Gaboxadol -- a different hypnotic profile with no tolerance to sleep EEG and sedative effects after repeated daily dosing

Gaboxadol, a selective extra synaptic GABA(A) receptor agonist, has been in clinical development for the treatment of insomnia. Development of tolerance to therapeutic effects (e.g. hypnotic and anticonvulsant and sedative) and withdrawal symptoms (e.g. REM sleep rebound and reduced seizure threshold) upon treatment discontinuation is reported for GABA(A) receptor allosteric modulators acting via the benzodiazepine binding site, e.g. zolpidem and indiplon. We conducted a head to head comparison in rats of the hypnotic (sleep EEG after 21 daily doses and 24 and 48 h after the last dose) and seizure threshold modifying (bicuculline assay 24 h after 28 daily doses) effects of gaboxadol and benzodiazepine ligands. Furthermore, we investigated in further details a previously reported apparent rapid development of tolerance to gaboxadol's effects in a rat rotarod motor coordination assay and related this effect to CNS exposure levels and in vitro potency at extra synaptic GABA(A) receptors. Sleep EEG studies demonstrated lack of tolerance and withdrawal effects after 28 daily doses with gaboxadol, whereas zolpidem produced both tolerance and withdrawal effects under a similar dosing regimen. Daily dosing with gaboxadol, zolpidem or indiplon for 28 days and acute discontinuation of treatment left the threshold to bicuculline-induced seizures unchanged. The rapidly attenuated effect of repeated gaboxadol dosing was confirmed in the rotarod model. However, re-challenge of gaboxadol insensitive animals with gaboxadol produced a maximum response, ruling out that receptor desensitisation accounts for these effects. By comparing CNS exposure at rotarod responses and concentration response relation at cloned GABA(A) receptors expressed in Xenopus oocytes it appears that the decline in response in the rotarod model coincides with the steep part of the concentration response curve for gaboxadol at extra synaptic GABA(A) receptors. In conclusion, rat sleep EEG repeated dose studies of gaboxadol confirm a hypnotic-like profile and no withdrawal effects, whereas tolerance and withdrawal effects were shown with zolpidem. Withdrawal from gaboxadol, zolpidem and indiplon did not affect the seizure threshold to bicuculline. Gaboxadol's apparent rapid development of tolerance in the rotarod assay appears to be kinetically determined.     

基于CYP3A4酶探讨灯盏花素对洛伐他汀的药动学的影响及机制

目的 探究灯盏花素与洛伐他汀联用对大鼠体内药动学的影响,从代谢酶的角度揭示灯盏花素对洛伐他汀药动学产生影响的机制。方法 采用探针药物法及RT-HPLC法测定咪达唑仑在肝微粒体孵育体系中的浓度,评价灯盏花素与洛伐他汀联用对CYP3A4酶活性的影响。通过RT-PCR反应来检测CYP3A4酶mRNA基因表达,采用Western blot法,从蛋白翻译水平上分析灯盏花素与洛伐他汀联用对大鼠肝脏CYP3A4蛋白表达的影响。结果 洛伐他汀与灯盏花素联合用药后,洛伐他汀在大鼠体内的血药浓度显著升高,从0.39 mg?L-1 上升到1.08 mg?L-1 ,清除率从3.36L?h-1?kg-1降低到1.08L?h-1?kg-1,药物半衰期从5.0h延长到6.2h,联合给药后洛伐他汀的AUC从2.42mg?L-1?h-1上升到4.22mg?L-1?h-1。洛伐他汀组与空白组比较CYP3A4酶活性均没有明显变化;灯盏花素组及灯盏花素联合洛伐他汀组与空白组比较发现均抑制CYP3A4酶活性;灯盏花素与灯盏花素联合洛伐他汀组CYP3A4酶mRNA 表达量均较空白组显著降低;CYP3A4酶蛋白含量结果表明,洛伐他汀组与灯盏花素联合洛伐他汀组与空白组比较CYP3A4酶蛋白含量均没有明显变化。结论 洛伐他汀与灯盏花素联用,灯盏花素通过抑制其基因转录水平抑制CYP3A4的活性,使大鼠体内药动学过程发生变化,洛伐他汀药物的代谢减慢。     

A new role for the Church. Dioceses should do more in providing care for dependent and dying persons

In 1988, with the publication of Catholic Health Ministry: A New Vision for a New Century, the Commission on Catholic Health Care Ministry called on the Church to redefine its healing mission in society. Unfortunately, despite various efforts, the Church has not yet fully articulated a shared vision of Catholic healthcare, healing, and support. Healing human brokenness has always been the Church's work in the world, whether the brokenness be physical, emotional, intellectual, moral, or spiritual. The Church, having a broader definition of brokenness than that of the larger healthcare system, must sometimes act as a countercultural critic of that system. Two of the great challenges facing healthcare today are providing care for dependent persons (people with chronic illnesses and older people) and for dying persons. In both cases, much more coordination of the various actors is needed. The Church could ensure that this coordination is carried out. In each diocese, the bishop should organize a pastoral health and social service planning group to assess community needs and apply Church resources to them. Local Catholic healthcare providers and social service agencies should develop a corporate culture of healing and support. Parishes should accept the idea that healing and supporting frail people are integral parts of parish life.     

