GC-MS, MS/MS and GC-IR Analysis of a Series of Methylenedioxyphenyl-Aminoketones: Precursors, Ring Regioisomers and Side-Chain Homologs of 3,4-Methylenedioxypyrovalerone.

A combination of GC-MS, MS/MS and GC-IR techniques were used to characterize the ring substitution pattern, the alkyl side-chain and the cyclic tertiary amine portions of a series of six homologous and regioisomeric methylenedioxyphenyl-aminoketones related to the designer drug, 3,4-methylenedioxypyrovalerone (MDPV). Chromatographic retention increases with the hydrocarbon content of the alkyl side-chain and the 3,4-methylenedioxy substitution pattern shows higher retention than the corresponding 2,3-methylenedioxy isomer. The aminoketones show major peaks in their mass spectra corresponding to the homologous series of iminium cation fragments from the loss of the regioisomeric methylenedioxybenzoyl radical species. Deuterium labeling experiments confirm the iminium cation base peaks to undergo the loss of a hydrocarbon molecular fragment to yield product ions characteristic of the side-chain and pyrrolidine ring portion of the parent cathinone derivative. The mass spectra for the designer drug MDPV and its regioisomeric 2,3-methylenedioxy isomer show equivalent fragments including the base peak at m/z 126 and major product ion fragments at m/z 84. The ring substitution pattern for these two isomers was differentiated by characteristic absorption bands in the 1,500 -1,200 cm-1 range in their vapor phase IR. These characteristic bands can also be used to identify the aromatic ring substitution pattern in the regioisomeric precursor ketones.

Synthesis and GC-MS analysis of a series of homologs and regioisomers of 3,4-methylenedioxypyrovalerone (MDPV).

A series of ten homologous and regioisomeric aminoketones related to the designer synthetic cathinone derivative MDPV were evaluated in this study. These compounds were prepared from a common precursor chemical, piperonal (3,4-methylenedioxybenzaldehyde). These aminoketones show major peaks in their mass spectra corresponding to the regioisomeric and homologous immonium cation fragments from the loss of the methylenedioxybenzoyl radical species. All ten compounds in this study show equivalent EI MS fragments for the 3,4-methylenedioxybenzoyl fragments (m/z 149) and the methylenedioxybenzene fragment at m/z 121. The m/z 149 results from ionization of the carbonyl oxygen followed by an alpha-cleavage fragmentation. The loss of CO from this ion yields the m/z 121 fragments common to all spectra. The regioisomeric aminoketones yield equivalent mass spectra including mass equivalent regioisomeric immonium cation base peaks. A subset of these compounds has the same molecular weight and almost identical mass spectra to that of the designer drug MDPV. An evaluation of the effects of homologation on gas chromatographic retention showed that addition of a methylene (CH(2)) in the nitrogen-containing ring increases retention more than the equivalent group added to the alkyl side-chain.

The range of the Oxford Shoulder Score in the asymptomatic population: a marker for post-operative improvement.

INTRODUCTION: The Oxford Shoulder Score (OSS) is a validated scoring system used to assess the degree of pain and disability caused by shoulder pathology. To date there is no knowledge of the range of the OSS in the healthy adult population. This study aimed to establish the range in asymptomatic individuals. METHODS: The OSS of 100 asymptomatic volunteers was compared with the pre-operative OSS of 100 symptomatic individuals who had had elective shoulder surgery performed at the Royal Preston hospital. RESULTS: The difference in mean scores in the operated group (36.7) and the asymptomatic group (15.3) was statistically significant (p<0.0001). There was, however, a substantial overlap between the scores of the two groups (operated group range: 19-55, asymptomatic group range: 12-47). Factors such as age, sex, body mass index, co-morbidities and smoking did not have a statistically significant impact on the eventual score in the asymptomatic group. CONCLUSIONS: This study has established the range of OSS in the asymptomatic adult population. Symptom scores can only be used effectively when the range in the asymptomatic population is known. This is so that disease severity can be gauged in the context of the normal population and post-operative improvements can be forecast more accurately.

Sino-nasal assessment questionnaire: a specific outcome measure for rhinosinusitis, but what is the range in the asymptomatic population?

The sino-nasal assessment questionnaire is a system used for scoring the symptoms of chronic rhinosinusitis. However, the range of scores for this questionnaire in the healthy adult population is unknown. We aimed to establish this by recruiting 100 healthy volunteers and comparing their sino-nasal assessment questionnaire scores with those of 100 individuals who had undergone sinus surgery for rhinosinusitis. The difference in mean scores in the symptomatic group (44.62) and the asymptomatic group (8.46) was statistically significant. However, there was substantial overlap between the scores of the two groups. Factors such as age, gender and smoking did not have a statistically significant impact on the eventual score in the asymptomatic group. We believe that symptom scores can only be used effectively when the range in the asymptomatic population is known. This is so that disease severity can be gauged in the context of the normal population and post-operative improvements can be forecast.

