Insulin degludec/insulin aspart produces a dose-proportional glucose-lowering effect in subjects with type 1 diabetes mellitus.

AIMS: To evaluate the pharmacodynamic dose-response relationship of insulin degludec/insulin aspart (IDegAsp), a novel, soluble co-formulation of the ultra-long-acting basal insulin, insulin degludec (IDeg), with the rapid-acting prandial insulin (IAsp), across different doses in patients with type 1 diabetes (T1DM). METHODS: This was a randomized, single-centre, double-blind, four-period, incomplete block, crossover trial. A cohort of 33 people with T1DM received single doses (0.4, 0.6 or 0.8 U/kg) of IDegAsp or the comparator, biphasic insulin aspart 30, in a randomized sequence of four treatment periods, each separated by a washout of 13-21 days. Pharmacodynamic response was assessed using a 26-h euglycaemic glucose clamp, with blood glucose stabilized at a target of 5.5 mmol/l (100 mg/dl). RESULTS: A rapid onset of action and a distinct peak attributable to IAsp was observed in the glucose infusion rate (GIR) profile, followed by a separate, flat and stable basal glucose-lowering effect attributable to the IDeg component. The mean area under the GIR curve over 24 h (AUC(GIR,0-24 h)), and the mean maximum GIR (GIR(max)) increased with increasing dose level of IDegAsp. A dose-response relationship for IDegAsp was demonstrated for AUC(GIR,0-24 h) and GIR(max), indicating dose proportionality. A dose-concentration relationship was also observed for both the basal and bolus components of IDegAsp. CONCLUSIONS: IDegAsp has a clear dose-response relationship, indicating the clinical potential for straightforward titration according to individual patient needs.

Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin.

AIM: Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin. METHODS: In this 28-day, randomized, open-label, parallel-group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 µg weeks 1-2, then 20 µg; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal. RESULTS: Lixisenatide reduced PPG significantly more than liraglutide [mean change in AUC(0:30-4:30h) : -12.6 vs. -4.0 h·mmol/L, respectively; p < 0.0001 (0:30 h = start of meal)]. Change in maximum PPG excursion was -3.9 mmol/l vs. -1.4 mmol/l, respectively (p < 0.0001). More lixisenatide-treated patients achieved 2-h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (-0.3 vs. -1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C-peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (-1.6 kg vs. -2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported. CONCLUSIONS: Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C-peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide.

The role of new vessels and macrophages in the development and resolution of edema following a cortical freeze lesion in the mouse.

The role of an influx of macrophages and neovascularity in the resolution of vasogenic edema is not well defined. The inhibition of these processes with x-irradiation or parenteral corticosteroid administration was used to evaluate their contribution to the resolution of edema around a cortical freeze lesion in mice. The resorption of Evans blue, a marker of protein extravasation, was delayed in x-irradiated mice on the second day following a freeze lesion (p = 0.0075), which correlates with a delay in macrophage infiltration around the lesion. The specific gravity of the lesion and its border regions was significantly less in x-irradiated animals on day 7 than in controls (p = 0.00062), which correlates with a delay in new vessel formation around the lesion. Administration of corticosteroids from the time of production of the freeze lesion resulted in a specific gravity significantly less than control when measured eight days after the lesion (p = 0.01). Macrophages may participate by inhibiting the development of the macromolecular portion of vasogenic edema. The development of neovascularity correlates with the resorption of the aqueous portion of vasogenic edema. As with x-irradiation, corticosteroids administered from the time of freeze lesion inhibited the resorption of the aqueous portion of vasogenic edema, but they may suppress the spread of edema in this experimental model.

Effects of naloxone on canine cerebral vascular smooth muscle.

