Termination Of Infusion Research Articles

Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information

The mechanisms supporting temporal processing of pain remain poorly understood. To determine the involvement of opioid mechanisms in temporal processing of pain, responses to dynamic noxious thermal stimuli and offset analgesia were assessed after administration of naloxone, a μ-opioid antagonist, and on a separate day, during and after intravenous administration of remifentanil, a μ-opioid agonist, in 19 healthy human volunteers. Multiple end points were sampled from real-time computerized visual analog scale ratings (VAS, 1 to 10) to assess thermal sensitivity, magnitude and duration of offset analgesia, and painful after sensations. It was hypothesized that the magnitude of offset analgesia would be reduced by direct opioid antagonism and during states of acute opioid-induced hypersensitivity (OIH), as well as diminished by the presence of exogenous opioids. Surprisingly, the magnitude of offset analgesia was not altered after naloxone administration, during remifentanil infusion, or after the termination of remifentanil infusion. Because thermal hyperalgesia was observed after both drugs, 8 of the original 19 subjects returned for an additional session without drug administration. Thermal hyperalgesia and increased magnitude of offset analgesia were observed across conditions of remifentanil, naloxone, and no drug within this subset analysis, indicating that repeated heat testing induced thermal hyperalgesia, which potentiated the magnitude of offset analgesia. Thus, it is concluded that the mechanisms subserving temporal processing of nociceptive information are largely opioid-independent, but that offset analgesia may be potentiated by heat-induced thermal hyperalgesia in a proportion of individuals.

GAL‐021, a novel respiratory stimulant, attenuates opioid–induced respiratory depression without compromising analgesia

Opioid‐induced respiratory depression (OIRD) is a common side effect of opioid analgesics and can be life‐threatening, especially during the perioperative period and sleep. Current therapy for OIRD includes administering opioid antagonists and/or decreasing subsequent opioid doses, both of which can compromise analgesia. Here, we describe a novel respiratory stimulant, GAL‐021, that increases minute ventilation (Vmin) and reverses OIRD without diminishing analgesia. GAL‐021 administered as an IV bolus (0.01 – 3 mg/kg) to anesthetized rats or by infusion (0.01 – 0.4 mg/kg/min × 60‐min) to conscious rats increased Vmin, tidal volume (VT), and respiratory frequency (f). In anesthetized rats, the ED50 for increasing Vmin was 140 μg/kg. In conscious rats, OIRD was induced with morphine (10 mg/kg, IV), which increased PaCO2 and decreased Vmin, VT, f, pH, and PaO2 for up to 2 hours. Subsequent infusion of GAL‐021 (0.03 – 0.4 mg/kg/min, IV) resulted in dose‐dependent diminution of the evoked respiratory depression for the duration of the infusion (20 min). The increase in Vmin induced by GAL‐021 was due to an increase in VT but not f. Termination of GAL‐021 infusion restored OIRD. In contrast, GAL‐021 did not diminish morphine‐induced analgesia assessed by the tail‐flick assay. These data demonstrate that GAL‐021 stimulates breathing in conscious and anesthetized rats and reverses OIRD without attenuating analgesia.

Pharmacokinetics, pharmacodynamics, and safety of clevidipine after prolonged continuous infusion in subjects with mild to moderate essential hypertension

PurposeClevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion.MethodDoses of 2, 4, 8, or 16.0 mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0 mg/h and force-titrated in doubling increments every 3 min to target dose, then maintained for 72 h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8 h after termination of infusion, although oral therapy could be restarted at 4 h. Clevidipine blood levels were obtained during infusion and for 1 hour after termination.ResultsRapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6 h after termination of the clevidipine infusion. At 8 h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8 h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline.ConclusionThis study supports the use of up to 72 h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated.

Stress cardiovascular MR in routine clinical practice: referral patterns, accuracy, tolerance, safety and incidental findings

The use of stress cardiovascular MR (CMR) to evaluate myocardial ischaemia has increased significantly over recent years. We aimed to assess the indications, incidental findings, tolerance, safety and accuracy of stress CMR in routine clinical practice. We retrospectively examined all stress CMR studies performed at our tertiary referral centre over a 20-month period. Patients were scanned at 1.5 T, using a standardised protocol with routine imaging for late gadolinium enhancement. Angiograms of patients were assessed by an interventional cardiologist blinded to the CMR data. 654 patients were scanned (mean age 65±29 years; 63 inpatients; 9.6%). 14% of patients had incidental extracardiac findings, the commonest being liver or renal cysts (6%) and pulmonary nodules (4%). 639 patients (97.7%) received intravenous adenosine, 10 received intravenous dobutamine and 5 patients had both. Of the 15 patients who received dobutamine, 12 had no side-effects/complications, 2 experienced nausea and 1 chest tightness. Of the 644 patients who received adenosine, 43% experienced minor symptoms, 1% had transient heart block and 0.2% had severe bronchospasm requiring termination of infusion. There were no cases of hospitalisation or myocardial infarction. 241 patients also had coronary angiography. For detecting at least moderate stenosis of ≥50%, sensitivity was 86%, specificity 98% and accuracy 89%. For detecting severe stenoses of ≥70%, sensitivity was 91%, specificity 86% and overall accuracy 90%. These results compare very favourably with previous smaller research studies and meta-analyses. We conclude that stress CMR, with adenosine as the main stress agent, is well tolerated, safe and accurate in routine clinical practice.

