). Double product, an indicator of myocardial oxygen consumption, significantly decreased during and after ANP administration at all doses in the CHF(+). These findings indicate that even at low dose, exogenous ANP improves cardiac performance and reduces myocardial oxygen consumption in the CHF(+), and suggest that ANP has beneficial effects in the treatment of dogs with overt congestive heart failure resulting from MR.

Pilot study of topotecan and high‐dose cyclophosphamide for resistant pediatric solid tumors

Background The recommended dosages of topotecan and cyclophosphamide in combination for prior-treated patients—3.75 mg/m2 and 1,250 mg/m2 in children, 5 mg/m2 and 600 mg/m2 in adults, respectively—are well below those of each agent when used singly. We tested the hypothesis that much higher dosing would meet critical goals of salvage therapy: antitumor effect and a lack of toxicity to key organs, so as not to preclude subsequent consolidative treatments needed for cure. Procedure Patients with resistant pediatric solid tumors received cyclophosphamide 4,200 mg/m2 by 48 hr infusion, and topotecan 6 mg/m2 by 72 hr infusion (HD-Cy/Topo). Mesna and granulocyte colony-stimulating factor were used. Cycles were repeated when neutrophil counts were >1,000/uL and platelet counts were >75,000/uL. Results Twenty-eight patients, aged 2 to 33 years (median, 14), received one (n = 4), two (n = 15), or ≥3 (n = 9) cycles of HD-Cy/Topo. All patients had previously received ≥6 cycles of other therapy, high-dose alkylator-based chemotherapy, and/or etoposide- and doxorubicin-containing regimens. HD-Cy/Topo was given in an outpatient setting. Profound myelosuppression was the major toxicity, but retreatment was possible by day 28, and preliminary results with peripheral blood stem cell collections showed a sparing effect on hemopoietic stem cells. Mucositis was uncommon. After HD-Cy/Topo, cardiac, renal, hepatic, and pulmonary function remained within the normal range. Partial or minor responses were noted in neuroblastoma, desmoplastic small round-cell tumor, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Conclusions Its antitumor potential and limited toxicity make HD-Cy/Topo an attractive choice for inclusion in aggressive salvage programs aimed at achieving cures of resistant tumors. It may also merit incorporation into frontline treatment protocols. Med. Pediatr. Oncol. 35:468–474, 2000. © 2000 Wiley-Liss, Inc.

Pretreatment with tumor necrosis factor-alpha attenuates arterial hypotension and mortality induced by endotoxin in pigs.

Tumor necrosis factor (TNF)-alpha administration in large amounts can induce a state of shock similar to that seen during severe sepsis. The objective of this study was to determine whether small doses of TNF-alpha might decrease the disposition for the development of shock induced by a subsequent infusion of endotoxin and to determine whether the mechanism of this protective effect of TNF-alpha pretreatment could be associated with up-regulation of the anti-inflammatory cytokine interleukin (IL)-10. Prospective, randomized, experimental study. Investigative intensive care unit at an academic medical center. A total of 14 female Yorkshire pigs, weighing 20-25 kg. We studied two groups of animals-pigs treated with 500 ng/kg recombinant porcine TNF-alpha (n = 7) and pigs given diluent alone (n = 7). At 24 hrs after treatment, both groups of pigs were subjected to a 24-hr continuous infusion of lipopolysaccharide (LPS) at a rate of 80 ng/kg/min. The mortality rate was determined in both groups. Hemodynamic indices, oxygen transport variables, total and differential white cell counts, and serum concentrations of TNF and IL-10 were determined at frequent intervals before and after TNF-alpha administration and during the LPS infusion. Additionally, peripheral blood mononuclear cells were collected for determination of messenger ribonucleic acid expression of IL-10 by reverse transcription-polymerase chain reaction. The administration of TNF-alpha at the dose used in this study did not have any profound effect. No pig treated with TNF-alpha died in response to the LPS infusion. In contrast, three of seven control pigs died during the LPS infusion. Lipopolysaccharide-induced arterial hypotension and arterial hypoxemia were attenuated in the TNF-alpha-treated group. Both groups had significant increases in serum concentrations of TNF-alpha in response to LPS, with no significant difference in peak serum TNF-alpha between groups. Neither serum concentrations of IL-10 nor expression of IL-10 messenger ribonucleic acid in circulating mononuclear cells differed between groups. The administration of TNF-alpha attenuated the severity of hyperdynamic shock induced by a subsequent infusion of endotoxin. This effect could not be associated with increased expression or elaboration of the anti-inflammatory cytokine IL-10.

