Analgesic profile of the sodium salt of pemedolac

Pemedolac Na, 1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)-pyrano [3,4-b] indole-1-acetic acid sodium salt, exhibited equipotent analgesic effects after oral, iv, and im administration, suggesting that it is well absorbed. In mouse writhing models, the ED₅₀ values ranged from 0.3 mg (0.81 μmol)/kg (vs. acetylcholine) to 4.3 mg (11.6 μmol)/kg (vs. paraphenylbenzoquinone [PBQ]). In the rat Randall-Selitto model, the ED₅₀ o the compound was approximately 0.001 mg (2.7 nmol)/kg, with a flat dose response curve. The peak effects lasted for 7–9 h, 10–18 h, and 5 h following oral, im, and iv injections, respectively. Intracerebroventricular (i.c.v.) injections of pemedolac Na inhibited the PBQ-induced writing in mice with an ED₅₀ of 43.5 μg (0.12 μmol)/mouse, and this effect was not antagonized by naloxone. It was inactive in the hot plate and tail flick tests, demonstrating that pemedolac Na does not act via an opiate mechanism. These results indicate that pemedolac Na is a viable parenteral and oral analgesic, typified by high analgesic potency, a rapid onset and long duration of action, and an extremely wide safety index. © Wiley-Liss, Inc.     

Exogenous Modulation of TGF-β1 Influences TGF-βR-III-Associated Vascularization during Wound Healing in Irradiated Tissue

BACKGROUND AND PURPOSE: Following preoperative radiotherapy prior to ablative surgery of squamous epithelial cell carcinomas of the head and neck region, wound-healing disorders occur. Previous experimental studies showed altered expression of transforming growth factor-(TGF-)beta isoforms following surgery in irradiated graft beds. Altered levels of TGF-beta(1) are reported to promote fibrosis and to suppress vascularization during wound healing, whereas expression of TGF-beta receptor-III (TGF-betaR-III) is associated with vascularization. The aim of the study was to analyze the influence of anti-TGF-beta(1) treatment on TGF-betaR-III-associated vascularization in the transition area between irradiated graft bed and graft. MATERIAL AND METHODS: Wistar rats (male, weight 300-500 g) underwent preoperative irradiation of the head and neck region with 40 Gy (four fractions of 10 Gy each; n = 16 animals). A free myocutaneous gracilis flap taken from the groin was then transplanted to the neck in all rats. The time interval between operation and transplantation was 4 weeks. Eight animals received 1 micro g anti-TGF-beta(1) into the graft bed by intradermal injection on days 1-7 after surgery. On days 3, 7, 14, 28, 56, and 120, skin samples were taken from the transition area between transplant and graft bed and from the graft bed itself. Immunohistochemistry was performed using the ABC-POX method to analyze the TGF-betaR-III and E-selectin expression. Histomorphometry was performed to analyze the percentage and the area of positively stained vessels. RESULTS: A significantly higher expression of TGF-betaR-III was seen in the irradiated and anti-TGF-beta(1)-treated graft bed in comparison to the group receiving preoperative irradiation followed by transplantation alone. The percentage of TGF-betaR-III positively staining capillaries from the total amount of capillaries in the anti-TGF-beta(1)-treated graft bed was higher than in the group irradiated only. The total area of capillaries was also higher in the TGF-beta(1)-treated group. CONCLUSION: Neutralizing of TGF-beta(1) activity in irradiated tissue undergoing surgery leads to a higher expression of TGF-betaR-III and increased vascularization. TGF-betaR-III seems to be associated with newly formed blood vessels during neovascularization in wound healing.     

Efficacy and safety of topical application of human fibrinogen/thrombin-coated collagen patch (TachoComb) for treatment of air leakage after standard lobectomy.

OBJECTIVES: Persisting air leakage after pulmonary resection remains a significant problem. The aim of the study was to evaluate the incidence of air leakage after standard lobectomy and test the efficacy and safety of TachoComb (TC). METHODS: A total of 189 patients undergoing lobectomy were enrolled in a multi-centre, open, randomised, and prospective study to test the efficacy and safety of TachoComb (TC) for air leakage treatment. Air leakage was assessed by water submersion test, and scored as grades 0 if no, 1 if countable, 2 if a stream of and 3 if coalescent bubbles have been observed. Any sites with grade 3 air leakage received further stapling or limited suturing until grade 0, 1 or 2 was obtained. Treatment of air leakage was done with TC or suturing according to randomisation. Air leakage was assessed by further submersion tests. Postoperative air leakage was assessed using the Pleur-Evac system. RESULTS: Overall incidence of air leakage 48+/-6 h after surgery was 34% for TC and 37% for standard treatment (P=0.76). The reduction of intra-operative air leak intensity in the subgroup with grades 1-2 was significantly higher for the TC group (P=0.015). Postoperative air leakage intensity in the subgroup with air leakage grades 1-2 was lower for TC than standard treatment (P=0.047). The mean duration of postoperative air leakage in the subgroup with grades 1-2 was shorter for the TC group than for standard treatment, i.e. 1.9+/-1.4 vs. 2.7+/-2.2 days (P=0.015). CONCLUSIONS: TC could be proven as well-tolerated and safe. In the subgroup of patients with established air leakage, TC showed superior potential in reduction of intra-operative air leakage as well as in reduction of intensity and duration of postoperative air leakage.     

