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PubMed1994

Effects of route and formulation on clinical pharmacokinetics of interleukin-2.

Interleukin-2 (IL-2) is a hormone of the immune system responsible for control of the proliferation and cytotoxicity of T lymphocytes and natural killer cells as well as the proliferation of B lymphocytes. Recombinant IL-2 has been only minimally to modestly successfully to date in the treatment of cancer and infectious diseases, largely because the drug is associated with toxicity and a narrow therapeutic index. Quantitative measurement of IL-2 can be quickly done by enzyme immunoassay. IL-2 bioassay provides an index of biologically active cytokine. IL-2 action and pharmacokinetics can be understood in the context of the effect IL-2 on high (alpha, beta, gamma trimer) vs intermediate (alpha, beta) vs low (beta only or alpha only) affinity IL-2 receptors on various cells of the immune system. IL-2 undergoes rapid renal elimination. The route of administration is important to determine the provision of sustained drug concentrations adequate to support the proliferation and cytotoxicity of immune cells. When IL-2 is given intravenously it has rapid elimination pharmacokinetics with an initial elimination half-life and terminal elimination half-life (t1/2 beta) of 6 to 12 minutes and 40 to 80 minutes, respectively. Subcutaneous or intramuscular administration of IL-2 results in sustained systemic absorption and approximately 30% of the injected dose is absorbed. Because IL-2 is less rapidly cleared from the site of intracavitary injection, when the drug is given by these less traditional routes (e.g. intraperitoneal, intrapleural, intrathecal, intraventricular, intravesicular, and inhalational administration) sustained local IL-2 activity can result. In some cases this has resulted in an improved therapeutic index compared with that resulting after administration of the drug by high dose intravenous bolus or continuous infusion. Depot IL-2 preparations may offer more convenient administration (e.g. t1/2 beta of polyethylene glycolated IL-2 is approximately 10-fold higher than that of recombinant IL-2) or more favourable biodistribution (e.g. IL-2 liposomes are more potent against lung metastases) compared with IL-2 administered by more conventional routes. An understanding of IL-2 clinical pharmacokinetics in relation to immunobiology of this central cytokine should lead to less toxicity and more effective clinical use.

Amino Acid Sequence↗
PubMed1976

Cerebral circulation and norepinephrine: relevance of the blood-brain barrier.

The systemic administration of norepinephrine has minimal effects on the cerebral circulation, perhaps due to blood-brain barrier mechanisms. To test hypothesis, the cerebrovascular effects of norepinephrine beyond the blood-brain barrier were studied in anesthetized baboons, Intraventricular norepinephrine (40 mug/kg) resulted in significant increases in cerebral blood flow (40%), cerebral oxygen consumption (21%), and cerebral glucose uptake (153%). Intracarotid hypertonic urea opens the blood-brain barrier by osmotic disruption; Consequent to hypertonic urea, the intracarotid infusion of norepinephrine, 50 ng/kg-min, significantly increase cerebral blood flow (49%), cerebral oxygen consumption (21%), and cerebral glucose uptake (76%), It appears probable that the cerebrovascular responses to norepinephrine are dependent on the integrity of the blood-brain barrier; It is likely that the increase in cerebral blood flow, associated with norepinephrine when it bypasses the barrier, is secondary to an increase in cerebral metabolism.

Animals↗
PubMed1993

Effect of adding heparin in very low concentration to the infusate to prolong the patency of umbilical artery catheters.

A randomized controlled study was done to determine whether the addition of heparin, in very low concentration (0.25 U/ml), to fluids administered through an umbilical artery catheter (UAC) would affect the duration of catheter patency. UAC occlusion occurred in 2 of 15 patients in the heparin group and in 11 of 15 patients in the control group (p = 0.001). Using life-table analysis, the functional life span of UAC was estimated. On day 8, 100% of UACs in heparin group and 9% of UACs in control group were patent (p < 0.05). Coagulation profile remained unaltered after addition of heparin compared with that before the start of the therapy. There was no difference in the incidence of subependymal intraventricular hemorrhage between the two groups. It is concluded that heparin in such low concentration is effective in prolonging duration of UAC patency without causing adverse effects.

Blood Gas Analysis↗
PubMed1978

Effects of enkephalins on arterial blood pressure are reduced by propranolol.