Peritoneal cytokine concentrations and survival outcome in an experimental bacterial infusion model of peritonitis.

To correlate the dynamics of peritoneal cytokines with systemic concentrations and survival outcome. Randomized, controlled study using a recently developed rat model of peritonitis. Government research facility. Male Sprague-Dawley rats. Infected animals (INF) received an intraperitoneal infusion of 6.5 x 10(8) colony-forming units of Escherichia coli over 12 hrs, whereas control rats (CON) received a sterile inoculum. Peritoneal fluid and plasma samples were obtained from all rats at the end of the 12-hr infusion period as well as from all animals that survived the 7-day study (SURV). Interleukin (IL)-1beta concentration in the peritoneal fluid at 12 hrs tended to be higher in nonsurvivors (NONSURV) than in SURV. Tumor necrosis factor-alpha and IL-6 peritoneal concentrations at 12 hrs were significantly greater in NONSURV than in SURV. There were no significant differences in IL-2 and IL-4 peritoneal concentrations at 12 hrs between SURV and NONSURV. Although the concentrations of IL-1beta and tumor necrosis factor-alpha in the peritoneal fluid of INF decreased gradually during the study, these concentrations remained significantly higher than those of CON at 7 days. In contrast, peritoneal IL-2 concentrations remained lower in INF than in CON for most of the experiment. Peritoneal IL-6 concentrations in INF were transiently elevated above those of CON for 12 hrs. Cytokine concentrations in the peritoneal fluid of INF were always higher than those in plasma, which remained relatively unchanged throughout the study. For most of the variables as. sessed, CON showed no significant changes compared with INF. This model of peritonitis is associated with a significant and prolonged peritoneal inflammatory response that is adversely correlated with survival outcome. Our data would suggest that to be effective, novel immunotherapies should target mainly the peritoneal compartment.

Minimal Toxicity to Myeloid Progenitor Cells of Weekly24‐Hr Infusion of High‐Dose 5‐Fluorouracil: Direct Evidence from Colony Forming Unit‐Granulocyte andMonocyte (CFU‐GM) Clonogenic Assay

Abstract:Although very high doses of 5‐fluorouracil was used in the weekly 24‐h infusion, high‐dose 5‐fluorouracil (2600 mg/m2/week) and leucovorin (500 mg/m2/week) protocol, myelosuppression was surprisingly low. The current study was conducted to investigate the possible mechanism underlying the low myelosuppression. To mimic the clinical situation, peripheral blood progenitor cells collected from 12 patients were used for colony forming unit‐granulocyte and monocyte clonogenic assay; and 2 representative modes of 5‐fluorouracil exposure (30 min. versus 24 hr) were examined for cytotoxic effects on human myeloid progenitor cells. Previous pharmacokinetic studies have estimated the concentrations of 5‐fluorouracil in the bone marrow to be 200–400 μM and 1–2 μM for the 30 min. infusion (600–900 mg/m2) and the 24 hr‐infusion (1000–2000 mg/m2) regimens, respectively. The results of our colony‐forming unit‐granulocyte and monocyte clonogenic assay showed that 24‐hr exposure to 5‐fluorouracil (2 μM) and 30 min. exposure to 5‐fluorouracil (100 μM) resulted in 27.2% and 78.2% inhibition of the colony formation, respectively. Our data provided direct evidence which may explain why myelotoxicity is significantly less in weekly 24 hr infusion of fluorouracil than in the conventional bolus regimens.

Minimal toxicity to myeloid progenitor cells of weekly 24-hr infusion of high-dose 5-fluorouracil: direct evidence from colony forming unit-granulocyte and monocyte (CFU-GM) clonogenic assay.

