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Biomedical subjects

J A Russell

Publications and source records attributed to J A Russell.

At least 37 records · Page 2Linked to original sources
PubMed2001

Responses of magnocellular neurons to osmotic stimulation involves coactivation of excitatory and inhibitory input: an experimental and theoretical analysis.

How does a neuron, challenged by an increase in synaptic input, display a response that is independent of the initial level of activity? Here we show that both oxytocin and vasopressin cells in the supraoptic nucleus of normal rats respond to intravenous infusions of hypertonic saline with gradual, linear increases in discharge rate. In hyponatremic rats, oxytocin and vasopressin cells also responded linearly to intravenous infusions of hypertonic saline but with much lower slopes. The linearity of response was surprising, given both the expected nonlinearity of neuronal behavior and the nonlinearity of the oxytocin secretory response to such infusions. We show that a simple computational model can reproduce these responses well, but only if it is assumed that hypertonic infusions coactivate excitatory and inhibitory synaptic inputs. This hypothesis was tested first by applying the GABA(A) antagonist bicuculline to the dendritic zone of the supraoptic nucleus by microdialysis. During local blockade of GABA inputs, the response of oxytocin cells to hypertonic infusion was greatly enhanced. We then went on to directly measure GABA release in the supraoptic nucleus during hypertonic infusion, confirming the predicted rise. Together, the results suggest that hypertonic infusions lead to coactivation of excitatory and inhibitory inputs and that this coactivation may confer appropriate characteristics on the output behavior of oxytocin cells. The nonlinearity of oxytocin secretion that accompanies the linear increase in oxytocin cell firing rate reflects frequency-facilitation of stimulus-secretion coupling at the neurohypophysis.

Animals↗
PubMed2001

Pulmonary hypertension alters soluble guanylate cyclase activity and expression in pulmonary arteries isolated from fetal lambs.

The nitric oxide (NO)-guanosine 3',5'-cyclic monophosphate (cGMP) signaling pathway plays an important role in the pulmonary vascular transition at birth. We studied pulmonary arteries and veins isolated from normal late-gestation fetal lambs and from fetal lambs with persistent pulmonary hypertension (PPHN) following prenatal ligation of the ductus arteriosus. We additionally used double immunolabeling and immunoblot analysis to determine relative vascular contents of endothelial nitric oxide synthase (NOS-III) and soluble guanylate cyclase (sGC). Cyclic GMP content and sGC activity were significantly lower in arteries from hypertensive lambs than controls. A rank order for contents of both soluble guanylate cyclase and NOS-III was observed by both immunolabeling and immunoblotting: Control vein = Hypertensive vein > Control artery > Hypertensive artery. Our data demonstrate that the relative expression of sGC correlates well with the relative expression of NOS-III, and indicate the potential importance of soluble guanylate cyclase in the regulation of the perinatal pulmonary circulation. These data may help us understand vascular mechanisms producing PPHN, as well as patterns of response to exogenous NO.

Animals↗
PubMed2001

The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series.

OBJECTIVE: To review all cases of septic shock treated with vasopressin to determine the effects on hemodynamic and renal function and to document any adverse effects. SETTING: A 14-bed mixed medical-surgical ICU of St. Paul's Hospital, a 450-bed tertiary referral hospital affiliated with the University of British Columbia. PATIENTS: All ICU patients who received vasopressin for treatment of severe septic shock between August 5, 1997, and March 21, 1999. RESULTS: We identified 50 patients: age 60 (+/-14); APACHE II score 27 (+/-7). Baseline data (T0) was compared to data at T4, T24 and T48 (4, 24 and 48 h) on infusion. Mean arterial pressure (MAP) increased by 18% from T0 to T4 and remained stable at T24 (p=0.006) and T48 (p=0.008). Systolic pulmonary artery pressure (PAP) was unchanged at 45+/-13 mmHg. Mean cardiac index (CI) decreased by 11% at T4 (p=0.03). Urine output increased 79% at T4 (p=0.005) and further increases were not significant at T24 and T48. Mean pressor dosage decreased by 33% at T4 (p=0.001), by 53% at T24 (p=0.002) and by 48% at T48 (p=0.01). Hospital mortality was 85%. There were six cardiac arrests; all but one occurred at a vasopressin dose of 0.05 U/min or more. CONCLUSIONS: In this group of patients with severe septic shock, vasopressin infusion increased MAP and urine output and decreased catecholamine requirements. Doses higher than 0.04 U/min were not associated with increased effectiveness and may have been associated with higher adverse effects.