1. The cardiovascular effects of enkephalins have been tested in normotensive Wistar-Kyoto rats. Methionine-enkephalin and leucine-enkephalin increased blood pressure and heart rate after infusion into the brain ventricles. 2. After intravenous injection, blood pressure was increased by methionine-enkephalin and leucine-enkephalin, but heart rate was increased by methionine-enkephalin only. 3. Propranolol treatment reduced the increases in blood pressure following intraventricular methionine-enkephalin and leucine-enkephalin, while only the methionine-enkephalin-induced increases in heart rate were reduced by propranolol. 4. Heart rate and blood pressure responses after intravenous administration of methionine-enkephalins and leucine-enkephalin were not affected by propranolol. 5. Since opioid peptides occur in the blood and in regions of the brain involved in blood pressure regulation, the demonstrated cardiovascular effects to intraventricular and intravenous enkephalins support a role of these peptides in central and peripheral mechanisms of blood pressure control.

Animals↗
PubMed1990

Differential blood pressure responses to oral and central salt administration in two substrains of Dahl rats.

Studies were made on whether oral or intraventricular (icv) NaCl had different effects on the blood pressure (BP) of Dahl rats. Five groups of each strain of Dahl rats, salt-sensitive (S) and salt-resistant (R) rats, were given, respectively, a diet containing 0.3% and icv infusion of 0.15 mol/L NaCl (group 1, control group) or 0.8 mol/L NaCl (group 2), a diet containing 8% NaCl and icv infusion of 0.15 mol/L (group 3) or 0.8 mol/L NaCl (group 4) for 12 days, or an 8% NaCl diet and icv infusion of 5% glucose (group 5). The icv infusions were made into the third cerebral ventricle with an osmotic minipump. In the control group of S rats (group 1) the BP was 120 +/- 4 mm Hg, whereas the BP in groups 3, 4 and 5 were 154 +/- 4, 161 +/- 5 and 153 +/- 3 mm Hg, respectively, and that in group 2 was 142 +/- 3 mm Hg on day 12. In the R rat, group 2 and group 4 showed a significant increase in BP over that of the control group. Multivariate analysis (quantification I) of these data confirmed that the BP of S rats was more sensitive to oral salt loading and that of the R rat was more strongly influenced by central salt administration. These results indicate that the two substrains of Dahl rats show different BP responses to oral and central administrations of NaCl.

Animals↗
PubMedDate not supplied

Relationships between total and unbound propofol in plasma and CSF during continuous drug infusion.

BACKGROUND: Propofol is one of the most frequently applied intravenous anesthetics. Although it has been used for a long period, its pharmacokinetics, especially central nervous system pharmacokinetics, are not fully recognized. OBJECTIVE: Investigation of the relationships between total propofol concentration in blood, total propofol concentration in cerebrospinal fluid (CSF), free propofol concentration in blood, and free anesthetic concentration in CSF in patients undergoing elective neurosurgery and anesthetized with propofol. METHODS: Eleven patients scheduled for elective intracranial procedures were studied. Propofol was applied in the form of target control infusion. During anesthesia, fractional doses of fentanyl and cisatracurium were administered as necessary. After tracheal intubation the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (Fi O2 = 0.33). CSF and blood were taken at the moment of intraventricular drainage application. RESULTS: The unbound propofol concentration in plasma is 1.12% (SD 0.61%; SEM 0.18%) of the total concentration in plasma, and the free propofol concentration in plasma is 71.6% (SD 61.0%; SEM 18.4%) of the total CSF propofol concentration. The free anesthetic concentration in CSF is 30.9% (SD 15.7%; SEM 4.7%) of the total CSF propofol concentration, and 61.8% (SD 34.9%; SEM 10.5%) of the free propofol concentration in plasma. CONCLUSION: The relationship between unbound drug concentrations in plasma and in CSF determined in this study leads to the postulate that propofol is transported from blood to CSF by passive diffusion.

Adult↗
PubMed1979

Restoration of CSF [HCO3-] after its experimental lowering in normocapnic conditions.

It is accepted that in hypercapnia the rise in cerebrospinal fluid bicarbonate concentration (CSF [HCO3-]) occurs because of local HCO3--generating mechanisms, dependent on carbonic anhydrase, as well as on diffusion of HCO3- from plasma. To investigate further the regulation of CSF [HCO3-], CSF HCO3- formation was studied under conditions of pure isocapnic CSF "metabolic" acidosis. In anesthetized normocapnic dogs CSF [HCO3-] was lowered to approximately 15 mmol/l by perfusing the brain ventricles with a low HCO3- solution for 45 min. In dogs with normal plasma [HCO3-], CSF [HCO3-] rose by approximately 7 mmol/l in 2 h after the end of the perfusion. Lowering plasma [HCO3-] to 10 mmol/l by infusing HCl, limited the CSF [HCO3-] rise to 2 mmol/l, indicating the importance of plasma HCO3- for the restoration of CSF [HCO3-]. The small and persistent rise of CSF [HCO3-] at low plasma [HCO3-] occurred against a concentration gradient with blood. Intraventricular injection of acetazolamide had no further effect on this small rise. It is concluded that under the conditions of our experiments the CSF [HCO3-] rise is significantly dependent on plasma [HCO3-] and the caronic anhydrase-dependent HCO3- generation in the CNS is less important.