Although very high doses of 5-fluorouracil was used in the weekly 24-h infusion, high-dose 5-fluorouracil (2600 mg/m2/week) and leucovorin (500 mg/m2/week) protocol, myelosuppression was surprisingly low. The current study was conducted to investigate the possible mechanism underlying the low myelosuppression. To mimic the clinical situation, peripheral blood progenitor cells collected from 12 patients were used for colony forming unit-granulocyte and monocyte clonogenic assay; and 2 representative modes of 5-fluorouracil exposure (30 min. versus 24 hr) were examined for cytotoxic effects on human myeloid progenitor cells. Previous pharmacokinetic studies have estimated the concentrations of 5-fluorouracil in the bone marrow to be 200-400 microM and 1-2 microM for the 30 min. infusion (600-900 mg/m2) and the 24 hr-infusion (1000-2000 mg/m2) regimens, respectively. The results of our colony-forming unit-granulocyte and monocyte clonogenic assay showed that 24-hr exposure to 5-fluorouracil (2 microM) and 30 min. exposure to 5-fluorouracil (100 microM) resulted in 27.2% and 78.2% inhibition of the colony formation, respectively. Our data provided direct evidence which may explain why myelotoxicity is significantly less in weekly 24 hr infusion of fluorouracil than in the conventional bolus regimens.

Safety and efficacy of abciximab use in conjunction with intracoronary urokinase in patients requiring angioplasty

Abciximab decreases ischemic complications during angioplasty. Intracoronary urokinase lyses intracoronary thrombus. We studied the combination of both drugs. Twenty-six consecutive patients with acute coronary syndromes and intracoronary thrombus underwent intervention with abciximab and intracoronary urokinase. All received aspirin and IV heparin. The dose of abciximab was a weight-adjusted bolus and a 12-hr infusion. The dose of urokinase was 250,000 to 633,000 units. Hemorrhagic complications were classified according to the TIMI study group. Hemoglobin and platelet counts were measured before and 12 and 48 hr after the procedure. Procedural success was achieved in 24 patients. There were no deaths or repeat interventions. No patient had a major bleeding complication. Only two had minor complications. One patient needed blood transfusion. None had a stroke or thrombocytopenia. The use of abciximab and intracoronary urokinase in the presence of intracoronary thrombus is associated with encouraging efficacy and few complications. Cathet. Cardiovasc. Intervent. 49:113-116, 2000.

Endothelin-1 in angiotensin II-dependent hypertension Answer to the Letter to the Editor

We are delighted that our paper [1] succeeded in generating interest and discussion. Gardiner and Bennett raised an important issue concerning the potential role of endothelin-1 (ET-1) in the high blood pressure (BP) of transgenic TGR(mREN-2)27 rats [2], a monogenic renin-dependent model of severe hypertension. As far as we can understand, they found a slow-onset hypotensive effect during an acute 8 hr infusion of a mixed ETA/ETB receptor antagonist (SB 209670) in male heterozygous TGR(mREN-2)27 rats, where they recorded invasively intra-arterial blood pressure [3]. This hypotensive effect was surpassed by that induced by losartan. Interestingly, a synergistic hypotensive effect of the two drugs was also noticed. Based on this evidence Gardiner and Bennett would seem to caution on our statement that ET-1 does not play a major role in this form of hypertension. In a previous study in female heterozygous TGR(mREN-2)27 rats we had also found that the BP in vivo and the aortic contractile responses in vitro followed parallel changes with ageing. We therefore suggested that ET-1 could play a role in this model of hypertension [4]. However, chronic studies with ET antagonists in younger rats have given opposite results. In 25 day-old male heterozygous HanRen2/Edin-rats, derived from crossing homozygous TGR(mREN-2)27 with …

Experimental infusion phlebitis: tolerance pH of peripheral vein.

This study aims to determine the pH that peripheral veins can tolerate. Intravenous nutrient solutions with different pHs (from 4.52 to 6.71) were infused into rabbit ear veins, and the veins were examined histopathologically. After 6-hr infusion at 10 mL/kg/hr, a commercial 2.72% amino acid/7.5% glucose solution with electrolytes (AG) caused obvious phlebitic changes, such as loss of venous endothelial cells, inflammatory cell infiltration, and perivascular edema, in all 6 rabbits because of its low pH (4.52) and high titratable acidity (22 mEq/L). The phlebitis was reduced when the solution was neutralized with NaOH to pH 5.93, and was almost eliminated when the pH was neutralized to 6.49. After 8-hr infusion at 15 mL/kg/hr, AG-adjusted pH to 6.30 caused slight phlebitic changes, but AG-adjusted pH to 6.71 scarcely caused any change. Furthermore, 24-hr infusion of the pH 6.49 solution caused no histopathological changes in 3 rabbits. These results suggest that the tolerance pH for the peripheral vein is about 6.5, and that an infusion solution does not cause phlebitis due to acidity if the pH is not lower than the tolerance pH.