The pharmacological effects of naloxone on cerebral arterial smooth muscle in vitro were examined using canine basilar arterial strips. Naloxone exerted two different effects on canine basilar artery: (1) at a high concentration (3 X 10(-4) M) it produced nonspecific vasodilation, and (2) at lower concentrations (3 X 10(-7), 3 X 10(-6), and 3 X 10(-5) M) it inhibited the vasoconstrictor effects of norepinephrine without altering KCl-, serotonin-, or hemoglobin-induced constriction. Morphine (2 X 10(-5) or 2 X 10(-4) M) did not reverse the specific vasodilating effect of naloxone (3 X 10(-5) M) on norepinephrine-induced constriction. Rather, morphine and naloxone together produced a greater vasodilating effect on norepinephrine-induced constriction than either agent alone. Naloxone (3 X 10(-5) M) failed to alter either phenylephrine-induced constriction or clonidine-induced constriction. The vasodilating effect of naloxone (3 X 10(-5) M) on 10(-3) M norepinephrine-induced constriction was not reduced with 10(-6) M propranolol. These results suggest that the vasodilating effect of naloxone on norepinephrine-induced constriction does not result from an antagonistic action on opiate receptors, direct inhibition of alpha-adrenoreceptors, or direct stimulation of beta-adrenoreceptors in canine cerebral arterial smooth muscle. The vasodilating effect of naloxone on norepinephrine-induced constriction may influence the CBF changes following naloxone administration.

Adenosine triphosphate-induced arterial hypotension in the dog.

This study was designed to investigate the potential use of adenosine triphosphate (ATP), a naturally occurring vasodilator, for producing profound intraoperative hypotension. Six mongrel dogs were anesthetized with morphine, nitrous oxide, and oxygen, paralyzed with pancuronium, and ventilated to a PaCO2 of 40. The mean arterial pressure was lowered to 40 mm Hg with an intravenous infusion of ATP (10.6 +/- 3.5 (SE) mg/kg/minute). Blood flow was determined using the radioactive microsphere technique. Measurements were made before and 20, 40, and 60 minutes after the induction of hypotension and after a 40-minute recovery. Infusion of ATP to lower the mean arterial pressure to 40 mm Hg resulted in a reduction of mean arterial pressure of 64% and an increase in heart rate of 11% accompanied by frequent cardiac arrhythmias. However, cardiac output decreased only 8%. Myocardial flow increased 137%, kidney flow decreased 71%, and masseter muscle flow increased 333%. A severe metabolic acidosis developed with a reduction in pH from control values of 7.39 +/- 0.03 to 7.16 +/- 0.03 after 60 minutes of hypotension. The cerebral metabolic rate of oxygen, determined using the oxygen content of the sagittal sinus, was not affected. Cerebral hemisphere blood flow decreased 21%, caudate nucleus flow decreased 31%, and corpus callosum flow decreased 43%. Blood flow to the brain stem and cerebellum was unchanged. Hypotension was readily induced, maintained, and reversed using ATP, without apparent tachyphylaxis. However, the profound metabolic acidosis and cardiac arrhythmias that occurred may be serious contraindications to the use of this agent clinically.

Comparison of systemic and cerebrovascular effects of isoflurane and halothane.

This study was carried out to compare the cerebral and systemic circulatory effect of halothane and isoflurane. Six mongrel dogs were anesthetized with 1.3 minimal alveolar concentration (MAC) (1%) halothane and were compared with six mongrel dogs anesthetized with 1.3 MAC (1.5%) isoflurane. Likewise, 6 dogs anesthetized with 1.7 MAC (1.3%) halothane were compared with 6 dogs anesthetized with 1.7 MAC (2%) isoflurane. Blood flow (using the radioactive microsphere technique) and cardiovascular measurements were obtained 2 hours after the induction of anesthesia and were repeated 5 more times at hourly intervals. The heart rate was similar in all groups of dogs, except that it was significantly lower with 1.7 MAC halothane. The mean arterial pressure was statistically higher with isoflurane at both concentrations than with halothane. The cardiac index was similar in all groups, except with 1.7 MAC isoflurane, when it was higher. At the early measurements, total cerebral blood flow (CBF) was above "normal" levels in all groups. At 1.3 MAC, the total CBF tended to be lower with isoflurane, but did not reach statistically significant levels. Blood flow decreased over time in all groups. The cerebral vascular resistance (CVR) mirrored the changes in blood flow, showing no difference between agents at 1.7 MAC, but the CVR with isoflurane was significantly higher at 1.3 MAC than it was with halothane. Regional cerebral blood flow showed marked differences. Regional flow to the hemispheres and the cortical gray matter showed that isoflurane tended to produce lower blood flow, particularly at the 1.3 MAC concentration. The reverse was true in the posterior fossa structures, with the brain stem and cerebellum showing higher blood flows with isoflurane, particularly at 1.7 MAC. Isoflurane may have several advantages over halothane for neurosurgical procedures.