P.1.003 Brain-derived neurotrophic factor as a biomarker of clinical response in bipolar disorder: 16-week follow-up study

Simultaneous infusion of the selective 5-HT2A-receptor antagonist M100907, as well as asenapine, completely blocked the DOI-induced increase in dopamine and serotonin release and partially the increased noradrenaline release, indicating a similar mechanism by M100907 and asenapine. When given alone, infusion of M100907 or asenapine, in the concentrations used, did not affect monoamine release. Intracortical administration of the selective a2adrenoceptor agonist clonidine significantly decreased dopamine, noradrenaline and serotonin release in the mPFC (maximal effects; 61.0±8.0, 50.4±7.6, and 67.0±4.1% of baseline, respectively; p< 0.01–0.001). Simultaneous infusion of the a2-adrenoceptor antagonist idazoxan blocked the clonidine-induced reduction of dopamine and noradrenaline release. The effect of idazoxan on serotonin was less pronounced and not statistically significant. Simultaneous infusion of asenapine did not acutely block the clonidine-induced decrease in transmitter release. However, following termination of the clonidine infusion the transmitter release remained at a low level. During this interval, i.e. the following hour after the clonidine infusion, intracortical infusion of asenapine restored the catecholamine release to baseline level, indicating an a2-adrenoceptor blocking effect of asenapine which was somewhat delayed. When given alone, the infusion of idazoxan or asenapine, in the concentrations used, did not affect monoamine release. Our results propose that local application of asenapine in the mPFC indeed exhibits a pharmacological significant 5-HT2Aand, to a weaker extent, a2-receptor antagonistic activity. Whereas its 5-HT2A blocking property preferentially influenced the release of serotonin and dopamine but only to a lesser extent noradrenaline, blockage of a2-adrenoceptors preferentially influenced dopamine and noradrenaline release, albeit the effect was somewhat delayed. Thus, 5-HT2A-receptor antagonism and a2-adrenoceptor blockage induced by asenapine in the mPFC may contribute to enhance prefrontal monoamine release in vivo and, secondarily, its effect on positive and negative symptoms as well as pro-cognitive and antidepressant effects [1,2].

The Relationship Between Preoperative and Primary Care Blood Pressure Among Veterans Presenting from Home for Surgery

American College of Cardiology/American Heart Association guidelines describe the perioperative evaluation as "a unique opportunity to identify patients with hypertension"; however, factors such as anticipatory stress or medication noncompliance may induce a bias toward higher blood pressure, leaving clinicians unsure about how to interpret preoperative hypertension. Information describing the relationship between preoperative intake blood pressure and primary care measurements could help anesthesiologists make primary care referrals for improved blood pressure control in an evidence-based fashion. We hypothesized that the preoperative examination provides a useful basis for initiating primary care blood pressure referral. We analyzed retrospective data on 2807 patients who arrived from home for surgery and who were subsequently evaluated within 6 months after surgery in the primary care center of the same institution. After descriptive analysis, we conducted multiple linear regression analysis to identify day-of-surgery (DOS) factors associated with subsequent primary care blood pressure. We calculated the sensitivity, specificity, and positive and negative predictive value of different blood pressure referral thresholds using both a single-measurement and a 2-stage screen incorporating recent preoperative and DOS measurements for identifying patients with subsequently elevated primary care blood pressure. DOS systolic blood pressure (SBP) was higher than subsequent primary care SBP by a mean bias of 5.5 mm Hg (95% limits of agreement + 43.8 to -32.8). DOS diastolic blood pressure (DBP) was higher than subsequent primary care DBP by a mean bias of 1.5 mm Hg (95% limits of agreement +13.0 to -10.0). Linear regression of DOS factors explained 19% of the variability in primary care SBP and 29% of the variability in DBP. Accounting for the observed bias, a 2-stage SBP referral screen requiring preoperative clinic SBP ≥140 mm Hg and DOS SBP ≥146 mm Hg had 95.9% estimated specificity (95% confidence interval [CI] 94.4 to 97.0) for identifying subsequent primary care SBP ≥140 mm Hg and estimated sensitivity of 26.8% (95% CI 22.0 to 32.0). A similarly high specificity using a single DOS SBP required a threshold SBP ≥160 mm Hg, for which estimated specificity was 95.2% (95% CI 94.2 to 96.1). For DBP, a presenting DOS DBP ≥92 mm Hg had 95.7% specificity (95% CI 94.8 to 96.4) for subsequent primary care DBP ≥90 mm Hg with a sensitivity of 18.8% (95% CI 14.4 to 24.0). A small bias toward higher DOS blood pressures relative to subsequent primary care measurements was observed. DOS factors predicted only a small proportion of the observed variation. Accounting for the observed bias, a 2-stage SBP threshold and a single-reading DBP threshold were highly specific though insensitive for identifying subsequent primary care blood pressure elevation.