Analysis of Variance↗
PubMed2001

Brain preparations for maternity--adaptive changes in behavioral and neuroendocrine systems during pregnancy and lactation. An overview.

Pregnancy, parturition and lactation comprise a continuum of adaptive changes necessary for the development and maintenance of the offspring. The endocrine changes that are driven by the conceptus and are essential for the maintenance of pregnancy and are involved in the preparations for motherhood are outlined. These changes include large increases in the secretion of sex steroid hormones, and the secretion of peptide hormones that are unique to pregnancy. The ability of these pregnancy hormones to alter several aspects of brain function in pregnancy is considered, and the adaptive importance of some of these changes is discussed, for example in metabolic and body fluid adjustments, and the induction of maternal behavior. The importance of sex steroids in determining the timing of the various adaptive changes in preparing for parturition and maternal behavior is emphasized, and the concept that the actions of prolactin and oxytocin, quintessential mammalian motherhood neuropeptides, can serve to coordinate a spectrum of adaptive changes is discussed. The part played by oxytocin neurons and their regulatory mechanisms is reviewed to illustrate how neural systems involved in maternity are prepared in pregnancy via changes in phenotype, synaptic organization and in the relative importance of their different inputs, to function optimally when needed. For oxytocin neurons secreting from the posterior pituitary, important in parturition and essential in lactation, these changes include mechanisms to restrain their premature activation, and adaptations to support synchronized burst firing for pulsatile oxytocin secretion in response to stimulation via afferents from the birth canal, olfactory system or suckled nipples. Within the brain, expression of oxytocin receptors permits centrally released oxytocin to facilitate the expression of maternal behavior. Changes in other neuroendocrine systems are similarly extensive, leading to lactation, suppression of ovulation, reduced stress responses and increased appetite; these changes in lactation are driven by the suckling stimulus. The possible link between these adaptations and changes in cognition and mood in pregnancy and post partum are considered, as well as the dysfunctions that lead to common problems of depression and puerperal psychoses.

Adaptation, Physiological↗
PubMed2001

Endogenous opioid regulation of oxytocin and ACTH secretion during pregnancy and parturition.

Progress of parturition in the rat is optimal when there is increased oxytocin secretion, thus ensuring quick birth and otherwise risking adverse neonatal health. To ensure that the mechanisms for this are available, oxytocin neurons adapt in pregnancy and this includes development of a tonic inhibition by endogenous opioids. Endogenous opioid inhibition of oxytocin secretion increases in pregnancy, initially acting on the nerve terminals in the posterior pituitary and later on oxytocin cell bodies and their inputs. This inhibition enhances stores of oxytocin and enables restraint of oxytocin neuron responsiveness to selected excitatory inputs. The hypothalamic neurons which mediate stress also adapt in late pregnancy so that hypothalamo-pituitary-adrenal axis and oxytocin secretory responses to stressor exposure are attenuated. This is also partly due to endogenous opioid inhibition. Thus, in pregnancy oxytocin and hypothalamo-pituitary-adrenal axis secretion in response to stimulation is restrained, protecting the unborn fetus(es) from premature delivery and glucocorticoid exposure and preparing the oxytocin neurons for their important secretory role during parturition. In parturition itself, endogenous opioids continue to inhibit these neurons. Stress exposure during parturition delays births, probably due to endogenous opioid inhibition of pulsatile oxytocin secretion. On the other hand, basal ACTH and corticosterone secretion are reduced in parturition through inhibition by endogenous opioids. So, opioids continue to regulate the activity of oxytocin and hypothalamo-pituitary-adrenal mechanisms in labor; inhibition of oxytocin neurons at this time may control the spacing of pup births.