Comparison of sodium thiopental and methohexital for high-dose barbiturate anesthesia.

High-dose sodium thiopental is frequently used in neuroanesthesia. The authors performed a study to compare a shorter-acting barbiturate, methohexital, to sodium thiopental in producing high-dose barbiturate anesthesia. In two groups of five mongrel dogs each, regional cerebral blood flow (CBF) was determined using the radioactive-microsphere technique, and cardiovascular parameters were measured before, during, and 1 hour after a 1 1/2-hour period of deep barbiturate anesthesia with either sodium thiopental or methohexital. Doses of the barbiturates were adjusted to produce electroencephalogram burst suppression of greater than 30 seconds. Both agents produced a similar degree of cardiac depression, reduction in CBF, and decrease in cerebral metabolic rate of oxygen (CMRO2). Changes in cerebral and peripheral vascular resistance indicated that methohexital caused less vasoconstriction than sodium thiopental. When the barbiturate infusions were discontinued, CMRO2 and CBF returned more rapidly toward control values in the methohexital group than in the thiopental group. The more rapid recovery time and decrease in cerebral vascular resistance with methohexital suggest that it may have some advantage over sodium thiopental during certain neurosurgical procedures.

Cerebrovascular effects of hypocapnia during adenosine-induced arterial hypotension.

Profound arterial hypotension is a commonly used adjunct in surgery for aneurysms and arteriovenous malformations. Hyperventilation with hypocapnia is also used in these patients to increase brain slackness. Both measures reduce cerebral blood flow (CBF). Of concern is whether CBF is reduced below ischemic thresholds when both techniques are employed together. To determine this, 12 mongrel dogs were anesthetized with morphine, nitrous oxide, and oxygen, and then paralyzed with pancuronium and hyperventilated. Arterial pCO2 was controlled by adding CO2 to the inspired gas mixture. Cerebral blood flow was measured at arterial pCO2 levels of 40 and 20 mm Hg both before and after mean arterial pressure was lowered to 40 mm Hg with adenosine enhanced by dipyridamole. In animals where PaCO2 was reduced to 20 mm Hg and mean arterial pressure was reduced to 40 mm Hg, cardiac index decreased 42% from control and total brain blood flow decreased 45% from control while the cerebral metabolic rate of oxygen was unchanged. Hypocapnia with hypotension resulted in small but statistically significant reductions in all regional blood flows, most notably in the brain stem. The reported effects of hypocapnia on CBF during arterial hypotension vary depending on the hypotensive agents used. Profound hypotension induced with adenosine does not eliminate CO2 reactivity, nor does it lower blood flow to ischemic levels in this model, even in the presence of severe hypocapnia.

Ligamentum flavum hematoma. Report of two cases.

Two patients presenting with signs and symptoms suggestive of nerve root compression secondary to extradural masses were found to have ligamentum flavum hematomas. Both patients had neurological deficits preoperatively and regained normal function postoperatively. There was no significant antecedent injury in either case. The symptom course was longer than that for spontaneous epidural hematoma. In one case, there was remodeling of bone, initially suggesting either infection or tumor.

Effect of steroid therapy on ischaemic brain oedema and blood to brain sodium transport.

Dexamethasone has been shown in some studies to reduce ischaemic brain oedema, however, the mechanism is unknown. One possible mechanism is through inhibition of active transport of sodium across the blood-brain barrier (BBB) since some steroids, especially progesterone, inhibit sodium transport in isolated brain capillaries. Therefore, we measured brain oedema and BBB permeability to sodium and a passive permeability tracer, alpha-aminoisobutyric acid (AIB), 4 hr after middle cerebral artery occlusion (MCAO) in rats that had been treated 1 hr before MCAO with vehicle (control) or 2 mg/kg of either dexamethasone or progesterone. In controls, the water content of tissue in the center of the ischaemic zone was 82.4 +/- 0.2%. Brain oedema was significantly reduced following pretreatment with either dexamethasone (80.6 +/- 0.1, p less than 0.001) or progesterone (81.5 +/- 0.3, p less than 0.05). Both steroids also reduced BBB permeability to AIB by about 40% in normal brain but to a lesser extent in ischaemic brain. In contrast, steroid treatment had no effect on BBB permeability to sodium in either normal or ischaemic brain. We conclude that pretreatment with dexamethasone and progesterone reduces brain oedema accumulation during the early stages of ischaemia, however, this effect does not result from a reduction in BBB permeability to sodium.