Effect of landiolol hydrochloride, an ultra-short-acting beta 1-selective blocker, on supraventricular tachycardia, atrial fibrillation and flutter after pulmonary resection

Supraventricular tachycardia is a common complication after pulmonary resection. The objective of this study was to investigate the efficacy of landiolol hydrochloride, an ultra-short-acting β1-blocker, in patients with post-operative supraventricular tachycardia after pulmonary resection. The response to continuous intravenous infusion of landiolol was evaluated in 25 patients who developed post-operative atrial fibrillation or atrial flutter after major pulmonary resection. Four patients had preoperative rate-controlled chronic atrial fibrillation. The heart rate and blood pressure were compared before and after infusion of landiolol. Side effects and recurrence of supraventricular tachycardia after termination of landiolol infusion were also monitored. The heart rate was reduced from 135±24 bpm before landiolol infusion to a plateau rate of 85±19 bpm during infusion (P<0·0001). Heart rate reduction occurred in all but two patients. Conversion to normal sinus rhythm from supraventricular tachycardia occurred in 14 patients (56%). Recurrence of supraventricular tachycardia after stopping landiolol infusion was observed in 17 patients (68%), but all patients without preoperative AF were cured of post-operative AF. There were no detectable side effects, including no adverse influence on the circulatory and respiratory systems. Continuous intravenous infusion of landiolol was found to be effective and safe for supraventricular tachycardia after pulmonary resection.

Dynamic manganese‐enhanced magnetic resonance imaging can detect chronic cryoinjury‐induced infarction in pig hearts in vivo

The purpose was to investigate whether MnCl(2) can serve as an MRI contrast agent to detect chronic cryoinjury infarction in pigs in vivo and whether MnCl(2) causes significant hemodynamic disturbances. Hearts were subjected to a topical 2 min cryothermia to establish myocardial infarction (MI). Thereafter GdDTPA-enhanced MRI was performed at 0, 1, 2 and 3 weeks using a 3 T scanner. Four weeks post-cryoinjury the pigs underwent in vivo Mn-enhanced magnetic resonance imaging (MEMRI). MnCl(2) (70 μmol/kg, 14 min) was infused i.v. intermittently (n = 4) or continuously (n = 5) and T(1)-weighted images were acquired every 2 min simultaneously recording heart rate and arterial blood pressure. Either infusion scheme led to an immediate increment in MR signal intensity (SI) within the left ventricular (LV) blood pool and LV normal and cryoinjured myocardium, which reached a maximum at the end of infusion. No significant difference was observed between the normal and cryoinjured myocardium. After infusion termination, SI decreased faster within the LV blood pool and the MI, as compared with the normal myocardium in either group, resulting in significant contrast between the MI and normal tissue (intermittent: 18 ± 7 vs 49 ± 13%, p = 0.002; continuous: 19 ± 8 vs 36 ± 9%, p = 0.004). Infarction sizes were similar in Mn(2+)- and GdDTPA-enhanced images at 4 and 3 weeks post injury, respectively. Thus, in vivo MEMRI differentiated infarcted from normal myocardium in pig hearts subjected to 4-week cryoinjury. Compared with intermittent infusion, continuous infusion minimized hemodynamic fluctuations.

Closed-loop Continuous Infusions of Etomidate and Etomidate Analogs in Rats

Etomidate is a sedative-hypnotic that is often given as a single intravenous bolus but rarely as an infusion because it suppresses adrenocortical function. Methoxycarbonyl etomidate and (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) are etomidate analogs that do not produce significant adrenocortical suppression when given as a single bolus. However, the effects of continuous infusions on adrenocortical function are unknown. In this study, we compared the effects of continuous infusions of etomidate, methoxycarbonyl etomidate, and carboetomidate on adrenocortical function in a rat model. A closed-loop system using the electroencephalographic burst suppression ratio as the feedback was used to administer continuous infusions of etomidate, methoxycarbonyl etomidate, or carboetomidate to Sprague-Dawley rats. Adrenocortical function was assessed during and after infusion by repetitively administering adrenocorticotropic hormone 1-24 and measuring serum corticosterone concentrations every 30 min. The sedative-hypnotic doses required to maintain a 40% burst suppression ratio in the presence of isoflurane, 1%, and the rate of burst suppression ratio recovery on infusion termination varied (methoxycarbonyl etomidate > carboetomidate > etomidate). Serum corticosterone concentrations were reduced by 85% and 56% during 30-min infusions of etomidate and methoxycarbonyl etomidate, respectively. On infusion termination, serum corticosterone concentrations recovered within 30 min with methoxycarbonyl etomidate but persisted beyond an hour with etomidate. Carboetomidate had no effect on serum corticosterone concentrations during or after continuous infusion. Our results suggest that methoxycarbonyl etomidate and carboetomidate may have clinical utility as sedative-hypnotic maintenance agents when hemodynamic stability is desirable.