Adrenocorticotropic Hormone↗
PubMed2001

Effects of the endogenous opioid peptide, endomorphin 1, on supraoptic nucleus oxytocin and vasopressin neurones in vivo and in vitro.

We investigated the actions of the endogenous opioid tetra-peptide endomorphin 1, a selective mu-opioid receptor agonist, on oxytocin and vasopressin cell activity in vivo and in vitro. The activity of antidromically-identified supraoptic nucleus cells were recorded from urethane-anaesthetized female rats. The firing rates of both oxytocin and vasopressin cells were reduced by intracerebroventricular endomorphin 1 (5 - 100 pmol); this inhibition was prevented by intravenous naloxone (5 mg kg(-1)). A second group of rats was infused intracerebroventricularly with endomorphin 1 (27 pmol min(-1)) over 5 days. The firing rates of oxytocin and vasopressin cells in endomorphin 1 pre-treated rats were similar to those of endomorphin 1 naïve rats, indicating tolerance to the inhibitory effects of endomorphin 1. Intravenous naloxone induced similar modest and transient increases in the firing rate of oxytocin cells in endomorphin 1 pre-treated rats and endomorphin 1 naïve rats, indicating that endomorphin 1, unlike the mu-opioid alkaloid agonist, morphine, does not induce mu-opioid dependence in these cells. In vitro, whole-cell current clamp recordings were made from supraoptic nucleus cells in superfused coronal hypothalamic slices from young female rats. Endomorphin 1 (100 nM) inhibited the firing rate of oxytocin cells but had no significant effect on vasopressin cells at up to 10 microM. Inhibition of oxytocin cells was reversed by naloxone, and remained when synaptic transmission was blocked by superfusion with low Ca(2+)/Co(2+)-containing medium. Thus, endomorphin 1 directly inhibits oxytocin cells but inhibits vasopressin cells by indirect actions. Chronic endomorphin 1 administration induces mu-opioid tolerance in oxytocin and vasopressin cells but not mu-opioid dependence in oxytocin cells.

Action Potentials↗
PubMed2001

The CD3- 16+ 56+ NK cell count independently predicts autologous blood stem cell mobilization.

Better predictive factors for autologous blood stem cell mobilization (BSCM) are needed. The purpose of this study was to determine if an independent association exists between lymphocyte or NK cell counts and BSCM. Data were analyzed on 141 consecutive patients aged 19-69 years (median 45) who received combined chemotherapy plus G-CSF for BSCM, and who had measurements of immune cells prior to BSCM. Of the 141 patients, 41% had breast cancer, 14% Hodgkin's disease, 34% non-Hodgkin's lymphoma, and 11% other diagnoses. BSCM involved dose-intensive cyclophosphamide, etoposide, cisplatin (DICEP) plus G-CSF 300 microg (<70 kg) or 480 microg (>70 kg) for 45% of patients, while the remaining 55% received other chemotherapy plus similar doses of G-CSF. Only a single apheresis was performed for 94% of patients. The following factors were analyzed for predictors of BSCM: age, gender, prior chemotherapy, prior radiotherapy, diagnosis, disease status, marrow involvement, mobilization regimen, Hb, WBC, platelet count, B cell, T cell, and NK cell counts. The peripheral blood CD34+ counts on the first day of apheresis (PBCD34) were 6-1783 x 10(6)/l (median 150). The PBCD34 count correlated strongly with the number of CD34+ cells collected/l blood apheresed and with the number of CD34+ cells collected/kg. By multivariate analysis using continuous variables, relapsed status (P = 0.0003), not using DICEP mobilization (P = 0.0001), female gender (P = 0.0057), low platelet count (P = 0.051), and low CD3- 16+ 56+ count (P = 0.0158) were associated with low PBCD34 counts. Using categorical variables, the only factors that independently predicted a PBCD34 count <150 x 10(6)/l were: >1 prior chemotherapy regimen (odds ratio = 5.12, P = 0.0003), not using DICEP mobilization (odds ratio = 4.94, P = 0.0001), and CD3- 16+ 56+ count <125 x 10(6)/l (odds ratio= 2.58, P = 0.0157). In conclusion, the CD3- 16+ 56+ count may be a useful additional predictor of BSCM and warrants further study.

