实验性矽肺支气管肺泡灌洗液及血清中脂质过氧化物含量的动态变化

本文对实验性矽肺大鼠支气管肺泡洗液(BALF)和血清中脂质过氧化物(LPO)含量进行动态观察。对矽肺发病机理进行初步探讨。实验结果表明:不同染尘时间矽肺大鼠,在BALF和血清中LPO的含量均高于对照组。差别有显著或非常显著性(P<0.05或P<0.01)。提示SiO_2能诱发肺组织产生大量自由基,细胞或细胞膜的脂质过氧化反应引起细胞的破坏,崩解,最终导致矽肺病变的发生和发展。     

Erbium-YAG and holmium-YAG laser ablation of bone

Results are presented for the latent heat of ablation of bone using an erbium-YAG laser operating at 2.9m, and a holmium-YAG laser operating at 2.1m. The values are 8.2±1.0 kJ cm^–3 and 18±2.0 kJ cm^–3, respectively. Secondary damage to surrounding tissue is found to extend approximately 5m with the erbium laser and is greatly increased to 80m with significant charring in the case of holmium. These secondary damage zones are much smaller than those produced by the CO₂ laser.     

Pharmacokinetics and pharmacodynamics of cicaprost in healthy volunteers after oral administration of 5 to 20 μG

Summary In a Phase I study, the tolerability, pharmacodynamics and pharmacokinetics of cicaprost have been investigated in 6 male volunteers given 5, 10, 15 and 20 g as tablets of the -cyclodextrin clathrate.Individual inhibition of platelet aggregation and changes in facial colour (measured by chromametry) were dose-dependent and reached a maximum 30 to 60 min post-dose. The maximum inhibition of platelet aggregation was about 40%. After 3 to 4 h pre-treatment values had returned. Blood pressure remained within the normal range. The peak plasma level of cicaprost was reached within 15 to 90 min after drug intake. Both C_max-and AUC were individually dose-dependent. The terminal half-life in plasma of cicaprost was approx. 1 h, and its total clearance amounted to 4–7 ml·min^–1·kg^–1. The time courses of the plasma levels and of the pharmacodynamic actions were in agreement. Interindividual differences were observed in the occurrence of unwanted effects (e.g. headache).Thus, cicaprost is an orally available PGI₂-mimetic, for which effects on platelet aggregation and vascular perfusion have been demonstrated in healthy volunteers after doses of 5 to 15 g.The results will form part of the M.D. thesis of T.Staks. Some of the findings were presented at the CPT meeting, Mannheim/Heidelberg, 1989     

Effects of taprostene,a stable prostacyclin analogue,on haemodynamics,platelet function and arachidonate metabolism in healthy volunteers

Summary In order to assess the effect of taprostene on haemodynamics, platelet function and arachidonate metabolism in 4 healthy volunteers an intravenous infusion of 25 ng · kg^–1 · min^–1 was given for 6 h.During the infusion period systolic blood pressure dropped from 130 to 111 mm Hg and diastolic blood pressure from 77 to 69 mm Hg. The heart rate rose from 77 to 84 beats/min.During the taprostene infusion the slope and height of the ADP and collagen induced platelet aggregation curves were significantly inhibited and the sensitivity of platelets to PGI₂ and PGE₁ was increased.Plasma and serum thromboxane B₂, conversion of exogenous radiolabelled arachidonic acid, WU-test, circulating endothelial cell count, concentration of platelet factor 4, -thromboglobulin, malondialdehyde and the PGI₂-synthesis stimulating plasma factor did not show any clear drug-related alteration.It is concluded that infusion of taprostene 25 ng · kg^–1 · min^–1 caused measurable inhibition of platelet function ex vivo.     

“In vitro” and “ex vivo” effects of picotamide,a combined thromboxane A2-synthase inhibitor and -receptor antagonist,on human platelets

Summary Picotamide (G 137), a new non prostanoid inhibitor of in vitro arachidonic acid induced platelet aggregation, has been further characterized in in vitro and ex vivo studies.When whole blood was activated with collagen in the presence of picotamide 5×10^–4 M, thromboxane B₂ production was decreased, and 6-keto-PGF₁ generation was significantly increased, suggesting a reorientation of platelet endoperoxide metabolism following blockade of thromboxane synthetase. Picotamide also inhibited platelet aggregation and clot retraction induced by the endoperoxide analogue U46619 in human platelets, indicating thromboxane A₂-receptor antagonism, possibly of competitive nature.A single oral dose of picotamide 1 g in 24 healthy volunteers produced a significant inhibition of collagen, arachidonic acid and U46619-induced platelet aggregation. Serum levels of thromboxane B₂ were also reduced.Chronic administration of picotamide 1.2 g/d to patients with vascular disease resulted in a prompt and persistent fall in their increased plasma levels of -thromboglobulin.The results indicate that picotamide is a combined thromboxane B₂-synthetase inhibitor and thromboxane A₂-receptor antagonist in human platelets, and that it may prove useful as an antithrombotic agent.     