Effect of somatostatin infusion on peptide YY secretion: studies in the acute and recovery phase of anorexia nervosa and in obesity

Changes in many gastrointestinal peptides, including the anorexigenic peptide YY (PYY), which is produced by L cells, occur in both anorexia nervosa (AN) and obesity (OB). High PYY levels are present in AN, whereas in morbid OB fasting and postprandial PYY secretion is blunted. Somatostatin (somatotropin release-inhibiting factor (SRIF)) reportedly inhibits plasma PYY concentrations in animals and healthy humans, but the effect of a SRIF infusion on spontaneous PYY secretion in AN and OB is unknown. A total of 18 young women, seven with acute AN (A-AN), four with AN in the recovery phase (R-AN), and seven with morbid OB, were studied. All subjects underwent an infusion of SRIF (9 μg/kg i.v./h, over 60 min), with blood samples drawn before and at different time intervals after SRIF administration. Plasma PYY levels were measured at each time point. SRIF significantly inhibited plasma PYY concentrations in R-AN and OB, without affecting PYY titers in A-AN. In OB, the inhibitory effect of SRIF also persisted at 90 min. Withdrawal of SRIF infusion in R-AN resulted in a prompt restoration of basal plasma PYY levels, whereas termination of SRIF infusion in OB was followed by a slower increase of PYY titers toward baseline levels. After infusion, PYY Δ area under the curve (ΔAUC) in R-AN was significantly higher than those in A-AN and OB patients. A significant difference in PYY ΔAUC between A-AN and OB was present. These results suggest the existence of a hypo- and hyper-sensitivity of L cells to the inhibitory effect of SRIF in A-AN and OB respectively.

Effect of lipo prostaglandin E1 in ductus-dependent congenital heart disease

Prostaglandin E1 incorporated in lipid microspheres (lipo PGE1) was administered to 42 infants with ductus-dependent congenital heart disease (CHD). At the onset of infusion, the patients were 5 hours to 141 days old (mean 19.0 days). The dose of lipo PGE1 was initially 5 ng/kg/minute. The infusion continued for 1–1008 hours (mean 213.2 hours). Lipo PGE1 was effective in 34 of the 42 patients (81.0%). In the 8 patients in whom lipo PGE1 was not effective, the ductus arteriosus had closed before initiation of infusion. In all patients but one in whom the preparation was effective (33/34), the response was observed within 12 hours after the initiation of the infusion. Only mild side effects, such as low grade apnea and fever, were observed in 7 of the 42 patients. In 8 patients who received lipo PGE1 infusion for a long period (more than 200 hours), the effect continued for more than 4 days after the termination of infusion. In the patients who received PGE1 CD, the effect disappeared less than 9 hours after discontinuation of administration. These findings indicate that lipo PGE1 was effective at a lower dose, with a low incidence of side effects and a long duration of action. Lipo PGE1 was considered to be useful and safe in patients with ductus-dependent CHD.

Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: A randomized, prospective, double blind, active placebo-controlled trial

To assess the analgesic efficacy of the N-methyl-D-aspartate receptor antagonist S(+)-ketamine on fibromyalgia pain, the authors performed a randomized double blind, active placebo-controlled trial. Twenty-four fibromyalgia patients were randomized to receive a 30-min intravenous infusion with S(+)-ketamine (total dose 0.5 mg/kg, n = 12) or the active placebo, midazolam (5 mg, n = 12). Visual Analogue Pain Scores (VAS) and ketamine plasma samples were obtained for 2.5-h following termination of treatment; pain scores derived from the fibromyalgia impact questionnaire (FIQ) were collected weekly during an 8-week follow-up. Fifteen min after termination of infusion the number of patients showing a reduction in pain scores >50% was 8 vs. 3 ( P < 0.05), at t = 180 min 6 vs. 2 (ns), at the end of week-1 2 vs. 0 (ns) and at end of week-8 2 vs. 2 in the ketamine and midazolam groups, respectively. Ketamine effect on VAS closely followed ketamine plasma concentrations. For VAS and FIQ scores no significant differences in treatment effects were observed in the 2.5-h following infusion or during the 8-week follow-up. Side effects as measured by the Bowdle questionnaire (which scores for 13 separate psychedelic symptoms) were mild to moderate in both study groups and declined rapidly, indicating adequate blinding of treatments. Efficacy of ketamine was limited and restricted in duration to its pharmacokinetics. The authors argue that a short-term infusion of ketamine is insufficient to induce long-term analgesic effects in fibromyalgia patients.