Acetazolamide↗
PubMed2005

Morphine, hypotension, and adverse outcomes among preterm neonates: who's to blame? Secondary results from the NEOPAIN trial.

OBJECTIVES: Hypotension occurs commonly among preterm neonates, but its cause and consequences remain unclear. Secondary data analyses from the NEOPAIN trial identified the clinical factors associated with hypotension and examined the contributions of morphine treatment or hypotension to severe intraventricular hemorrhage (IVH) (grades 3 and 4), any IVH (grades 1-4), or death. METHODS: In the NEOPAIN trial, 898 ventilated neonates between 23 and 32 weeks of gestation were enrolled, with equal numbers randomized to receive masked morphine or placebo infusions. Additional doses of open-label morphine were administered as necessary by medical staff members. IVH was diagnosed with centralized readings of early and late cranial ultrasonograms. Hypotension was assessed before study drug infusion, during the loading dose, and at 24 and 72 hours during study drug infusion. Logistic regression analyses with stepdown elimination identified the predictor factors associated with the hypotension, severe IVH, any IVH, or death outcomes at each time point. RESULTS: Hypotension was associated with 23 to 26 weeks of gestation, morphine infusions, severity of illness, additional morphine doses, and prior hypotension. Severe IVH was associated with shorter gestation, higher Clinical Risk Index for Babies scores, no prenatal steroids, pulmonary hemorrhage, hypotension before the loading dose, and morphine doses before intubation and at 25 to 72 hours. Neonatal deaths were associated with 23 to 26 weeks of gestation, higher Clinical Risk Index for Babies scores, pulmonary hemorrhage, patent ductus arteriosus, thrombocytopenia, and hypotension before the loading dose. Morphine infusions were not a significant factor in logistic models for severe IVH, any IVH, or death. CONCLUSIONS: Preemptive morphine infusions, additional morphine, and lower gestational age were associated with hypotension among preterm neonates. Severe IVH, any IVH, and death were associated with preexisting hypotension, but morphine therapy did not contribute to these outcomes. Morphine infusions, although they cause hypotension, can be used safely for most preterm neonates but should be used cautiously for 23- to 26-week neonates and those with preexisting hypotension.

Age Factors↗
PubMed1977

Norepinephrine-induced reflex bradycardia after central administration of angiotensin II.

Central angiotensin effects may include baroreceptor alterations and/or ventilated, were given angiotensin intravertebrally (10 ng/kg/min), into a lateral cerebroventricle (0.4 microgram/min) or intravenously (10 ng/kg/min). Surgery was completed under methoxyflurane anesthesia; wounds were periodically infiltrated with viscous tetracaine and the methoxyflurane discontinued. The experiments were performed with the brain unanesthetized to optimize detection of an angiotensin effect on the cardioinhibitory component of the baroreceptor reflex. Bradycardia was evoked by norepinephrine injections (2 microgram/kg i.v.). Intraventricular and intravertebral angiotensin increased basal mean blood pressure 16 mm Hg (p less than 0.05); norepinephrine-induced pressor responses and bradycardia were unaffected by the peptide. Intravenous angiotensin did not affect basal blood pressure; a 16 mm Hg increase (p less than 0.05) in the norepinephrine pressor response with no change in bradycardia was observed. Atropine reversed the norepinephrine bradycardia and increased the pressor response in all cats, thus demonstrating the integrity of the reflex. We conclude that centrally administered angiotensin produces no change in the cardioinhibitory reflex to an acute pressor stimulus. The possibility of a peripheral effect of the peptide exists. The hypertensive response observed in the conscious spinal cats after central angiotensin infusions could be due to vasopressin release and/or action of the peptide at cardiovascular sites at high spinal levels.

Angiotensin II↗
PubMed1998

Consequences of the inhibition of the sarcoplasmic reticulum calcium ATPase on cardiac function and coronary flow in rabbit isolated perfused heart: role of calcium and nitric oxide.