The impact of the establishment of a surgical high dependency unit on management of abdominal aortic aneurysm.

BACKGROUND: Our ability to maintain satisfactory levels of outcome after elective abdominal aortic aneurysm (AAA) surgery is increasingly strained by rising levels of co-morbidity in the presenting population. In this study we present a comparative outcome analysis of patients undergoing elective AAA surgery 18 months before and after the establishment of a surgical high dependency unit (HDU). METHODS: The preoperative status (ASA and POSSUM scores), operative factors and postoperative outcomes as well as duration of stay were calculated for 104 patients undergoing elective AAA repair (57 prior to the HDU opening and 47 patients afterwards). RESULTS: Patients undergoing surgery in the latter period had significantly higher ASA (2.5 +/- 0.06 versus 2.7 +/- 0.7; p = 0.007), overall POSSUM (33.2 +/- 0.5 versus 35.5 +/- 0.8; p = 0.02) and physiological POSSUM (16.3 +/- 0.3 versus 15.5 +/- 0.2; p = 0.048) scores than those operated on prior to establishment of the HDU (data are mean +/- SEM; 2-tailed p-score). The two groups had similar total lengths of hospital stay (518 versus 534 days). However, following establishment of the HDU patients occupied fewer ICU bed days (110 versus 181). This resulted in a saving of Euro 50,750. CONCLUSION: The efficiency and quality of care following elective AAA surgery can be improved by provision of HDU step-down facilities without significantly increased expenditure.

A novel phospholipid derivative of indomethacin, DP-155 [mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido]hexanoyl}-sn-glycero-3-phosophatidyl [corrected] choline], shows superior safety and similar efficacy in reducing brain amyloid beta in an Alzheimer's disease model.

Indomethacin has been suggested for the treatment of Alzheimer's disease (AD), but its use is limited by gastrointestinal and renal toxicity. To overcome this limitation, D-Pharm Ltd. (Rehovot, Israel) developed DP-155 (mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] hexanoyl}-Sn-glycero-3-phosophatidyl [corrected] choline), a lecithin derivative of indomethacin. Safety was tested by daily oral administration of DP-155 or indomethacin to rats in a dose range of 0.007 to 0.28 mmol/kg. The prevalence of gastrointestinal ulceration was significantly lower (10-fold) for DP-155 than for indomethacin, and the ulcerations were delayed. Signs of renal toxicity, namely reduced urine output and increased urine N-acetyl glycosaminidase to creatinine ratio, were 5-fold lower for DP-155. Indomethacin, but not an equimolar dose of DP-155, reduced urine bicyclo-prostaglandin E(2). An equimolar oral dose of DP-155 or indomethacin, administered every 4 h for 3 days, was equally efficacious in reducing the levels of Abeta42 in the brains of Tg2576 mice. Indomethacin was the principal metabolite of DP-155 in the serum. After DP-155 oral administration, indomethacin's half-life in the serum and the brain was 22 and 93 h, respectively, compared with 10 and 24 h following indomethacin oral administration. The brain to serum ratio was 3.5 times higher for DP-155 than indomethacin. This finding explains the efficacy of DP-155 in reducing Abeta42 brain levels, despite the low systemic blood concentrations of indomethacin derived from DP-155. In conclusion, compared with indomethacin, DP-155 has significantly lower toxicity in the gut and kidney while maintaining similar efficacy to indomethacin in lowering Abeta42 in the brains of Tg2576 mice. This superior safety profile highlights DP-155's potential as an improved indomethacin-based therapy for AD.

Aorto-enteric fistula: changing management strategies.

BACKGROUND: Traditionally treatment of aorto-enteric fistulae involved placement of an extra-anatomic bypass and graft excision. This is associated with limb loss (10-40%) and high mortality (10-70%). More recently in situ revascularisation has been advocated. AIMS: To examine our experience with the changing management of aorto-enteric fistulae over a 22-year period. METHODS: Demographic, clinical, operative and pathological data were recorded retrospectively. RESULTS: Twenty-one patients were included. Seven had primary fistulae. Six died prior to intervention. Five had an extra-anatomical bypass (60% mortality, 40% limb loss), four had in-situ revascularisation (25% mortality), four had a primary repair (25% mortality) and two had insertion of a tube graft (primary fistulae). The overall survival rate was 38%. The postoperative survival rate was 6o%. CONCLUSION: Techniques for operative management continue to evolve. The current trend is towards a local surgical approach with prolonged and intensive postoperative antimicrobial therapy. In our experience this approach has yielded acceptable outcomes.