A Phase I Study of the Potent Hsp90 Inhibitor STA-9090 Administered Twice Weekly In Subjects with Hematologic Malignancies

AbstractAbstract 2898 Background:STA-9090 is a potent, second-generation, small-molecule Hsp90 inhibitor, with a chemical structure unrelated to the first-generation, ansamycin family of Hsp90 inhibitors (e.g., 17-AAG or IPI-504). STA-9090 induces the loss of Hsp90 client proteins that are important in hematologic cancers, including BCR-ABL, c-KIT, FLT3, WT1, and JAK2. In preclinical studies, STA-9090 has shown potency up to 100 times greater than the first-generation Hsp90 inhibitors as well as activity against a wider range of kinases. In in vitro and in vivo models, STA-9090 has shown potent activity against a broad range of leukemias, lymphomas, and multiple myeloma. Methods:The primary objective of this Phase I multicenter study (NCT00858572) was to determine the maximum tolerated dose (MTD) of STA-9090 given twice weekly in patients with acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and myeloproliferative neoplasms (MPN). An adaptive statistical design methodology was used to determine dose escalation. Safety, pharmacokinetics (PK), pharmacodynamic (PD), and clinical activity were evaluated. Dosing for 4 consecutive weeks constituted one dosing cycle. Serial pharmacokinetic (PK) samples were collected pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours post-dose on study days 1 and 22, and pre-dose and 1 hour post at all other visits in cycle 1. Plasma samples were collected for HSP70 protein analysis. Safety assessments included the number and grade of adverse events (AEs), changes from baseline in laboratory parameters, and evaluation of electrocardiogram changes. Results:22 patients (14 males, 8 females; median age 62 years, range 33–80; Eastern Cooperative Oncology Group [ECOG] status range [0-2]) received STA-9090 twice weekly. Patients with the following disease types were treated: AML (n=7), CML (n=8), MDS (n=3), and MPN (n=4). The median time from initial diagnosis to first treatment was 19 months; patients had received a median of 2 (range, 1–9) prior treatments and 27% were refractory to their most recent therapy. Dosing with STA-9090 was at 14 mg/m2 (4 patients), 22 mg/m2 (4 patients), 30 mg/m2 (3 patients), 70mg/m2 (3 patients), and 110 mg/m2 (8 patients). Patients received a median of 2 (range, 1–8) cycles of STA-9090. AEs reported in ≥25% of patients were diarrhea, nausea, fatigue, abdominal pain, anemia, increased alanine aminotransferase, arthralgia, increased aspartate aminotransferase, dyspnea, hypokalaemia, thrombocytopenia, and vomiting. The majority of AEs were mild to moderate in severity. There have been 3 patients with dose limiting toxicities: one at 14 mg/m2 (grade 3 hyponatremia and hyperbilirubinemia) and two at 110 mg/m2 (grade 3 prolonged QTc and transaminitis). At the time of abstract submission, the MTD has not been defined. STA-9090 exhibited linear PK with exposures (AUC and Cmax) increasing in proportion to dose. One hour following infusion termination, plasma concentrations declined by approximately 10 fold, and by 100 fold within approximately 8 to 10 hours. STA-9090 showed no drug accumulation with twice weekly dosing. STA-9090 was well distributed, exhibiting an apparent volume of distribution greater than total body water. HSP70 protein levels increased following STA-9090 administration and remained elevated prior to subsequent doses indicating a durable biological impact of the drug. Clinical responses include 1 patient with CML (dosed at 14 mg/m2) and 1 patient with AML (dosed at 110 mg/m2) who had best responses of hematological improvement lasting 2 and 3 months, respectively. In addition, 4 patients with myelofibrosis (1 patient dosed at 14 mg/m2 and 3 dosed at 70 mg/m2) had stable disease as best response; 1 of these responses lasted for 7 months and the patient went on to receive an allogenic stem cell transplant. Further response evaluation is ongoing. Conclusions:In patients with hematologic malignancies, STA-9090 is well tolerated up to dose levels of 110 mg/m2 given twice weekly. Induction of HSP70 protein levels provides evidence of in vivo biological activity. A favorable PK profile, preliminary signs of pharmacodynamic activity, and early clinical activity signals warrant continued evaluation of single-agent STA-9090 using a twice weekly dosing regimen. Disclosures:Off Label Use: Phase I clinical study. Bradley:Synta Pharmaceuticals Corp.,: Employment, Equity Ownership. Teofilovici:Synta Pharmaceuticals Corp.,: Employment, Equity Ownership.

