Nitric oxide and thromboxane A2-mediated pulmonary microvascular dysfunction

OBJECTIVES: To examine whether the lung releases nitric oxide (NO) in response to thromboxane A2 and to examine the local release of NO as a protective compensatory mechanism by which the lung responds to the proinflammatory and vasoactive effects of thromboxane A2. DESIGN: The lungs of anesthetized Sprague-Dawley rats were perfused in vitro with Krebs-Henseleit buffer that contained an inhibitor of NO synthase (nitroglycerinenitro-L-arginine methyl ester [L-NAME]) (10(-4) mol/L), an NO donor (sodium nitroprusside) (10(-8) mol/L), or perfusate alone. Following equilibration, the thromboxane A2 receptor agonist 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F2alpha(U-46619) (7.1 X 10(-8) mol/L) was added to the perfusate. Fifteen minutes later, the capillary filtration coefficient, pulmonary arterial pressure, and vascular resistance were measured. Pulmonary NO release was assessed by quantitating the release of cyclic guanosine monophosphate into the perfusate. RESULTS: The capillary filtration coefficient of lungs exposed to U-46619 was 3.5 times greater than that of lungs perfused with buffer alone (P<.05). The addition of sodium nitroprusside reduced the increase in capillary filtration coefficient associated with U-46619 by 50% (P<.05) whereas L-NAME had no effect. The addition of U-46619 to the perfused lung caused a 3.0+/-0.4 mm Hg increase in pulmonary artery pressure (P<.01) with a corresponding rise in total vascular resistance (P<.05). This effect was exacerbated by L-NAME (P<.05) and inhibited by sodium nitroprusside (P<.05). Exposure of the isolated lungs to U-46619 caused a 4-fold increase in cyclic guanosine monophosphate levels within the perfusate. CONCLUSION: These data are consistent with the hypothesis that NO release may be an important protective mechanism by which the lung responds to thromboxane A2.     

In vitro and in vivo characterisation of [3H]ANSTO-14 binding to the sigma 1 binding sites

N-(4-phenylbutyl)-3-hydroxy-4-azahexacyclo[5.4.1.0(2,6).0(3, 10).0(5,9) .0(8,11)]dodecane (ANSTO-14) showed the highest activity for the sigma 1 site (Ki = 9.4 nM) and 19-fold sigma 1/sigma 2 selectivity. The present study showed that [3H]ANSTO-14 binds to a single high-affinity site in guinea pig brain membranes with an equilibrium Ki of 8.0 +/- 0.3 nM, in good agreement with the kinetic studies (Kd = 13.3 +/- 5.4 nM, n = 4), and a Bmax of 3.199 +/- 105 fmol/mg protein (n = 4). The in vivo biodistribution of [3H]ANSTO-14 showed a high uptake in the diencephalon. Pretreatment of rats with sigma ligands including (+)-pentazocine (sigma 1), ANSTO-14 (sigma 1), and DTG (sigma 1 and sigma 2) did not significantly reduce radiotracer uptake in the brain, but did in the spleen. A labelled metabolite was found in the liver and brain. Due to its insensitivity to sigma ligands, the accumulation of [3H]ANSTO-14 in the brain indicates high nonspecific binding. Therefore, [3H]ANSTO-14 is a suitable ligand for labelling sigma 1 sites in vitro but is not suitable for brain imaging of sigma binding sites in vivo.     

Combining non-depolarizing neuromuscular blocking agents: synergism, addition or antagonism?

As the quality of currently available relaxants has improved, the need to combine relaxants to minimize the incidence and severity of their side-effects has decreased. Little work has been done in the past year characterizing the effects of combining different non-depolarizing neuromuscular blocking agents. That which has been done sheds some light on the nature of their interactions.     

One and the same androgen for all? Towards designer androgens

The introduction of designer oestrogens as a treatment modality in hormone replacement in women has invited to consider the concept of compounds with selective androgenic effects for male hormone replacement therapy. The full spectrum of the actions of testosterone may not be necessary of even undesired for certain indications for testosterone treatment. To define for what indications certain androgenic properties are desired and undesired more insight in basic androgen (patho)physiology is required. There is convincing evidence that aromatization of androgenic compounds to oestrogens might be an advantage for maintenance of bone mass and it might also mitigate negative effects of androgens on biochemical parameters of cardiovascular risks; the potentially negative effects of oestrogens on prostate pathology in ageing men needs further elucidation. While the role of dihydro-testosterone (DHT) for the male sexual differentiation and for pubertal sexual maturation is evident, its role in mature and ageing males seems less significant or may even be harmful. It is, however, of note that a negative effect of DHT on prostate pathophysiology is certainly not proven. For male contraception a progestational agent with strong androgenic properties might be an asset. For most of the androgenic actions the critical levels of androgens are not well established. The latter is relevant since the large amount of androgen molecules required for its biological actions (as compared to oestrogens) is an impediment in androgen replacement modalities. There may be room for more biopotent androgens since delivery of large amounts of androgen molecules to the circulation poses problems for treatment modalities.     