Second-Line Chemotherapy with 96-Hour Infusional Paclitaxel in Refractory Non-Small Cell Lung Cancer: Report of a Phase II Trial

Advanced metastatic non-small cell lung cancer (NSCLC) that has progressed on initial cisplatin-based chemotherapy has a poor prognosis. Although paclitaxel is an active agent in the first-line therapy of NSCLC, 24-hr infusion of paelitaxel in patients with NSCLC failing first-line cisplatin-based regimens has shown minimal activity. Prolonged infusions of paclitaxel have shown activity in breast cancer patients who have failed short infusions of paclitaxel. In this study, 13 patients with refractory NSCLC who progressed on or after initial chemotherapy were treated with 96-hr paclitaxel (140 mg/m2 over 96 hr every 3 weeks) infusions as outpatients using a CADD infusion pump via a central catheter. Nine patients received only one or two cycles of treatment because of disease progression and had a median survival of 3 months (range, 1–5 months). Four patients had stabilization of disease for two to six cycles of treatment and had a median survival of 8 months (range, 8–12+ months). Grade 3–4 hematologic and nonhematologic toxicity occurred in <10% of cycles, and no treatment-related hospitalizations occurred. Quality of life (QOL) assessments using the Functional Assessment of Cancer Therapy-Lung questionnaire were performed at baseline and with each treatment cycle. In conclusion, although no objective responses were seen, disease stabilization occurred in 31% of patients. Overall toxicity was tolerable with no major negative impact on QOL in those patients receiving two or more cycles of treatment.

Tissue retention and subcellular distribution of continuously infused melatonin in rats under near physiological conditions

The fate and disposition of the melatonin released into the circulation is still poorly understood, and almost all current knowledge is derived from measurements made after a single and often a very large dose of labelled melatonin. In continuous infusion experiments in freely moving rats, we have recently demonstrated that considerable amounts of melatonin must be endogenously released in order to achieve and maintain approximately a 10-fold elevation of the low daytime plasma levels of this hormone. We have now applied this infusion paradigm to study the fate and tissue accumulation of [3H]-melatonin continuously infused under near physiological conditions into the jugular vein for a period of 2 hr. The retention of [3H]-melatonin and chloroform-insoluble [3H]-melatonin-metabolites was measured in almost all body tissues and their subcellular compartments immediately at the end of the infusion period and 6 hr later. At the end of the 2 hr infusion period, about 45% of the administered melatonin was recovered as water-soluble metabolites in the urine and about 20% in the small intestine. Some accumulation of [3H]-melatonin-derived water-soluble radioactivity was also noticed in the liver, colon, adrenals, and pituitary, as well as in the feces. The subcellular distribution of this radioactivity differed between tissues. During the period of 6 hr after the termination of infusion, a considerable amount of melatonin-derived radioactivity was found to become increasingly attached to the proteous interlayer of chloroform extracts of tissues and subcellular fractions, from where it could only be liberated by protease treatment.

Temporal effects of estradiol (E) on luteinizing hormone-releasing hormone (LHRH) and LH release in castrated male sheep

We tested the hypothesis that rapidly expressed inhibitory effects of estradiol (E) on luteinizing hormone (LH) release in the male are attributable, in part, to suppression of luteinizing hormone-releasing hormone (LHRH) release. Hypophyseal-portal cannulated, castrated male sheep were infused with E (15 ng/kg/hr) or vehicle. Portal and jugular blood samples were collected at 10-min intervals for 4 hr before, and for either 12 hr (E, n = 4; vehicle, n = 4) or 24 hr (E, n = 8; vehicle, n = 3) after the start of infusion. In animals sampled for 16 hr, temporal changes in both LHRH and LH were assessed. In animals sampled for 28 hr, only LH data were analyzed. Before either the 12-hr or 24-hr infusion, LHRH and/or LH mean concentrations, pulse amplitude and interpulse interval (IPI) did not differ between E- and vehicle-infused animals. In animals sampled for 16 hr, no effects of time or steroid × time interactions were detected for mean LHRH and LHRH pulse amplitude; however, both were greater (P < 0.01) in vehicle-infused than in E-infused males. LHRH IPI was unaffected by infusion. In contrast, both mean LH and LH pulse amplitude declined (P < 0.01) within 4–8 hr after the start of E infusion, whereas mean LH IPI was unaffected. In animals sampled for 28 hr, an effect of time (P < 0.01) and a steroid × time interaction (P < 0.01) was detected for mean LH, and there was an effect of time (P < 0.01) on LH pulse amplitude. Mean LH IPI was not affected. Our results show that in male sheep E rapidly reduces LH release in the absence of a detectable change in LHRH release.