Antilipolytic and lipolytic effects of administering free or ruminally protected nicotinic acid to feed-restricted Holstein cows

The objectives were to determine effects of 12 hourly infusions of different quantities of nicotinic acid (NA) on plasma nonesterified fatty acid (NEFA; experiment 1) and whether longer (108h) continuous infusions of NA could induce sustained reductions of plasma NEFA (experiment 2) in nonlactating, nongestating Holstein cows that were feed restricted. Experiment 1 was a 5×5 Latin square with 6-d periods and 9 recovery days between each period. Each period consisted of 5 d of partial feed restriction to increase plasma NEFA concentration. Treatments were abomasal infusions of 0, 0.25, 0.5, 1, or 3mg of NA/h per kilogram of body weight (BW), infused as hourly boluses for 12h, starting 4 d after initiation of partial feed restriction. Plasma NEFA was decreased for the highest dose: from 448μEq/L to 138±75μEq/L at 1h after the first bolus of 3mg of NA/h per kilogram of BW. This initial reduction in plasma NEFA concentration was followed by an increase in concentration at 2, 3, and 4h relative to initiation of infusions. Plasma NEFA then decreased to 243μEq/L 6h after initiation of treatments and remained low until termination of infusions. A rebound in plasma NEFA concentration occurred at 3 and 4h after termination of infusion for cows that received 3mg of NA/h per kilogram of BW. Experiment 2 was a 5×5 Latin square with 7-d periods and 9 recovery days between each period. Each period consisted of 5 d of partial feed restriction to increase plasma NEFA concentration. Treatments were continuous abomasal infusion of 0, 0.5, 1, or 3mg of free NA/h per kilogram of BW for 4.5 d starting at feed restriction or 0.5mg of NA/h per kilogram of BW infused directly into the rumen in a form protected from microbial degradation. The ruminal administration of protected NA was initiated 2 d before abomasal infusions and initiation of feed restriction to establish steady postruminal delivery of NA by start of abomasal infusions. Plasma NEFA was approximately 70μEq/L before initiation of feed restriction and increased to 509, 587, 442, 850, and 108μEq/L at 4.5 d for cows that received 0, 0.5 (protected NA), 0.5 (free NA), 1, and 3mg of NA/h per kilogram of BW, respectively. An antilipolytic response was achieved with the highest abomasal dose, which maintained plasma NEFA concentration lower than the control group. An increase in plasma NEFA concentration was observed after termination of infusions for cows that received 1 and 3mg of NA/h per kilogram of BW. Plasma NEFA was 1,900μEq/L at 4h after termination of infusion for cows receiving 1mg of NA/h per kilogram of BW and 1,360μEq/L at 5h after termination of infusion for cows receiving 3mg of NA/h per kilogram of BW. In nongestating, nonlactating cows it is unlikely that a dose of NA exists that will reduce plasma NEFA concentration and prevent the rebound that occurs following termination of NA administration.

Coronary steal: Revealing the diagnosis with quantitative cardiac PET/CT

A 68-year-old male was evaluated at our chest pain unit because of recent onset exertional anginal chest pain. The symptoms commenced after an initial episode of angina that had lasted for several hours. The electrocardiogram (ECG) showed signs of a recent inferior myocardial infarction (Figure 1) after which the patient was treated with antiplatelet agents, a statin, and beta-blockers. To further evaluate the extent of coronary artery disease and ischemia, a cardiac PET/ CT was performed. The imaging protocol consisted of a 64-slice CT coronary angiography (CTCA) and myocardial perfusion measurements using oxygen-15labeled water PET during rest and pharmacologically induced vasodilation (adenosine). During vasodilation, the patient reported anginal chest pain and the ECG displayed ST-segment elevation in the Q-wave leads suggestive of transmural inferior ischemia, although it should be noted that stress-induced ST segment elevation in Q-leads may also occur in the absence of ischemia. Heart rate and blood pressure did not change appreciably during the stress study, and the ECG abnormalities and symptoms resolved immediately after termination of adenosine infusion. CTCA revealed an occlusion of the right coronary artery (RCA) with collateral filling of the distal segment (Figure 2). PET images displayed a mild resting perfusion defect in the inferior wall (Figure 3). During hyperemia, the perfusion defect expanded toward the inferior distal wall and part of the septum and lateral wall. Of interest, quantitative perfusion analysis displayed a restflow in the RCA perfusion territory of 0.70 mL/minute/g of perfusable tissue, which paradoxally decreased during hyperemia to 0.49 mL/minute/g, yielding a flow reserve of 0.7 (Figure 4). The patient was referred for invasive coronary angiography, which confirmed

Pharmacokinetic and pharmacodynamic analysis of cyclosporine A (CsA) to find the best single time point for the monitoring and adjusting of CsA dose using twice-daily 3-h intravenous infusions in allogeneic hematopoietic stem cell transplantation