The effects of thapsigargin (Tg) and cyclopiazonic acid (CPA), two selective blockers of the sarcoplasmic reticulum Ca2+-ATPase were studied in rabbit isolated perfused hearts. Tg and CPA were infused into the hearts for 60 min followed by 60 min of wash-out. Left-ventricular developed pressure (LVDP), left-ventricular end diastolic pressure (LVEDP) and the relaxation time constant,tau, were assessed with a fluid-filled LV intraventricular balloon. Both Tg and CPA induced a concentration-dependent reduction in LVDP and dose-dependently altered diastolic function parameters LVEDP and tau. After 60 min of perfusion, both Tg (0.01, 0.1 and 1.0 microM) and CPA (0.1, 1.0 and 10.0 microM) decreased LVDP from 98+/-1 mmHg in control to 83+/-4; 81+/-5 and 55+/-7 mmHg and to 91+/-3, 80+/-5 and 65+/-4 mmHg, respectively. LVEDP increased from 5+/-1 mmHg in controls to 6+/-0.2, 10+/-1 and 29+/-4 mmHg and to 7+/-0.2, 9+/-1 and 11+/- mmHg; while tau elevated from 28+/-1 ms to 32+/-1, 38+/-4 and 99+/-18 ms and to 34+/-1, 38+/-2 and 48+/-4 ms in Tg (0.01, 0.1 and 1.0 microM) and CPA (0.1, 1.0 and 10.0 microM), respectively. The effects of Tg were more pronounced than those of CPA and were modulated by extracellular Ca2+. With 1 mm Ca2+, both agents Tg (0.03 microM) and CPA (0.1 microM) produced a vasodilatation (81.7+/-2. 6 and 89.1+/-3.1% of pre-drug values, respectively). Pretreatment of the hearts with L-NMMA, a specific inhibitor of nitric oxide production, completely abolished the relaxing effect of Tg and CPA as well as the production of cGMP. These data show that the two SR-Ca2+ ATPase inhibitors, Tg and CPA, are negatively inotropic and lusitropic agents and that both Tg and CPA induce a vasodilatation mediated by a NO-dependent mechanism.

Animals↗
PubMed1988

Occlusion of rostroventral 3rd ventricle abolishes drinking but not AVP release in response to central osmotic stimulation.

Dogs were implanted with a device for chronic cannulation of the anterior part of the 3rd ventricle (A3V). Intracerebroventricular (i.c.v.) infusion of artificial cerebrospinal fluid (CSF) containing 0.35 M NaCl into the A3V of 7 normally hydrated dogs induced thirst (average water intake 11.8 +/- 2.0 ml.kg-1 b. wt.) and significantly increased arginine-vasopressin (AVP) concentration in the blood plasma from 3.4 +/- 0.3 to 8.2 +/- 1.2 pg.ml-1. When repeating the i.c.v. hypertonic infusion at intervals of one week or more in two dogs, its dipsogenic effect vanished within 3-5 months. X-ray analysis revealed an occlusion of the rostroventral part of the A3V. Subsequent controls on 3 other dogs confirmed that the dipsogenic response to i.c.v. osmotic stimulation was abolished in association with similar partial occlusions of the A3V. However, this stimulus still produced a significant increase of plasma AVP from 3.7 +/- 0.5 to 5.7 +/- 0.7 pg.ml-1 in the 5 dogs. Control of drinking in these dogs was otherwise unimpaired as indicated by their normal plasma osmolalities. Histological examination revealed that the loss of the dipsogenic response to i.c.v. infusion of 0.35 M NaCl was in each case associated with fibrinous occlusion of the A3V between its rostral wall and the mass intermedia, preventing the passage of the infusate to the supraoptic and infundibular recesses.

Animals↗
PubMed1989

Bombesin microinfusion into the rat hypothalamic paraventricular nucleus increases blood glucose, free fatty acids and corticosterone.

Bombesin is a particularly potent hyperglycemic agent when administered intraventricularly or intracisternally in the rat. Because bombesin-like immunoreactivity is found in several forebrain regions implicated in glucoregulation, the ability of direct hypothalamic microinfusions of this peptide to affect serum metabolic fuel levels was tested. Three experiments, using anesthetized, acutely infused rats, or unanesthetized rats with chronic intracranial implants, showed that microinfusion of bombesin into the hypothalamic paraventricular nucleus caused significant, dose-related increases in serum glucose; infusions into the lateral hypothalamus or the caudate nucleus were ineffective. Infusions into the ventromedial nucleus significantly elevated glucose only in acutely anesthetized rats. In unanesthetized rats with chronic intracranial cannulae, bombesin infusions into all 3 hypothalamic sites, but not the caudate-putamen, significantly elevated blood free fatty acids, while only infusions into the paraventricular nucleus caused significant dose-related increases in blood corticosterone. The results demonstrate that the paraventricular nucleus is a sensitive site for bombesin-induced elevation of blood glucose, free fatty acids, and corticosterone. They also imply that the bombesin binding sites and immunoreactive terminals previously identified in these regions may be involved in the central regulation of circulating metabolic fuel levels and the pituitary-adrenal axis, and that the effects of acute surgery may augment the hyperglycemic response to intrahypothalamic bombesin administration.

Animals↗