The chemical and pharmacological importance of morphine analogues.

The object of this review is to summarize the efforts which resulted in the discovery of therapeutically useful morphine-like drugs. The search for new analgesics can be divided into three stages: (a) search for analgesics with high efficacy and reduced unwanted side-effects; (b) understanding of structure-activity relationships; (c) studies on the mechanism of pain perception and its alleviation by investigation of the pharmacology of opioids. An immense body of literature has been produced on the syntheses of thousands of new compounds which resulted in the development of detailed structure-activity relationships.

Employee resistance to organizational change: managerial influence tactics and leader-member exchange.

The authors explored the relationship between managerial influence tactics and employee resistance to organizational change. Using attribution theory, the authors developed a series of hypotheses concerning the effects of influence tactics on employee resistance to change and the ways in which these relationships are moderated by leader-member exchange. Results, which are based on multisource data, suggest that employee resistance reflects both the type of influence a manager uses and the strength of leader-member exchange.

Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma.

The aim of this retrospective analysis was to assess the benefit of reduced-intensity conditioning allo SCT (RIC allo-SCT) in a cohort of 32 relapsed multiple myeloma (MM) patients. A total of 19 patients had an HLA-identical sibling donor ('donor' group), while 13 patients had no donor ('no-donor' group). There were no significant differences between these two groups as for prognosis risk factors.

High response rate and improved graft-versus-host disease following bortezomib as salvage therapy after reduced intensity conditioning allogeneic stem cell transplantation for multiple myeloma.

We describe the results of 37 myeloma patients who received bortezomib following reduced intensity allogeneic stem cell transplantation (RIC-allo-SCT). Grade 1-2 peripheral neuropathy (35%), mild thrombocytopenia (24%) and fatigue (19%) were the most frequent adverse events, while there was no worsening of graft-vs-host disease symptoms. Twenty-seven patients (73%; 95% CI, 59-87%) achieved an objective response.

Cardiac capsaicin-sensitive sensory nerves regulate myocardial relaxation via S-nitrosylation of SERCA: role of peroxynitrite.

Background And Purpose: Sensory neuropathy develops in the presence of cardiovascular risk factors (e.g. diabetes, dyslipidemia), but its pathological consequences in the heart are unclear.

DAMGO and 6beta-glycine substituted 14-O-methyloxymorphone but not morphine show peripheral, preemptive antinociception after systemic administration in a mouse visceral pain model and high intrinsic efficacy in the isolated rat vas deferens.

Peripheral micro-opioid receptors (MOR) have emerged as important components of inhibitory nociceptive pathways. Here, the antinociceptive effects of MOR agonists, the 6beta-glycine derivative of 14-O-methyloxymorphone (HS-731), DAMGO and morphine were evaluated in a mouse model of visceral pain. The abdominal acetic acid-induced writhing test was used to examine the peripheral, preemptive antinociceptive opioid action on visceral nociception.

Purine ionotropic (P2X) receptors.

Purinergic signaling is involved in the proper functioning of virtually all organs of the body. Although in some cases purines have a major influence on physiological functions (e.g.

Ten-year follow-up of endometrial ablation.

Background: This paper presents a ten-year follow-up of a randomized, controlled trial which gives the long-term hysterectomy rate and patient satisfaction rate of transcervical hysteroscopic endometrial ablation in the treatment of heavy dysfunctional bleeding.

Methods: There were 120 women enrolled in the study, from June 10, 1993 to August 31, 1995, all requiring endometrial ablation for the treatment of heavy dysfunctional bleeding. All patients were offered a clinical examination two years postoperatively.

High-dose weekly liposomal amphotericin B antifungal prophylaxis following reduced-intensity conditioning allogeneic stem cell transplantation.

The use of high-dose corticosteroids for graft-versus-host disease (GVHD) treatment represents a major risk factor for long-term invasive fungal infections. The aim of this study was to investigate the safety and tolerance of weekly prophylactic administration of once-weekly high-dose (7.5 mg/kg) of liposomal amphotericin B (L-AmB) therapy in 21 adult patients receiving high-dose prednisone (2 mg/kg/day) for acute GVHD therapy after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT).

Low-dose methotrexate as salvage therapy for refractory graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation.

This study investigated the use of low dose methotrexate (MTX) (5 mg/m2/infusion) for the treatment of graft-versus-host disease (GVHD), after failure of corticosteroids. Twelve patients had refractory acute GVHD, while eight received MTX for severe chronic GVHD and/or the side effects of corticosteroids. Thirteen patients responded to MTX with six complete remissions and little toxicity, suggesting that low dose MTX is beneficial in refractory GVHD and deserves further investigations.

Alterations in prodynorphin gene expression and dynorphin levels in different brain regions after chronic administration of 14-methoxymetopon and oxycodone-6-oxime.

Previous studies showed that opioid drugs-oxycodone-6-oxime and 14-methoxy-5-methyl-dihydromorphinone (14-methoxymetopon)-produced less respiratory depressive effect and slower rate of tolerance and dependence, respectively. It was also reported that morphine decreased the prodynorphin gene expression in the rat hippocampus, striatum and hypothalamus. In this study, we determined the prodynorphin gene expression and dynorphin levels in selected brain regions of opioid tolerant rats.