Experimental closed head injury: analysis of neurological outcome, blood-brain barrier dysfunction, intracranial neutrophil infiltration, and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines.

Cytokines are important mediators of intracranial inflammation following traumatic brain injury (TBI). In the present study, the neurological impairment and mortality, blood-brain barrier (BBB) function, intracranial polymorphonuclear leukocyte (PMN) accumulation, and posttraumatic neuronal cell death were monitored in mice lacking the genes for tumor necrosis factor (TNF)/lymphotoxin-alpha (LT-alpha) (TNF/LT-alpha-/-) and interleukin-6 (IL-6) and in wild-type (WT) littermates subjected to experimental closed head injury (total n = 107). The posttraumatic mortality was significantly increased in TNF/LT-alpha-/- mice (40%; P < 0.02) compared with WT animals (10%). The IL-6-/- mice also showed a higher mortality (17%) than their WT littermates (5.6%), but the difference was not statistically significant (P > 0.05). The neurological severity score was similar among all groups from 1 to 72 hours after trauma, whereas at 7 days, the TNF/LT-alpha-/- mice showed a tendency toward better neurological recovery than their WT littermates. Interestingly, neither the degree of BBB dysfunction nor the number of infiltrating PMNs in the injured hemisphere was different between WT and cytokine-deficient mice. Furthermore, the analysis of brain sections by in situ DNA nick end labeling (TUNEL histochemistry) at 24 hours and 7 days after head injury revealed a similar extent of posttraumatic intracranial cell death in all animals. These results show that the pathophysiological sequelae of TBI are not significantly altered in mice lacking the genes for the proinflammatory cytokines TNF, LT-alpha, and IL-6. Nevertheless, the increased posttraumatic mortality in TNF/LT-alpha-deficient mice suggests a protective effect of these cytokines by mechanisms that have not been elucidated yet.

Antioxidants attenuate acute toxicity of tumor necrosis factor-alpha induced by brain injury in rat.

Tumor necrosis factor-alpha alpha (TNF-alpha) and reactive oxygen species (ROS) are produced in the brain after traumatic injury and have deleterious effects. In a rat model of closed head injury (CHI), the synthetic antioxidant from the nitroxide family, Tempol, improved recovery and protected the blood-brain barrier. Similar protection was found after CHI in heat-acclimated rats, in which the endogenous antioxidants have been shown to be elevated after CHI. The present study examined the relationship between TNF-alpha and ROS after CHI, namely, whether after CHI, antioxidants that afforded cerebroprotection also attenuated brain levels of TNF-alpha. Three groups of rats were subjected to CHI: (1) control, nontreated, (2) Tempol-treated, and (3) heat-acclimated (30 days at 34 degrees C). Four hours after injury (time for peak production of TNF-alpha), the activity of TNF-alpha was measured. Although clinical recovery was facilitated in rats of the two treated groups, TNF-alpha activity was as high as in the traumatized, untreated rats. Moreover, direct injection of TNF-alpha into mouse brain induced disruption of the blood-brain barrier, indicating its acute harmful effect. This toxic effect was attenuated by before and after treatment with Tempol. Our results support the hypothesis that in vivo antioxidants neutralize TNF-alpha toxicity, probably by interfering with activation of the transcription factor NF-kappa-B.

The value of metastatic screening in early primary breast cancer.

Up to 25 per cent of patients presenting with "early" breast cancer subsequently develop distant metastases indicating that this group must have occult disseminated disease when initially evaluated. Routine pre-operative haematological and radiological investigation is recommended in order to identify these patients and alter their management accordingly. The aim of this study was to examine the outcome of a pre-operative metastatic screening programme in patients presenting with early breast cancer. Eighty-two patients underwent surgery for stage I-II breast cancer over a 5 yr period from 1990-1995. Before surgery all patients underwent screening tests for metastatic disease. These included a full blood count, liver function tests, chest x-ray, skeletal survey and abdominal ultrasound. Of the 82 patients, metastatic screening significantly altered management in only 1 patient who was found to have asymptomatic lymphangitis carcinomatosa on chest x-ray. The results of this study suggest that the number of patients restaged by screening for metastatic breast cancer may be small and questions the necessity for its routine use in the management of early primary breast cancer.

Sixteen months experience with cyclosporin-A in human kidney transplantation.

CY-A is a potent immunosuppressive agent and can prevent graft rejection. In our experience hirsutism and viral infections are marked. Lymphomas may be more common in CY-A-treated patients than in those treated conventionally. Smaller doses of CY-A given for shorter periods before conversion to conventional treatment may be a better way to use this new agent.