Highly resolved in vivo 1H NMR spectroscopy of the mouse brain at 9.4 T.

An efficient shim system and an optimized localization sequence were used to measure in vivo 1H NMR spectra from cerebral cortex, hippocampus, striatum, and cerebellum of C57BL/6 mice at 9.4 T. The combination of automatic first- and second-order shimming (FASTMAP) with strong custom-designed second-order shim coils (shim strength up to 0.04 mT/cm2) was crucial to achieve high spectral resolution (water line width of 11-14 Hz). Requirements for second-order shim strengths to compensate field inhomogeneities in the mouse brain at 9.4 T were assessed. The achieved spectral quality (resolution, S/N, water suppression, localization performance) allowed reliable quantification of 16 brain metabolites (LCModel analysis) from 5-10-microL brain volumes. Significant regional differences (up to 2-fold, P < 0.05) were found for all quantified metabolites but Asp, Glc, and Gln. In contrast, 1H NMR spectra measured from the striatum of C57BL/6, CBA, and CBA/BL6 mice revealed only small (<13%, P < 0.05) interstrain differences in Gln, Glu, Ins, Lac, NAAG, and PE. It is concluded that 1H NMR spectroscopy at 9.4 T can provide precise biochemical information from distinct regions of the mouse brain noninvasively that can be used for monitoring of disease progression and treatment as well as phenotyping in transgenic mice models.     

Correlation with age and sex of flash-evoked electroretinogram and retinal oscillatory potentials recorded with skin electrodes

Electroretinograms and retinal oscillatory potentials to full-field flash stimulation were recorded by dermal electrodes in a population of subjects (1 to 84 yrs) balanced for age and sex (119 females, 133 males), without evidence or history of ocular and/or relevant systemic diseases. The electroretinogram latencies and b-wave amplitude increased, while the a-wave amplitude decreased linearly with age. The oscillatory potential amplitude initially increased, to decrease approximately at the age of 50, with an inverted U-shaped distribution.Presented in part at the XXV ISCEV Symposium, Sarasota (Florida), April 26–30, 1987.     

Haemodynamics as a determinant of the pharmacokinetics of and the plasma catecholamine responses to isoprenaline

Summary The total body clearance and fractional extraction of isoprenaline (ISO) have been determined, and the relation between these parameters and cardiac output established. Whether desipramine, an inhibitor of neuronal uptake, altered the plasma catecholamine response to ISO was also investigated.Seven healthy subjects were given i.v., infusions of ISO in two, consecutive 25-min periods, at constant dose rates of 31–43 and 80–124 pmol·kg^–1·min^–1, respectively. The total-body (ER), pulmonary (ER_p) and forearm (ER_f) fractional extractions and the total body clearance (CL) of ISO were obtained from measurements of cardiac output and the steady-state ISO concentration in mixed central venous, arterial and forearm venous plasma.ISO-induced increases in cardiac output resulted in increases in CL, decreases in ER and no consistent change in ER_f. ER_p did not differ from zero. ISO also produced a dose-dependent increase in the mixed venous plasma concentrations of noradrenaline and 3,4-dihydroxyphenylglycol (DOPEG), and a decrease in that of adrenaline. Pretreatment with desipramine did not alter any of the pharmacokinetic parameters of ISO. Desipramine, however, reduced the mixed venous baseline plasma levels of noradrenaline (47%) and DOPEG (40%), and tended to reduce that of adrenaline (34%). It enhanced the plasma noradrenaline response 2.4-fold, abolished the plasma DOPEG response and did not alter the plasma adrenaline response to ISO.Hence, owing to its haemodynamic effects, ISO modifies its own pharmacokinetics which involve non-neuronal removal processes only. The increased DOPEG in plasma resulting from the ISO-induced increase in noradrenaline release was presynaptic in origin. Desipramine appears to reduce sympathetic activity. The enhancement by desipramine of the ISO-induced increase in plasma noradrenaline points towards recapture by neuronal uptake of at least 58% of the noradrenaline released in response to ISO.     

Erbpathologische Hinweise in Morgagnis Hauptwerk: De sedibus et cansis morborum

Ohne Zusammenfassung     

The first two cases of living donor liver transplantation using dual grafts in Europe.

The major limitation in adult-to-adult living donor liver transplantation (LDLT) is an adequate graft size with special regard to the safety of the donor. Only 20% of the evaluated donors are suitable to donate the right liver, depending mainly on the critical remnant liver volume. We report 2 cases of adult-to-adult LDLT using dual grafts. In the first case we implanted a left lateral lobe together with a left lobe; in the second case we used a left lateral and a right lobe. Dual graft LDLT solves the problem of graft-size insufficiency and avoids critical right lobectomy in the donor. This procedure can be safely performed and opens up the possibility of LDLT to even more families in the Western world.