Quantification of blood--aqueous barrier breakdown after trabeculectomy: pseudoexfoliation versus primary open-angle glaucoma

PURPOSE: Impairment of the blood-aqueous barrier in unoperated eyes with pseudoexfoliation syndrome has been demonstrated by fluorescein angiography, fluorophotometry, measurement of aqueous flare, and determination of aqueous protein. We performed noninvasive quantification of aqueous flare using the laser flare-cell meter to compare blood-aqueous barrier breakdown after trabeculectomy in eyes with primary open-angle glaucoma (POAG) and in eyes with pseudoexfoliative glaucoma (PEX). METHODS: Twenty eyes with PEX and 20 eyes with POAG were included in the study. Trabeculectomy was performed by two surgeons according to a standard trabeculectomy technique. Intra- and postoperative treatments were identical in both groups. Aqueous flare was quantitatively determined using the laser flare-cell meter FC-1000 (Kowa, Tokyo, Japan) before and 3, 5, 7, and 9 days after trabeculectomy. Absolute flare and difference between post- and preoperative flare values were statistically analyzed using the Mann-Whitney U-Test for independent samples. RESULTS: Before surgery, aqueous flare values were significantly higher in PEX than in POAG. On days 3, 5, 7 and 9 after surgery, flare values were significantly higher in eyes with PEX than in eyes with POAG. Absolute differences between post- and preoperative flare values also were significantly higher in eyes with PEX, but this was not true for percentage values. CONCLUSION: These results show that substantial blood-aqueous barrier breakdown occurs in eyes with PEX after trabeculectomy. These alterations may contribute to early or late complications of trabeculectomy and indicate the need for close postoperative follow-up evaluation in eyes with PEX.     

Retigabine N-glucuronidation and its potential role in enterohepatic circulation.

The metabolism of retigabine in humans and dogs is dominated by N-glucuronidation (), whereas in rats, a multitude of metabolites of this new anticonvulsant is observed (). The comparison of the in vivo and in vitro kinetics of retigabine N-glucuronidation in these species identified a constant ratio between retigabine and retigabine N-glucuronide in vivo in humans and dog. An enterohepatic circulation of retigabine in these species is likely to be the result of reversible glucuronidation-deglucuronidation reactions. Rats did not show such a phenomenon, indicating that enterohepatic circulation of retigabine via retigabine N-glucuronide does not occur in this species. In the rat, 90% of retigabine N-glucuronidation is catalyzed by UDP-glucuronosyltransferase (UGT)1A1 and UGT1A2, whereas family 2 UGT enzymes contribute also. Of ten recombinant human UGTs, only UGTs 1A1, 1A3, 1A4, and 1A9 catalyzed the N-glucuronidation of retigabine. From the known substrate specificities of UGT1A4 toward lamotrigine and bilirubin and our activity and inhibition data, we conclude that UGT1A4 is a major retigabine N-glucuronosyl transferase in vivo and significantly contributes to the enterohepatic cycling of the drug.     

Synthetic nerve graft containing collagen and synthetic Schwann cells inproves functional, electrophysiological, and histological parameters of peripheral nerve regeneration

Current methods of peripheral nerve repair are to directly suture cut nerve stumps, or to bridge large gaps with an autograft repair. Autograft-associated problems include donor site morbidity and limited supply. Many of the present limitations of nerve repair might be overcome by expanding the patients own Schwann cells in vitro, then combining the cells with other neuro-tropic and -trophic materials into an Artificial Nerve Graft (ANG) for bridging a nerve gap. In this 4.5 month experiment, a rat peroneal nerve model with a 10 mm gap was used to evaluate the effect of live Schwann cells on peripheral nerve regeneration. Nerve gaps were repaired with cellular ANGs containing live Schwann cell, dead Schwann cell, or mixed fibroblast/Schwann cell populations suspended in a collagen I matrix, and with sutured autografts or ANGs containing just collagen or medium. Regenerated nerves were evaluated by walking track analysis, qualitative and quantitative histology, and electrophysiology. Overall, the autograft was the best repair method, while the ANG containing live Schwann cells was statistically superior to other ANG repair methods. This study demonstrates that an ANG containing cultured syngeneic Schwann cells improves functional, histological, and electrophysiological parameters of peripheral nerve regeneration.     

Personality of the parkinsonian. Clinical and psychometric approach

The personality of patients suffering from Parkinson's disease has been considered as the basis of a psychosomatic theory or more simply as a form of reaction. Between these two extremes the controversy continues and is modified by the use of dopaminergic agents. In this study, 30 patients suffering from parkinson's disease undergo a psychological examination and a M.M.P.I.; the results allow us to determine a pre-morbid obsessive personality coupled with agressivity and ambition. A transformation occurs with the arrival of illness; dependence, passivity, suggestibility evolve in a context where anxiety is relieved of all agressivity but acquires a depressive character. The people surrounding the patients play a part in this transformation. Moreover the pre-morbid characteristics of these patients remind the physician of H. Tellenbach's "typus melancholicus".     

Cancer chemotherapy in the elderly: a series of 51 patients aged>70 years

Summary A total of 2,238 new cancer patients were treated in our institution in 1988; among the 423 (18.9%) who were>70 years old, 51 underwent chemotherapy. The median age was 75.8 years, and the Karnofsky performance status (KPS) was 70% for 40 patients. Malignancies were hematopoietic in 24 cases (47%) and digestive in 15 patients (29%), and 12 subjects (24%) had other types of cancers. The first chemotherapy course was given at the full dose to 23/51 (45.1%) patients. The drug dose was reduced for 28/51 (54.9%) patients, due in 25 cases to the subjects being>70 years old. Neither age, KPS, pretreatment assessment, nor cancer extent was correlated with the modifications made to the first cycle. An overall toxicity of grade 3+4 (WHO grading scale) was noted in 10 subjects (19.6%). Although these elderly patients were probably selected, analysis of their charts did not evidence an increase in chemotherapy toxicity, regardless of the dose they received.Presented at the EORTC Pharmacokinetics and Metabolism Group Meeting, Bordeaux, November 1990