Selective Nutrient Feeding Induces Maturation of Gastrointestinal Hormone Release in Preterm Infants • 1498

We have previously shown that preterm infants given small enteral feedings have higher plasma concentrations of gastrin and gastric inhibitory peptide(GIP), while plasma concentrations of peptide YY (PYY) are unchanged. In adults, the ingestion of protein stimulates the release of gastrin which, in turn, stimulates the release of acid and stimulates an increase in gastroduodenal motor activity. Carbohydrate stimulates the release of GIP which regulates plasma glucose and inhibits small intestinal motor activity. Fats stimulate the release of PYY which inhibits small intestinal motor activity. We speculated that feeding babies with selective nutrients would induce hormone release in preterm infants as they do in adults, and, thus, enhance gastrointestinal function. Eighty preterm infants 25 to 30 wks gestation admitted to the Newborn Intensive Care Unit at Ben Taub General Hospital were fed 24 ml/kg/d for the first 10 days they received enteral feedings in addition to parenteral nutrition. Infants were given one of 4 formulas: full 24 cal/oz formula (n=20), its carbohydrate (n=20), protein(n=20), or fat component (n=20), all fed in 4 hr cycles consisting of 2 hr infusions interrupted by 2 hrs of fasting. On the tenth study day, blood was drawn to determine fasting plasma concentrations of gastrin, GIP, and PYY. In addition, motor responses to a full strength formula feeding were assessed via a low compliance continuous perfusion manometry. Compared to values seen at birth, fasting plasma concentrations of gastrin increased by feeding day 10 among infants fed protein, fat, or full formula (all p<0.05, paired t test) but not carbohydrate. GIP plasma concentrations increased in babies fed carbohydrate or full formula (both p<0.05) but not fat or protein. Plasma concentrations of peptide YY did not change in any feeding group. No group of study infants displayed the presence of a motor response to feeding before enteral feedings were begun. Babies fed protein or full formula displayed motor responses to feeding after 10 days of feeding while babies fed carbohydrate and fat did not. We conclude that the release of gastrointestinal hormones in response to selective nutrients is present in preterm infants, as well as motor responses to feeding that are mediated by those nutrients. We speculate that designing formulas that trigger intestinal hormonal release may be useful in enhancing the infant's endogenous mechanisms to improve gastrointestinal function.

A 4-week toxicity study of magnesium sulfate administered by 24-hr intravenous infusion in beagle dogs

A 4-week toxicity study of magnesium sulfate administered by 24-hr intravenous infusion at the dosage levels of 0, 12.5, 50 and 100 mg/kg/hr in female beagle dogs was conducted. No death occurred in any group. Changes attributable to the treatment with magnesium sulfate were decreased food consumption and body weight gain, anemic change, increased urine volume, decreased serum calcium level, increased inorganic phosphorus level, slight prolongation of conduction time in electrocardiogram and tubular basophilia in the kidneys in the group treated with 100 mg/kg/hr. In addition, essentially similar changes were also observed at the same dosage level in the 2-week study of this drug, in which recoverability was recognized with 2-week follow-up observation after drug withdrawal. In conclusion, the nontoxic dosage level was judged to be 50 mg/kg/hr under the condition of the present study.

A 2-week toxicity study of magnesium sulfate administered by 24-hr intravenous infusion in beagle dogs followed by 2-week recovery period

A 2-week toxicity study of magnesium sulfate administered by a 24-hr intravenous infusion at the dosage levels of 0, 12.5, 50, 100 and 200 mg/kg/hr in female beagle dogs was conducted, with 2-week follow-up observation after drug withdrawal. One of 2 animals in the 200 mg/kg/hr group died approx. 32 hr after the start of infusion. At the same time, the remaining 1 animal of the same group was sacrificed in a moribund state. Changes attributable to the treatment of magnesium sulfate were decreased food consumption and body weight gain, anemia, mild prolongation of conduction time in electrocardiogram and tubular basophilia in the kidneys in the animals treated with 100 mg/kg/hr. Furthermore, decreased calcium level was recorded in the animals treated with 50 mg/kg/hr or more. However, these changes disappeared after drug withdrawal, and reversibility was suggested. Judging from the mode of occurrence, since the change in calcium level observed in the group treated with 50 mg/kg/hr was slight, it was considered to be toxicologically insignificant. In conclusion, the nontoxic dosage level of magnesium sulfate was judged to be 50 mg/kg/hr under the condition of the present study.