Adult↗
PubMed2001

Independent origins and horizontal transfer of bacterial symbionts of aphids.

Many insect groups have obligate associations with primary endosymbionts: mutualistic bacteria that are maternally transmitted and derived from an ancient infection. Often, the same insects are hosts to 'secondary' bacterial symbionts which are maternally transmitted but relatively labile within host lineages. To explore the dynamics of secondary symbiont associations in aphids, we characterized bacteria infecting 15 species of macrosiphine aphids using DNA sequencing, diagnostic polymerase chain reaction (PCR), diagnostic restriction digests, phylogenetic analyses, and electron microscopy to examine aphids from nature and from laboratory colonies. Three types of bacteria besides Buchnera were found repeatedly; all three fall within the Enterobacteriaceae. The R-type has a 16S rDNA less than 0.1% different from that of the secondary symbiont previously reported from Acyrthosiphon pisum and is related to Serratia species. The T-type includes a symbiont previously reported from a whitefly; the U-type comprises a new cluster near the T-type. The T-type was found in every one of 40 Uroleucon ambrosiae clones collected throughout the United States. In contrast, A. pisum individuals were infected by any combination of the three symbiont types. Secondary symbionts were maternally transmitted for 11 months within laboratory-reared A. pisum clones and were present in sexually produced eggs. PCR screens for a bacteriophage, APSE-1, indicated its presence in both A. pisum and U. ambrosiae containing secondary symbionts. Electron microscopy of R-type and T-type bacteria in A. pisum and in U. ambrosiae revealed rod-shaped organisms that attain extremely high densities within a few bacteriocytes.

Animals↗
PubMed2001

Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis.

OBJECTIVES: To assess the safety and effect on coagulopathy of a range of doses of recombinant human activated protein C (rhAPC). To determine an effective dose and duration of rhAPC for use in future clinical trials. DESIGN: Double-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential), phase II clinical trial. SETTING: Forty community or academic medical institutions in United States and Canada. PATIENTS: One hundred thirty-one adult patients with severe sepsis. INTERVENTIONS: Intravenous infusion of rhAPC (12, 18, 24, or 30 microg/kg/hr) or placebo for 48 or 96 hrs. MEASUREMENTS AND MAIN RESULTS: No significant differences in incidence of serious bleeding events (4% rhAPC, 5% placebo, p >.999) or incidence of serious adverse events (39% rhAPC, 46% placebo, p = 0.422) between rhAPC- and placebo-treated patients were observed. One of 53 rhAPC-treated patients with suitable immunogenicity samples had a low level, transient, non-neutralizing anti-APC antibody response not associated with any clinical adverse event. Significant dose-dependent decreases in both D-dimer (p <0.001) and end of infusion interleukin 6 levels (p =.021) were demonstrated. No statistically significant effects on fibrinogen or platelet counts were observed. A nonstatistically significant 15% relative risk reduction in 28-day all-cause mortality was observed between rhAPC- and placebo-treated patients. CONCLUSIONS: rhAPC was safe and well-tolerated and demonstrated a dose-dependent reduction in D-dimer and interleukin 6 levels relative to placebo. The dose of 24 microg/kg/hr for 96 hrs was selected for use in future clinical studies.