Supplemental fructooligosaccharides and mannanoligosaccharides influence immune function, ileal and total tract nutrient digestibilities, microbial populations and concentrations of protein catabolites in the large bowel of dogs

The goal of this study was to examine whether supplemental fructooligosaccharides (FOS) and (or) mannanoligosaccharides (MOS) influenced indices of gut health of dogs. Adult female dogs (n = 4) surgically fitted with ileal cannulas were fed a dry, extruded, kibble diet twice daily. At each feeding, the following treatments were administered: 1) Control (no FOS or MOS); 2) 1 g FOS; 3) 1 g MOS; or 4) 1 g FOS + 1 g MOS. Fecal, ileal and blood samples were collected during the last 4 d of each 14-d period to measure protein catabolite concentrations, microbial populations, immune characteristics and nutrient digestibilities. Treatment means were compared using preplanned orthogonal contrasts. Dogs supplemented with MOS had lower (P = 0.05) fecal total aerobes and tended to have greater (P = 0.13) Lactobacillus populations. Ileal immunoglobulin (Ig) A concentrations were greater (P = 0.05) in dogs supplemented with FOS + MOS vs. control. Lymphocytes (% of total white blood cells) were greater (P < 0.05) in dogs supplemented with MOS. Serum IgA concentrations also tended (P = 0.13) to be greater in dogs supplemented with MOS. Dogs supplemented with FOS and FOS + MOS had lower (P < 0.05) fecal total indole and phenol concentrations. Dogs supplemented with MOS tended to have lower ileal DM (P = 0.149) and OM (P = 0.146) digestibilities vs. control. Results of this study suggest that dietary supplementation of FOS and MOS may have beneficial effects on colonic health and immune status of dogs.     

Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog

Cachectin/tumor necrosis factor has been implicated as a mediator of lethal endotoxemia, but the metabolic and hemodynamic responses to this macrophage-derived peptide have been incompletely characterized. Cachectin was administered by intra-arterial infusion in two groups of beagle dogs at lethal (100 micrograms per kilogram) and sublethal (10 micrograms per kilogram) doses. The infusion produced serum cachectin levels (1 to 50 nanomoles per liter) similar to those achieved after experimental endotoxemia. The lethal response to cachectin was characterized by progressive hypotension, shock and death within three hours. Histopathologic findings included acute inflammation of the pulmonary interstitium, intravascular thrombosis with hemorrhagic necrosis, adrenal medullary necrosis and acute renal tubular necrosis. Cachectin infusion precipitated significant increases of plasma catecholamines, cortisol and glucagon in a dose response manner. Cachectin infused directly into the isolated hindlimb mediated reductions of skeletal muscle resting transmembrane potential and stimulated lactate efflux. Cachectin appears to occupy a crucial role in physiopathologic responses to infection, and likely participates in the mobilization of host energy stores, intravascular depletion and shock after lethal endotoxemia.     

Acquired immune deficiency syndrome (AIDS) and neoplasia

The acquired immune deficiency syndrome (AIDS) is a novel epidemic form of immunodeficiency that has been widely recognized within the last six years. AIDS is characterized by Kaposi's sarcoma, B cell lymphoma, and/or life-threatening opportunistic infections superimposed on an immune deficiency state which consists of lymphopenia with a selective depletion of the CD4 T cells. In addition, lymphocytes from AIDS patients show decreased responses to antigen or mitogen stimulation in vitro. Although the secondary infections and malignancies seen in these patients may be successfully treated, the underlying immune defect persists, leaving the patient susceptible to further complications.     

Apparent digestibility and glycaemic responses to an experimental induced viscosity dietary fibre incorporated into an enteral formula fed to dogs cannulated in the ileum.

The purpose of this study was to evaluate the apparent digestibility and postprandial glycaemic responses of ileal-cannulated dogs when fed an experimental induced viscosity dietary fibre (IVF) incorporated into a liquid enteral formula. Dietary treatments were: (1) control; (2) Glucerna; (3) Glytrol; (4) IVF; and (5) Jevity. Diets varied in concentrations of crude protein (CP), fat, starch and total dietary fibre (TDF). Dry matter and starch intakes by dogs fed the Glucerna and Glytrol treatments were lower (P<0.05) than for those consuming the other diets. However, daily intakes of CP and fat followed a reverse trend. Digestibility of nutrients at the ileum was high (>80%) for all dietary treatments. Mineral absorption proximal to the ileum and from the total tract was not significantly different among treatments. Mean incremental area under the serum glucose response curves for dogs fed Glytrol, Glucerna, and IVF treatments were lower (P<0.05) than the control treatment. Induced viscosity fibre appears to have no negative effects on nutrient digestion throughout the gastrointestinal tract. Its ability to moderate serum glucose concentrations would make it a potentially good choice for a diabetic liquid formula.