Effect of steroids on edema and sodium uptake of the brain during focal ischemia in rats.

Steroids reduce permeability of the blood-brain barrier and inhibit active sodium transport by brain capillaries in vitro. Since the rate of edema formation during the early stages of ischemia is related to the rate of sodium transport from blood to brain, this study was designed to determine whether steroids reduce ischemic edema formation by inhibiting blood-brain barrier sodium transport. Dexamethasone was compared with progesterone since the latter is a more potent inhibitor of sodium transport in isolated capillaries. Sprague-Dawley rats were treated with vehicle (n = 22) or 2 mg/kg of either dexamethasone (n = 22) or progesterone (n = 17) 1 hour before occlusion of the middle cerebral artery. After 4 hours of ischemia, brain water content and blood-brain barrier permeability to [3H] alpha-aminoisobutyric acid and sodium-22 were determined. In controls, mean +/- SEM water content of tissue in the center of the ischemic zone was 82.4 +/- 0.2%. Brain edema was significantly reduced following pretreatment with either dexamethasone (80.6 +/- 0.1%, p less than 0.001) or progesterone (81.5 +/- 0.3%, p less than 0.05). There was also a significant reduction in blood-brain barrier permeability to alpha-aminoisobutyric acid in normal brain following either treatment (e.g., 2.21 +/- 0.19 and 1.37 +/- 0.10 microliters/g/min, p less than 0.001, for control and dexamethasone treatments, respectively), but no effect on the permeability to sodium (e.g., 1.19 +/- 0.05 and 1.12 +/- 0.11 microliters/g/min for control and dexamethasone treatments, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effect of naloxone on cerebral versus mesenteric arterial smooth muscle in feline and primate species.

This study was conducted in order to investigate naloxone's in vitro action on both epinephrine-induced constriction of mesenteric artery and norephinephrine-induced constriction of cerebral arteries in different species (cat and monkey). Naloxone (3 X 10(-5)M) augmented the epinephrine-induced constriction of both feline and monkey mesenteric artery at epinephrine concentrations of 10(-7) to 10(-5) M. Naloxone (3 X 10(-5)M) suppressed the constriction of feline basilar artery induced by high concentrations (10(-4), 10(-3) and 3 X 10(-3)M) of norepinephrine, while it failed to alter the constriction induced by lower concentrations (10(-7) to 10(-5)M) of norepinephrine. The constrictor response of monkey basilar artery to norepinephrine (10(-8) to 10(-5) M) was not altered by treatment with naloxone (3 X 10(-6) and 3 X 10(-5)M). Such varying effects of naloxone in different tissues and species may have to be taken into account when evaluating the cerebral blood flow changes following naloxone administration.

The effects of naloxone on canine splanchnic arterial smooth muscle.

The pharmacological properties of naloxone on vascular smooth muscle in vitro were examined using canine mesenteric arterial segments. Naloxone exerted two different effects on the artery: (A) naloxone at a high concentration (3 X 10(-4) M) produced a nonspecific vasodilation; and (B) naloxone at lower concentrations (3 X 10(-7), 3 X 10(-6), and 3 X 10(-5) M) augmented the vasoconstrictor effects of epinephrine and norepinephrine without altering KCl- or serotonin-induced constriction. Naloxone's augmenting effect on epinephrine-induced constriction was dose dependent. Even when the arterial strips were incubated in low calcium (0.8 mM) or calcium free Kreb's solution, naloxone (3 X 10(-5) M) still augmented epinephrine-induced constriction. With respect to naloxone's effect on another alpha-adrenoreceptor agonist, naloxone (3 X 10(-5) M) failed to alter phenylephrine-induced constriction. Naloxone's augmenting effect on norepinephrine-induced constriction was abolished when the specimens were incubated with 10(-5) M normetanephrine, while naloxone (3 X 10(-5) M) still augmented the constriction even when the specimens were incubated with 10(-5) M cocaine. These results suggest that naloxone at lower concentrations may augment the constrictor responses to catecholamines, at least in part, by inhibiting the extraneuronal uptake of those catecholamines.