Critical Care↗
PubMed2001

Altered endothelium-dependent relaxations in lambs with high pulmonary blood flow and pulmonary hypertension.

Congenital heart disease associated with increased pulmonary blood flow produces pulmonary hypertension. To characterize vascular alterations in the nitric oxide (NO)-cGMP cascade induced by increased pulmonary blood flow and pulmonary hypertension, 10 fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). When the lambs were 4-6 wk of age, we assessed responses of pulmonary arteries (PAs) and pulmonary veins (PVs) isolated from lungs of control and shunted lambs. PVs from control and shunted lambs relaxed similarly to exogenous NO (S-nitrosyl-acetyl-penicillamine), to NO produced endogenously (zaprinast and A-23187), and to cGMP (atrial natriuretic peptide). In contrast, relaxations to A-23187 and zaprinast were blunted in PAs isolated from shunted lambs relative to controls. Inhibitors of NO synthase (NOS) and soluble guanylate cyclase constricted control but not shunt PAs, indicating reduced basal NOS activity in shunt PAs. Pretreatment of shunt PAs with the substrates L-arginine and sepiapterin, a precursor for tetrahydrobiopterin synthesis, did not augment A-23187 relaxations. However, pretreatment with superoxide dismutase and catalase significantly enhanced A-23187 relaxations in shunt PAs. We conclude that increased pulmonary blood flow induces an impairment of endothelium-dependent relaxation that is selective to PAs. The impaired relaxation may be mediated in part by excess superoxide production.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

C-type natriuretic peptide system in fetal ovine pulmonary vasculature.

C-type natriuretic peptide (CNP) is a recently described endothelium-derived relaxing factor. CNP relaxes vascular smooth muscle and inhibits smooth muscle proliferation by binding to natriuretic peptide receptor (NPR) type B (NPR-B) and producing cGMP. Lung parenchyma and fifth-generation pulmonary arteries (PA) and veins (PV) were isolated from late-gestation fetal lambs. All three types of NPR mRNA were detected in PA and PV by RT-PCR. CNP and NPR-B immunostaining was positive in pulmonary vascular endothelium and medial smooth muscle. CNP concentration-response curves of PA and PV were compared with those of atrial natriuretic peptide (ANP) by use of standard tissue bath techniques. CNP relaxed PV significantly better than PA. ANP relaxed PA and PV equally, but ANP relaxed PA significantly better than CNP. Pretreating PA and PV with natriuretic peptide receptor blocker (HS-142-1) or cGMP-dependent protein kinase inhibitor Rp-beta-phenyl-1- N2-etheno-8-bromoguanosine 3',5'-cyclic monophosphorothionate significantly inhibited the CNP relaxation response, indicating that the response was mediated through the NPR-cGMP pathway. We conclude that CNP is important in mediating pulmonary venous tone in the fetus.

Animals↗
PubMed2001

Physiology of vasopressin relevant to management of septic shock.

Vasopressin is emerging as a rational therapy for the hemodynamic support of septic shock and vasodilatory shock due to systemic inflammatory response syndrome. The goal of this review is to understand the physiology of vasopressin relevant to septic shock in order to maximize its safety and efficacy in clinical trials and in subsequent therapeutic use. Vasopressin is both a vasopressor and an antidiuretic hormone. It also has hemostatic, GI, and thermoregulatory effects, and is an adrenocorticotropic hormone secretagogue. Vasopressin is released from the axonal terminals of magnocellular neurons in the hypothalamus. Vasopressin mediates vasoconstriction via V1-receptor activation on vascular smooth muscle and mediates its antidiuretic effect via V2-receptor activation in the renal collecting duct system. In addition, vasopressin, at low plasma concentrations, mediates vasodilation in coronary, cerebral, and pulmonary arterial circulations. Septic shock causes first a transient early increase in blood vasopressin concentrations that decrease later in septic shock to very low levels compared to other causes of hypotension. Vasopressin infusion of 0.01 to 0.04 U/min in patients with septic shock increases plasma vasopressin levels to those observed in patients with hypotension from other causes, such as cardiogenic shock. Increased vasopressin levels are associated with a lesser need for other vasopressors. Urinary output may increase, and pulmonary vascular resistance may decrease. Infusions of > 0.04 U/min may lead to adverse, likely vasoconstriction-mediated events. Because clinical studies have been relatively small, focused on physiologic end points, and because of potential adverse effects of vasopressin, clinical use of vasopressin should await a randomized controlled trial of its effects on clinical outcomes such as organ failure and mortality.

