Reactions of morphine derivatives with phenyliodo(III)diacetate (PIDA): synthesis of new morphine analogues

The reactions of morphine and its derivatives with phenyliodo(III)diacetate (PIDA) have been studied. This methodology has not been introduced to morphine alkaloids, despite the fact that such a strategy would ensure dearomatization of the electrophilic aromatic ring of morphine derivatives leading to nucleophilic ortho-quinoidal structures with potential pharmacological interest. The products, formed in regio- and diastereoselective or diastereospecific reactions, carry mixed-acetal or 1,3-dioxolane moieties. At low concentrations 6a has mu-opioid agonist character but in higher concentrations showed a non receptorial antagonist effect on isolated mouse vas deferens.     

Effects of ayahuasca on sensory and sensorimotor gating in humans as measured by P50 suppression and prepulse inhibition of the startle reflex,respectively

Abstract Rationale. Ayahuasca, a South American psychotropic plant tea, combines the psychedelic agent and 5-HT_2A/2C agonist N,N-dimethyltryptamine (DMT) with β-carboline alkaloids showing monoamine oxidase-inhibiting properties. Current human research with psychedelics and entactogens has explored the possibility that drugs displaying agonist activity at the 5-HT_2A/2C sites temporally disrupt inhibitory neural mechanisms thought to intervene in the normal filtering of information. Suppression of the P50 auditory evoked potential (AEP) and prepulse inhibition of startle (PPI) are considered operational measures of sensory (P50 suppression) and sensorimotor (PPI) gating. Contrary to findings in lower animals, unexpected increases in sensorimotor gating have been found in humans following the administration of the serotonergic psychedelic psilocybin and the serotonin releaser 3,4-methylenedioxymethamphetamine (MDMA). In addition, to our knowledge P50 suppression has not been assessed previously in humans following the administration of a 5-HT_2A/2C agonist. Objectives. To assess the effects of the acute administration of ayahuasca on P50 suppression and PPI in humans, in order to evaluate the drug's modulatory actions on these measures of sensory and sensorimotor gating. Methods. Eighteen healthy volunteers with prior experience of psychedelic drug use participated in a clinical trial in which placebo or ayahuasca doses (0.6 mg and 0.85 mg DMT/kg body weight) were administered according to a double-blind, cross-over balanced design. P50 and startle reflex (pulse-alone and 60 ms, 120 ms, 240 ms and 2000 ms prepulse-to-pulse intervals) recordings were undertaken at 1.5 h and 2 h after drug intake, respectively. Results. Ayahuasca produced diverging effects on each of the two gating measures evaluated. Whereas significant dose-dependent reductions of P50 suppression were observed after ayahuasca, no significant effects were found on the startle response, its habituation rate, or on PPI at any of the prepulse-to-pulse intervals studied. Conclusion. The present findings indicate, at the doses tested, a decremental effect of ayahuasca on sensory gating, as measured by P50 suppression, and no distinct effects on sensorimotor gating, as measured by PPI. Electronic Publication     

Morphine tolerance in mice is independent of polymorphisms in opioid receptor sequences

Pharmacogenomics links individual drug response variation to genetic differences, such as single nucleotide polymorphisms (SNPs). In particular, pharmacogenomics will allow clinicians to use genetic diagnostics to predict the response of a patient to a drug. We investigated whether SNPs in opioid receptors correlated with the development of morphine tolerance in mouse strains that showed either high or low tolerance to morphine. Sequencing identified five silent SNPs in the delta opioid receptor that varied from the published sequence in some strains, but which were found in both high and low tolerance strains. The mu and kappa opioid receptor sequences had no SNPs. Taken together, these data definitively demonstrate that morphine tolerance development in mice is independent of opioid receptor sequence.     