Phenolphthalein and bisacodyl: assessment of genotoxic and carcinogenic responses in heterozygous p53 (+/-) mice and syrian hamster embryo (SHE) assay.

Phenolphthalein (800 and 2400 mg/kg/day by gavage and 2400 mg/kg/day by diet) and bisacodyl (800-500, 4000-2000, and 8000 mg/kg/day by gavage) were administered to 15 male and 15 female and 20 male and 20 female p53(+/-) mice respectively for 26 weeks to investigate the potential carcinogenicity of each compound. Toxicokinetic analyses confirmed systemic exposure. p-Cresidine was administered by gavage (400 mg/kg/day) and served as the positive control agent in each study.

Effects of miglyol 812 on rats after 4 weeks of gavage as compared with methylcellulose/tween 80.

Miglyol 812 is a medium-chain triglyceride used in toxicology studies as an excipient to improve test compound solubility/absorption. As part of a larger toxicology study, 15 Wistar Han IGS rats/sex/group were dosed by oral gavage for 4 weeks with 10 mL kg(-1) day(-1) of 100% Miglyol 812 or 0.5% methylcellulose/0.

Capsaicin-sensitive sensory neurons regulate myocardial function and gene expression pattern of rat hearts: a DNA microarray study.

We have previously shown that capsaicin-sensitive sensory nerves contribute to the regulation of normal cardiac function and to the development of cardiac adaptation to ischemic stress; however, the underlying molecular mechanisms remain unknown. Therefore, here we assessed cardiac functional alterations and relative gene expression changes by DNA microarray analysis of 6400 genes in rat hearts 7 days after the end of systemic capsaicin treatment protocol leading to selective sensory chemodenervation. Capsaicin pretreatment resulted in a cardiac dysfunction characterized by elevation of left ventricular end-diastolic pressure and led to altered expression of 80 genes of known function or homology to known sequences.

Decrease of current responses at human recombinant P2X3 receptors after substitution by Asp of Ser/Thr residues in protein kinase C phosphorylation sites of their ecto-domains.

The whole-cell patch-clamp technique was used to record current responses to nucleotides in HEK 293 cells transiently transfected with the human (h) P2X(3) receptor. When GDP-beta-S was included into the pipette solution, UTP at concentrations which did not alter the holding current, facilitated the alpha,beta-methylene ATP (alpha,beta-meATP)-induced current. The substitution of Ser/Thr residues situated within protein kinase C (PKC) consensus phosphorylation sites of the P2X(3) receptor ecto-domain by the neutral amino acid Ala either abolished (T134A, S178A) or did not alter (T196A, S269A) the UTP-induced potentiation of the alpha,beta-meATP current.

Regulation of human recombinant P2X3 receptors by ecto-protein kinase C.

The whole-cell patch-clamp technique was used to record current responses to nucleotides and nucleosides in human embryonic kidney HEK293 cells transfected with the human purinergic P2X3 receptor. When guanosine 5'-O-(3-thiodiphosphate) was included into the pipette solution, UTP at concentrations that did not alter the holding current facilitated the alpha,beta-methylene ATP (alpha,beta-meATP)-induced current. ATP and GTP, but not UDP or uridine, had an effect similar to that of UTP.

P2X and P2Y receptors as possible targets of therapeutic manipulations in CNS illnesses.

Adenine and/or uridine nucleotide-sensitive receptors are classified into two types belonging to the ligand-gated ionotropic family (P2X) and the metabotropic, G-protein-coupled family (P2Y). In humans, seven different P2X receptors (P2X(1-7)) and eight different P2Y receptors (P2Y(1), P2Y(2), P2Y(4), P2Y(6), P2Y(11-14)) have been detected hitherto. All P2 receptors are expressed in the CNS, with the preferential expression of the P2X(2), P2X(4), P2X(6) and P2Y(1) receptors in neurons.

Outcome and long-term follow-up of alloreactive donor lymphocyte infusions given for relapse after myeloablative allogeneic hematopoietic stem cell transplantations (HSCT).

In order to study efficacy, toxicity and the long-term results of donor lymphocyte infusions (DLI), we retrospectively analyzed DLI given for relapse after conventional allogeneic hematopoietic stem cell transplantation (HSCT) in 30 patients with a median delay of 107.5 months after transplant and 58 months after DLI. After DLI, 15 patients established full donor chimerism, three patients developed grade III and one grade IV acute GVHD.

Impact of chimaerism analysis and kinetics on allogeneic haematopoietic stem cell transplantation outcome after conventional and reduced-intensity conditioning regimens.

This retrospective study aimed to analyse the impact on overall survival (OS) and event-free survival (EFS) of chimaerism status and kinetics following allogeneic conventional and reduced-intensity conditioning haematopoietic stem cell transplantation, and to compare this with the impact of other well-known factors. We investigated the chimaerism status of 187 patients [84 females, 103 males; median age 39.5 years (range, 17-62 years)].