Animals↗
PubMed2000

Nitric oxide and the oxytocin system in pregnancy.

We examined the functional role of the nitric oxide (NO)-producing system in magnocellular neurons and how this changes at the end of pregnancy, using a combination of blood sampling and oxytocin radioimmunoassay, electrophysiology, immunocytochemistry for Fos expression, and in situ hybridization histochemistry. In urethane-anesthetized virgin rats, systemic administration of NO synthase (NOS) inhibitors led to a facilitation of oxytocin release evoked by hyperosmotic stimulation. Direct application of the NO donor sodium nitroprusside to the supraoptic nucleus by in vivo microdialysis inhibited the electrical activity of both oxytocin neurons and vasopressin neurons, whereas direct application of an NOS inhibitor increased electrical activity, indicating that endogenous NO acts within the supraoptic nucleus to inhibit neuronal activity. However, during late pregnancy, the influence of endogenous NO is dramatically downregulated, reflected by a reduced expression of neuronal NOS mRNA in these neurons and a loss of efficacy of NOS inhibitors on stimulus-evoked oxytocin release. This downregulation may cause the oxytocin system to become more excitable at term, resulting in the capacity for greater release of oxytocin during parturition.

Animals↗
PubMed2000

Verapamil prevents withdrawal excitation of oxytocin neurones in morphine-dependent rats.

We investigated whether the full expression of morphine withdrawal excitation by supraoptic nucleus (SON) oxytocin neurones is a property of the neurones themselves or a partial function of their afferent inputs, by interrupting synaptic input activity via central administration of the L-type Ca(2+) channel blocker verapamil. In morphine-dependent rats, withdrawal-induced release of oxytocin from the posterior pituitary was suppressed by prior administration of intracerebroventricular (i.c.v.) verapamil (160 microg), as was release of oxytocin within the SON measured by microdialysis. During morphine withdrawal the increased electrical activity of SON neurones was also reduced both by i.c.v. verapamil and microdialysis application of verapamil or nifedipine into the SON. Oxytocin secretion evoked by electrical stimulation of the pituitary stalk was unaffected by i.c.v. verapamil suggesting a central site of action. To determine whether the inhibitory actions of verapamil were specific to morphine withdrawal, we also investigated the effects of verapamil on other oxytocin-secreting stimuli. I.C.V. verapamil given to morphine-naïve rats abolished pituitary oxytocin release in response to activation of brainstem or rostral excitatory inputs by cholecystokinin (20 microg kg(-1), i.v.) and 1.5 M saline (4 ml kg(-1), i.p.) respectively, whilst in lactating rats, i.c.v. verapamil reduced suckling-induced release of oxytocin within the SON. These results suggest that verapamil has a central site of action on stimulated oxytocin release (including an action within the SON) and that both pre and post-synaptic L-type Ca(2+) channels are required for the full expression of morphine withdrawal in SON oxytocin neurones.

Animals↗
PubMed2000

High-performance liquid chromatographic determination of 17beta-estradiol and 17beta-estradiol-3-acetate solubilities and diffusion coefficents in silicone elastromeric intravaginal rings.

