Interactions of NMDA antagonists and an alpha 2 agonist with mu,delta and kappa opioids in an acute nociception assay

Animal and clinical studies have reported potentiation of opioid antinociception by co-administration of alpha-2 adrenoceptor agonists such as clonidine and NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available compounds in combination with classical morphine, fentanyl-like opioids, the delta opioid agonist SNC80 and the kappa opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of clonidine, ketamine or dextromethorphan. Clonidine was also evaluated in combination with ketamine and dextromethorphan. ED50 values were calculated from the proportion of animals reaching a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED50 values for morphine, fentanyl and sufentanil but exerted no effect on SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive efficacy of morphine and sufentanil but not SNC80 or U50,488H. By contrast, clonidine potentiated all opioids tested. In addition, the potency of clonidine was found to increase with co-administration of ketamine but not dextromethorphan. The strongest opioid sparing interactions occurred between clonidine and the lipophilic mu opioids fentanyl and sufentanil and the delta opioid SNC80. In summary, these results suggest an important role for lipophilic opioids in combination therapies particularly with clonidine as well as possible advantages of specific delta or kappa opioid combinations with alpha-2 agonists.     

Comparison of tension-band and figure-of-eight wiring techniques for treatment of olecranon fractures

Two different internal fixation techniques for closed displaced fractures of the olecranon were evaluated at a mean of 18 years after injury. Thirty-two of the patients received tension-band wiring, and 35 received figure-of-eight wiring. There were 41 women (mean age, 52 years) and 26 men (mean age, 32 years) included. The results revealed that 80% of the patients had no subjective complaints, 16% had occasional pain, and 4% had daily pain. Comparison of the injured and uninjured elbows demonstrated a 3 degrees reduction of flexion (P <.05) and a 5 degrees loss of extension (P <.01). More than 50% of the fractured elbows had degenerative changes (joint space narrowing, subchondral cysts, subchondral sclerosis, and osteophytes) (P <.001), and 4 had osteoarthritis (P <.05). No subjective, objective, or radiographic differences were found when the two techniques were compared. Removal of the hardware was performed in 81% of the patients with tension-band wiring and in 43% of the patients with figure-of-eight wiring (P <.01). The figure-of-eight technique can, therefore, be recommended, as it is associated with less frequent secondary procedures for hardware removal.     

Contribution of solid-state properties to the aqueous solubility of drugs.

This study investigates the influence of the solid-state properties melting point (T(m)), enthalpy of melting (DeltaH(m)) and entropy of melting (DeltaS(m)) of a drug on its intrinsic solubility (S(0)). For this purpose, 26 chemically and structurally diverse drugs covering the oral drug space were selected and the S(0), T(m), DeltaH(m) and DeltaS(m) were determined experimentally. The influence of T(m), DeltaH(m) and DeltaS(m) on S(0) was studied using regression analysis. The overall improvement of the predictions were 0.3 log units, however, five compounds (astemizole, glyburide, fenbufen, gliclazide and griseofulvin) were improved by more than one log unit. T(m) and DeltaH(m) had a larger effect than DeltaS(m) on the solubility predictions. The well-known general solubility equation (GSE) and the Dannenfelser semi-empirical equation for the calculation of DeltaS(m) were evaluated using our data set. While predictions of drug solubility obtained using the GSE were acceptable, the use of the experimental DeltaS(m) values instead of the constant 56.5 J mol(-1)K(-1) improved the accuracy of the prediction. The Dannenfelser equation underestimated the DeltaS(m) for most compounds with on average 15 J mol(-1)K(-1). Our results show that solid-state properties should be considered for improved performance of future models for prediction of drug solubility. In addition our study provides accurate experimental data on intrinsic solubility for 26 compounds, supplying a useful external data set for validation of drug solubility models.     

VEGF and VEGF receptor-1 concentration in vestibular schwannoma homogenates correlates to tumor growth rate.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is one of the most potent mediators of angiogenesis, which is a mandatory process during tumor growth. Immunohistochemical studies have demonstrated VEGF expression in vestibular schwannomas (VS), and a semi-quantitation of staining intensity indicated a correlation between tumor growth rate and VEGF expression. The present objectives were to determine the concentration of VEGF and the high-affinity receptor VEGFR-1 in VS homogenates and to examine a possible correlation with symptom duration, tumor size, or growth rate. STUDY DESIGN, PATIENTS, AND METHODS: Prospective selection of 27 patients with VS growth determined by repeated magnetic resonance imaging. Patient files were reviewed for symptom duration and all magnetic resonance images reviewed for determination of tumor size and growth rate. ELISA was used for determination of the VEGF and VEGFR-1 concentration in tumor homogenates. SETTING: Tertiary University Hospital Clinic. RESULTS: All tumor homogenates contained VEGF and VEGFR-1. A significant correlation existed between the concentration of both VEGF and VEGFR-1 and tumor growth rate but not symptom duration or tumor size. CONCLUSION: The concentration of VEGF and VEGFR-1 in VS homogenates correlates with tumor growth rate but not with tumor size or symptom duration. We conclude that VEGF and VEGFR-1 appear to be directly involved in the growth pattern of VS.     

Influence of arm movements on saccades in humans

When reaching for an object we usually look at it before we touch it with the hand. This often unconscious eye movement prior to the arm movement allows guiding of the final part of the hand trajectory by visual feedback. We examined the temporal and spatial coordination of this control system by psychophysical measurements of eye and arm movements of naive human subjects looking or looking and pointing as fast as possible to visual targets in physical and virtual-reality setups. The reaction times of saccades to a step-displaced target were reduced, and the number of corrective saccades decreased, when the subject had to produce a corresponding simultaneous hand movement to the same target. The saccadic reaction time was increased when saccade and hand movement went in opposite directions. In a double-step task the reaction time for the second saccade was longer than for the first. Co-use of the hand leads to an additional increase of saccadic reaction time. Taken together this study shows an improvement in initial saccades if they are accompanied by hand movements to the same target. This effect might ensure that the reach target is foveated early and accurately enough to support the visual feedback control of the hand near the target. Longer reaction times for the second saccade to double-step displaced targets might reflect a saccadic refractory time intensified by simultaneous arm movements. These results are discussed in the light of recent findings from our laboratory on saccade- and reach-related neurons in the superior colliculus of macaque monkeys.     

Variant of Klippel-Trenaunay syndrome. A case report

Klippel-Trenaunay-Syndrome is a rare congenital vascular malformation with cutaneous naevi, varicose veins and limb hypertrophy. We report a patient with a variant of this syndrome presenting with extensive varicose veins and arteriovenous shunts within the left arm, bony hypotrophy of the left hand, mucocutaneous melanin spots in the face and thrombocytopenia. Imaging techniques play a major role in making a diagnosis in angiophakomatoses.     

Reversible cyclosporin A-induced leukoencephalopathy: a case report and differential diagnosis discussion

The pathogenesis of Cyclosporin A (CsA) induced toxic leukoencephalopathy is unclear. CCT and CMRI reveal hypodense respectively hyperintense bilateral and symmetrical changes predominantly in the posterior white matter. We report a patient with a severe CsA induced toxic leukoencephalopathy in whom clinical symptoms (complete loss of brainstem functions, coma) and morphological changes in CCT and CMRI were completely reversible after immunosuppression with CsA has been stopped. We furthermore discuss the differential diagnoses of CCT and CMRI findings.