Psychopharmacology in Psycho-oncology

Psychopharmacological intervention is a major clinical and research area in oncology and palliative care. Over the last 35 years, psychotropic drugs have been shown to have a number of important indications for the treatment of the most common psychiatric disorders, such as depression, anxiety, stress-related syndromes, severe adjustment disorders, sleep disorders and delirium, which combined affect at least 30-40% of patients with cancer and even a higher percentage of patients in an advanced phase of illness. The availability of new drugs, with less side-effects and safer pharmacological profiles, has been a major advance in clinical psycho-oncology. Interestingly, several drugs have also been found to be helpful for the adjuvant treatment of cancer-related symptoms, such as pain, hot flashes, pruritus, nausea and vomiting, fatigue, and cognitive impairment, making psychopharmacology an important tool for the improvement of cancer patients’ quality of life. The aim of this paper is to summarize recent relevant data concerning the use of psychotropic drugs, namely antidepressants, anxiolytics, antipsychotics, anticonvulsants and psychostimulants in patients with cancer.     

Orexin-A, an hypothalamic peptide with analgesic properties. (SmithKline Beecham Pharmaceuticals, Harlow, Essex, United Kingdom) Pain. 2001;92:81–90.

This study investigated the effects of acute and chronic tramadol treatment on T lymphocyte function and natural killer (NK) cell activity in rats receiving chronic constriction injury (CCI) of the sciatic nerve. T lymphocyte function was evaluated based on concanavalin-A (ConA)-induced and phytohemagglutinin (PHA)-induced splenocyte proliferation. NK cell activity was measured by lactic acid dehydrogenase release assay. The effects of tramadol on thermal hyperalgesia were also assessed by measuring paw withdrawal latency (PWL) in the rats. PWL was dose-dependently reversed by tramadol after acute treatment (single subcutaneous injection) with 10, 20, and 30 mg/kg, respectively. There was no significant change among acute treatments groups in NK cell activity, whereas splenocyte proliferation induced by ConA and PHA was significantly suppressed starting from a dose of 20 mg/kg. The reversal of the thermal hyperalgesia persisted throughout a period of chronic tramadol treatment of 40 and 80 mg/kg per day, respectively, with continuous subcutaneous infusion for 7 days at a uniform rate via osmotic minipumps. No modulation of NK cell activity was found in either dose group. However, the activity of splenocyte proliferation was decreased in the 80 mg/kg per day group when compared with the saline and 40 mg/kg per day groups. Suggest that tramadol treatment has an immunological profile different from pure μ-opioid agonists like morphine, which is known to suppress both NK cell activity and T lymphocyte proliferation at a subanalgesic dose in CCI rats. Conclude that tramadol treatment may be a better choice than morphine for treatment of chronic neuropathic pain, particularly in patients with compromised immunity.     

Relationship between the degree of osteolysis and cultures obtained by sonication of the prostheses in patients with aseptic loosening of a hip or knee arthroplasty

Introduction

The pathogenesis of prosthesis loosening is not well understood. The aim of our study was to sonicate components of joint prostheses removed due to aseptic loosening, culture the sonicate fluid, and to correlate these results with the degree of radiological osteolysis.

Methods

From January 2008 to June 2009 all consecutive patients who underwent a revision of hip or knee prosthesis due to aseptic loosening were included in the study. Aseptic loosening was established when the patient had radiological signs of loosening without symptoms or signs of infection. The diagnosis was confirmed when histology was negative, and ??5 out of 6 standard cultures of periprosthetic tissue were negative. Bone lysis was measured according to the Paprosky or Engh classifications without knowing the result of sonication cultures. Removed components were placed in sterile bags and immediately transported to the microbiology laboratory and sonicated. Sonicate fluid was cultured and the results were correlated with the degree of bone lysis. The proportion of components with positive sonication culture according to the bone lysis classification was compared using ??² test.

Results

A total of 52 patients were included and 123 components were sonicated. In 30 patients at least 1 sonicated component was positive (57.7%) and 44 out of 123 (35.8%) components were positive. The proportion of positive sonication cultures was significantly higher in the group of components with a higher degree of bone lysis of 3 (76.5%) than in those with lower degrees (33.9% for 1 and 24% for 2) (??² test, p?=?0.0004).

Conclusions

Sonication cultures were positive in 57% of patients who underwent revision arthroplasty for aseptic loosening. The percentage of positive sonication cultures was significantly higher in patients with severe osteolysis.

Level of evidence

level I of Prognostic Studies??Investigating the Effect of a Patient Characteristic on the Outcome of Disease.