A rapid, sensitive reversed-phase high-performance liquid chromatographic method has been developed for the determination of in vitro release of 17beta-estradiol and its ester prodrug, 17beta-estradiol-3-acetate, from silicone intravaginal rings. Partial hydrolysis of the acetate under the aqueous conditions provided by the 1% benzalkonium chloride release medium necessitates its conversion to 17beta-estradiol prior to HPLC analysis. Both steroid peaks have been fully resolved from the benzalkonium chloride peaks by the reported chromatographic method, which employs a C18 bonded reversed-phase column, an acetonitrile-water (50:50, v/v) mobile phase and a UV detection wavelength of 281 nm. The peak area versus 17beta-estradiol concentration was found to be linear over the range of 0.0137-1347 microkg ml(-1). The HPLC method has also been used to determine the silicone solubilities and diffusion coefficients of the two related steroids. The almost 100-fold increase in 17beta-estradiol-3-acetate release from the silicone core-type intravaginal rings compared to 17beta-estradiol is shown to be due to a 60-fold increase in silicone solubility and a one and a half-fold increase in diffusitivity. The results demonstrate that an effective estrogen replacement therapy dose of 17beta-estradiol may be administered from a silicone intravaginal reservoir device containing the labile 17beta-estradiol-3-acetate prodrug.

Administration, Intravaginal↗
PubMed2000

Rheological, mechanical and membrane penetration properties of novel dual drug systems for percutaneous delivery.

In this study it has been demonstrated that mixtures of two solid drugs, ibuprofen and methyl nicotinate, with different but complementary pharmacological activities and which exist as a single liquid phase over a wide composition range at skin temperature, can be formulated as o/w emulsions without the use of an additional hydrophobic carrier. These novel dual drug systems provided significantly enhanced in vitro penetration rates through a model lipophilic barrier membrane compared to conventional individual formulations of each active. Thus, for ibuprofen, drug penetration flux enhancements of three- and 10-fold were observed when compared to an aqueous ibuprofen suspension and a commercial alcohol-based ibuprofen formulation, respectively. Methyl nicotinate penetration rates were shown to be similar for aqueous gels and emulsified systems. Mechanisms explaining these observations are proposed. Novel dual drug formulations of ibuprofen and methyl nicotinate, formulated within the liquid range at skin temperature, were investigated by oscillatory rheology and texture profile analysis, demonstrating the effects of drug and viscosity enhancer concentrations, and disperse phase type upon the rheological, mechanical and drug penetration properties of these systems.

Administration, Topical↗
PubMed2000

Local injection of pertussis toxin attenuates morphine withdrawal excitation of rat supraoptic nucleus neurones.

Morphine inhibits oxytocin neurones via G(i/o)-protein-linked mu-opioid receptors. Following chronic morphine administration oxytocin cells develop dependence, shown by withdrawal excitation after administration of the opioid antagonist, naloxone. Here, inactivation of G(i/o)-proteins by pre-treatment of morphine-dependent rats with pertussis toxin injected into the left supraoptic nucleus reduced withdrawal-induced Fos protein expression within the injected nucleus by 41+/-10% compared to the contralateral nucleus, indicating that functional G(i/o)-proteins are essential for the development and/or expression of morphine dependence by oxytocin cells in the supraoptic nucleus. In another group of rats, pertussis toxin did not alter the responses to either systemic cholecystokinin administration or systemic hypertonic saline administration, indicating that pertussis toxin does not prevent oxytocin cells from responding to stimuli that are not mediated by G(i/o)-proteins. Finally, pertussis toxin reduced acute morphine inhibition of systemic hypertonic saline-induced Fos protein expression in the supraoptic nucleus, confirming that pertussis toxin effectively inactivates G(i/o)-proteins in the supraoptic nucleus. Thus, the expression of morphine withdrawal excitation by supraoptic nucleus oxytocin cells requires the functional integrity of G(i/o)-proteins within the nucleus.

Animals↗