Pharmacological study is predictably effective in establishing an optimal monitoring strategy for the usage of cyclosporine A (CsA) to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation recipients. Pharmacokinetic profiling of 33 recipients administered CsA twice daily by 3-h intravenous infusion revealed that levels peaked 2-3 h after the start of infusion, and an exponential decline of CsA concentrations after the termination of infusion was observed. The correlation between the area under the curve (AUC(0-12)) and CsA concentration at various time points after infusion revealed that C (2) and C (3) correlated best with AUC(0-12) (r (2) = 0.725), while the trough concentration correlated poorly. Ex vivo T cell stimulation followed by intracellular cytokine detection with flow cytometry revealed that the capacity of T cells to produce cytokines upon stimulation was inversely proportional to the CsA concentration, and reached a minimum at about 700 ng/mL with a marginal decrease above this concentration. Extrapolation using the regression equations of this study and the data from our retrospective study leads to the assumption that the dose adjustment of CsA based on maintaining the C (3) concentration above 800 ng/mL may effectively prevent acute GVHD. To confirm this assumption, a prospective clinical study is required.

Pharmacokinetics of Lidocaine, Bupivacaine, and Levobupivacaine in Plasma and Brain in Awake Rats

We have compared the pharmacokinetics and brain distribution of lidocaine, racemic bupivacaine (bupivacaine), and levobupivacaine in awake, spontaneously breathing rats. Lidocaine (0.5 mg x kg x min), bupivacaine (0.1 mg x kg x min), or levobupivacaine (0.1 mg x kg x min) was continuously administered to rats for 2 h (n = 12, each anesthetic). Blood samples and cerebral dialysate were collected during infusion and for 2 h after termination of infusion. Concentrations of anesthetics in the cerebral extracellular fluid were measured by microdialysis using the retrodialysis calibration method. Tissue-to-plasma partition coefficients calculated from the total (protein-bound and unbound) and unbound concentrations in plasma and brain as well as pharmacokinetic parameters in plasma and cerebral extracellular fluid were compared among the three anesthetics. There were no differences in plasma total or unbound concentrations between bupivacaine and levobupivacaine. Concentrations of bupivacaine in the cerebral extracellular fluid were significantly higher than levobupivacaine (P < 0.001). Despite no differences in the ratio of total brain concentration to total plasma concentration among the three anesthetics, the ratio of cerebral extracellular fluid concentration to plasma unbound fraction of bupivacaine was significantly higher than lidocaine and levobupivacaine (0.58 +/- 0.09, 0.47 +/- 0.18, and 0.40 +/- 0.09, respectively; P = 0.03 and 0.003, respectively). Although the ratio of total brain concentration to total plasma concentrations of lidocaine, bupivacaine, and levobupivacaine was similar, concentration ratio of bupivacaine in the cerebral extracellular fluid to plasma unbound fraction was significantly higher than lidocaine and levobupivacaine.

Multi-Day Low Dose Ketamine Infusion as Adjuvant to Oral Gabapentin in Spinal Cord Injury Related Chronic Pain: A Prospective, Randomized, Double Blind Trial

Background: Severe, intractable, chronic pain is a significant management problem for those involved in the long-term care of spinal cord injury (SCI) patients . Gabapentin, an anticonvulsant, is widely used for treating chronic pain. Ketamine, an NMDA receptor antagonist, has been available in clinical practice for 35 years. Its usefulness in pathological pain states is known. Despite this, no formal research on its effectiveness in treating neuropathic SCI pain exists. Objectives: This double-blind study sought to determine the safety and efficacy of adding a multi-day low dose ketamine infusion to oral gabapentin for treating chronic pain related to post spinal cord injury. Study Design: Randomized, controlled, double blind trial Setting: Hospital, in-patient setting. Methods: Forty patients diagnosed with neuropathic pain secondary to spinal cord injury were randomized into 2 equal groups. Group I received an 80 mg intravenous ketamine infusion diluted in 500 cc normal saline over a 5 hour period daily for one week and 300 mg of gabapentin 3 times daily. Group II received a placebo infusion and 300 mg of gabapentin 3 times daily (continued) after 300 mg of gabapentin 3 times daily. Using the visual analogue scale, pain was assessed prior to treatment, daily following ketamine or placebo infusions for 7 days, and then weekly for one month after infusion termination. Side effects, specifically those related to ketamine or gabapentin, were reported. Results: Both groups demonstrated significantly reduced pain scores compared with pretreatment values (P &lt; 0.05). Group I showed significant pain score improvements over Group II at all measurements (P &lt; 0.0001) during infusion and 2 weeks after infusion termination. There was no statistical difference between the groups at 3 weeks and 4 weeks after infusion termination (P = 0.54 and P = 0.25 respectively). Both drugs were tolerated by all patients; no side effects required intervention. Conclusion: Multi-day low dose ketamine infusion as adjuvant to gabapentin in post-spinal cord injury related chronic pain is safe and efficacious in reducing pain, but the effect compared to placebo ceased 2 weeks after infusion termination. Limitations: Study size limited to 40 patients. Key words: Ketamine, Gabapentin, Spinal, Pain, injury, chronic