Angioscopic evaluation of site-specific administration of ReoPro.

Systemic administration of newer antiplatelet agents such as the GP IIb/IIIa agent ReoPro (Centocor BV Leiden, The Netherlands) has been shown to decrease the early incidence of recurrent ischemia and recurrent myocardial infarction. The currently approved protocol for administration of ReoPro involves an initial weight adjusted bolus followed by a systemic infusion over the next 12 hr. The systemic administration is proposed as the only route of administration because it is stated that the drug must be exposed to circulating platelets. An alternative approach would be to deliver ReoPro locally and allow the platelets to disaggregate only when in contact with the local arterial wall. The optimal method of monitoring the efficacy of such a strategy is to visually assess the presence of platelet rich or red blood cell rich thrombus using angioscopy. We report our initial experience in 12 patients who received local administration of ReoPro using currently approved catheters for local administration of agents into coronary arteries who were evaluated before and after intervention using intracoronary angioscopy. None of the patients received a subsequent 12-hr infusion. There was successful resolution of thrombus in 11 of 12 patients. Recurrent ischemia occurred in one patient without myocardial infarction.

Pyridoxalated hemoglobin polyoxyethylene conjugate does not restore hypoxic pulmonary vasoconstriction in ovine sepsis.

Hypoxic pulmonary vasoconstriction, a protective mechanism, minimizes perfusion of underventilated lung areas to reduce ventilation-perfusion mismatching. We studied the effects of sepsis on hypoxic pulmonary vasoconstriction and attempted to determine whether hypoxic pulmonary vasoconstriction is influenced by pyridoxalated hemoglobin polyoxyethylene conjugate, a nitric oxide scavenger. Prospective, randomized, controlled experimental study with repeated measures. Investigational intensive care unit at a university medical center. Nineteen female merino sheep, divided into three groups: group 1, controls (n = 5); group 2, sheep with sepsis (n = 6); and group 3, septic sheep treated with pyridoxalated hemoglobin polyoxyethylene conjugate (n = 8). All sheep were instrumented for chronic study. An ultrasonic flow probe was placed around the left pulmonary artery. After a 5-day recovery, a tracheostomy was performed and a double-lumen endotracheal tube was placed. Animals in groups 2 and 3 received a 48-hr infusion of live Pseudomonas aeruginosa (6 x 10(4) colony-forming units/kg/hr). After 24 hrs, sheep in group 3 received pyridoxalated hemoglobin polyoxyethylene conjugate (20 mg/kg/hr) for 16 hrs; sheep in groups 1 and 2 received only the vehicle. Hypoxic pulmonary vasoconstriction was repeatedly tested by unilateral hypoxia of the left lung with 100% nitrogen. Hypoxic pulmonary vasoconstriction was assessed as the change in left pulmonary blood flow. In the animals in group 1, left pulmonary blood flow decreased by 62 +/- 8 (SEM)% during left lung hypoxia and remained stable during repeated hypoxic challenges throughout the study period. After 24 hrs of sepsis, left pulmonary blood flow decreased from 56 +/- 10% to 26 +/- 2% (group 2) and from 50 +/- 8% to 23 +/- 6% (group 3). In the sheep in group 2, there was no adaptation over time. Pulmonary shunt fraction increased. Pyridoxalated hemoglobin polyoxyethylene conjugate had no effect on hypoxic pulmonary vasoconstriction or pulmonary shunt. The animals receiving the bacterial infusion developed a hyperdynamic circulatory state with hypotension, decreased systemic vascular resistance, and increased cardiac output. Pyridoxalated hemoglobin polyoxyethylene conjugate increased mean arterial pressure and systemic vascular resistance but did not influence cardiac index. Pulmonary arterial pressure was increased during sepsis and increased even further after pyridoxalated hemoglobin polyoxyethylene conjugate administration. Oxygenation and oxygen delivery and uptake were not affected by pyridoxalated hemoglobin polyoxyethylene conjugate. Hypoxic pulmonary vasoconstriction is blunted during sepsis and there is no adaptation over time. It is not influenced by pyridoxalated hemoglobin polyoxyethylene conjugate. Pyridoxalated hemoglobin polyoxyethylene conjugate reversed hypotension and, with the exception of an increase in pulmonary arterial pressure, had no adverse effects on hemodynamics or oxygenation.