Abstract 2766: Multicenter pharmacokinetic evaluation of ON 01910. Na, a novel broad-spectrum anticancer agent, in Phase I single agent clinical trials in patients with solid tumors

Abstract Introduction: ON 01910. Na is an anti-cancer agent with demonstrated activity against both solid tumors and hematological cancers. The purpose of this research was to evaluate the effect of dose and administration schedule on ON 01910. Na pharmacokinetics (PK) in advanced, heavily pre-treated solid tumor patients. Methods: Data was collected in three Phase I protcols conducted in the US and in India covering a wide range of doses and intraveous infusion schedules: Protocol 1 (50-1375 mg/m2/day over 72 h); Protocol 2 (250 – 4450 mg/m2/day over 24 h) and Protocol 3 (2400-3200 mg over 2, 4 or 8 h). In several patients, pharmacokinetics were evaluated for more than 1 dosing cycle. Plasma samples were collected pre-dose and up to 72 hours post-infusion. ON 01910. Na plasma levels were determined by a validated LC/MS/MS method. Results: Ninety-five data sets from 81 patients were evaluated in this study. ON 01910. Na showed biphasic elimination from the plasma, regardless of dose and administration schedule. The functional half-life of ON 01910. Na, estimated from the initial decline of plasma levels following infusion termination, was less than 2 hours. This was confirmed in data from patients receiving prolonged infusions as ON. 01910. Na approached steady state levels within several hours after dose initiation. As noted in the table below, ON. 01910. Na clearance was lower at higher drug dosing rates. There were no differences in drug pharmacokinetics among the infusion schedules. Conclusion: The pharmacokinetics of ON 01910. Na is dose dependent. A continuous IV infusion would be recommended to treat patients because of its short plasma half-life and rapid clearance. Systemic drug exposure is not affected by type of dosing (flat dosing vs. BSA adjusted). No significant differences were noted between the PK profiles of patients in the US centers and the patients in the India centers.Effect of Dosing Rate on Clearance of ON 01910. NaDosing Rate (mg/m2/hr)NClearance (L/hr/m2)0-25189.3 ± 4.725-501610.0 ± 5.050-75209.2 ± 3.175-10065.5 ± 2.6100-200126.2 ± 3.8200-40083.3 ± 1.6400-800112.5 ± 1.8800-125041.9 +/− 0.47 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2766.

Left ventricular remodeling early after correction of mitral regurgitation: Maintenance of stroke volume with decreased systolic indexes

Mitral valve repair for mitral regurgitation is followed by left ventricle adjustment to new preload and afterload. We evaluated left ventricular geometry and function immediately after mitral valve repair for degenerative prolapse. We prospectively studied 25 patients undergoing mitral valve repair; 15 patients undergoing a coronary artery bypass graft served as controls to determine the impact of cardiopulmonary bypass and cardioplegic arrest on left ventricular function. Intraoperative transesophageal echocardiography was conducted after sternotomy before initiation of cardiopulmonary bypass and after termination of cardiopulmonary bypass and protamine infusion. Simultaneous pulmonary catheter data ensured that the images were obtained under similar hemodynamic conditions. Immediately after mitral valve repair, left ventricular fractional area change decreased significantly from 65% ± 7% to 52% ± 8% (P < .001). Left ventricular end-diastolic area decreased minimally (21.3 ± 5.3 cm(2) vs 19.4 ± 4.5 cm(2); P = .005), whereas left ventricular end-systolic area increased significantly (7.5 ± 2.3 cm(2) vs 9.3 ± 2.5 cm(2); P < .001). Notably, forward stroke volume (thermodilution) remained similar (63 ± 24 mL vs 66 ± 19 mL; P = .5). No significant difference was found in controls between pre- cardiopulmonary bypass and post-cardiopulmonary bypass fractional area change (54% ± 12% vs 57% ± 10%; P = .19), left ventricular end-diastolic area (16.6 ± 6.2 cm(2) vs 15.7 ± 5.0 cm(2); P = .32), and stroke volume (72 ± 29 mL vs 65 ± 19 mL; P = .15); they had a slight decrease in left ventricular end-systolic area (7.9 ± 4.4 cm(2) vs 6.9 ± 3.2 cm(2); P = .03). Early after correction of mitral regurgitation, left ventricular fractional area change decreases significantly, primarily as the result of a larger end-systolic dimension. This may be a compensatory mechanism to prevent augmentation of forward stroke volume after mitral valve repair.