Nonlinear Binding of Valproic Acid (VPA) and E-Δ2-Valproic Acid to Rat Plasma Proteins

The binding characteristics of valproic acid (VPA) and its pharmacologically active monounsaturated metabolite, E-²-VPA, to rat plasma proteins were compared. The plasma free fraction was determined by a rapid equilibrium procedure, which minimizes the interfering effects of nonesterified fatty acids liberated by in vitro lipolysis. Nonlinear binding behavior was observed with both compounds over their respective pharmacologic concentration range. Multiple binding-site models were invoked to explain the binding isotherm. The 2-unsaturated compound has a much higher affinity for the rat plasma proteins (mainly albumin) than its saturated precursor. The equilibrium association constants for the high- and intermediate-affinity sites were more than an order of magnitude higher with E-²-VPA than with VPA (10⁴–10⁶ versus 10³ M ^–1). This difference in binding affinity was also reflected by a lower plasma free fraction for E-²-VPA compared with VPA (<<10 versus >20% at total concentrations of less than 100 µg/ml). A more pronounced dose- and concentration-dependent variation in the distribution and clearance kinetics is predicted for the 2-unsaturated analogue compared to VPA. Also, the structural dependency in plasma protein binding observed with these branched-chain fatty acids may provide insights into the mechanism of interaction between fatty acyl molecules and albumin.     

Bile Salt–Fatty Acid Mixed Micelles as Nasal Absorption Promoters of Peptides. I. Effects of Ionic Strength,Adjuvant Composition,and Lipid Structure on the Nasal Absorption of [D-Arg2]Kyotorphin

Bile salts and synthetic surfactants have been used to promote nasal absorption of peptide drugs. Although a marked increase in nasal absorption has been achieved, this may not be adequate and the possibility of adjuvant-induced membrane toxicity exists. The present study employs a rat in situ nasal perfusion technique and mixed micelles between sodium glycocholate (NaGC) and various lipids as potential nasal absorption enhancers of a stable model dipeptide, [D-Arg²]kyotorphin. NaGC alone enhanced the nasal absorption of the dipeptide in a concentration-dependent manner. When linoleic acid was added to form mixed micelles with NaGC, the absorption was further enhanced (P < 0.01). The effect of mixed micelles was synergistic and much greater than with single adjuvants. Increasing ionic strength was found to increase the adjuvant activity of both NaGC and NaGC–lipid mixed micelles. Structure of the lipid component of the mixed micelles also affected the adjuvant potency. Oleic acid, a cis-unsaturated fatty acid, was more effective than elaidic acid, the trans-isomer, whereas cis-linoleic acid and trans-linolelaidic acid were equally effective ( = 0.05). Mixed micelles of mono-glycerides such as monoolein and monolinolein were also more effective than NaGC alone ( = 0.05). Micellar solubilization of these polar lipids by NaGC appears to be important for nasal absorption enhancement to occur. Reversal of the membrane permeability was also observed within approximately 20–40 min after removal of the adjuvants from the rat nasal cavity. These observations are similar to the effects of mixed micelles on the rectal mucosa and may involve the same mechanism.     

Decrease of lymphokine (interleukin-2)-activated killer activity in peripheral blood after administration of natural interferon-gamma

Interferon-gamma (IFN-gamma) acts on a large array of different types of cell and has potent immunomodulatory activities besides cytotoxic effects on tumors. In a phase I study, some immunologic parameters of blood mononuclear cells from healthy volunteers who received intramuscular injections of natural human IFN-gamma were analyzed. The percentage of Leu-11a positive cells, natural killer (NK) activity, lymphokine (interleukin-2)-activated killer (LAK) activity and monokine production were measured either in blood mononuclear cells or in purified samples of lymphocytes or monocytes of the donors before and 24 h after IFN-gamma injection. After IFN-gamma injection, the percentage of Leu-11a positive cells and the LAK activity in the blood were significantly reduced, but NK activity and monokine production remained unchanged. These findings suggest that in vivo IFN-gamma acts directly or indirectly on Leu-11a positive cells and reduces LAK activity by changing the recruitment of LAK precursors in the blood.     

Urinary arginine and ornithine in occupational exposure to 2-ethylhexanoic acid

Nine sawmill workers were divided into two groups according to their exposure to 2-ethylhexanoic acid, (EHA), a pesticide which has replaced the older pentochlorophenol. The men with lower exposure excreted 30±10 nmol EHA/mmol creatinine (mean ±SD,n=4) in urine samples taken after the workshift, whereas men with higher exposure excreted 1.8±1.6 mol EHA/mmol creatinine (mean±SD,n=5,p<0.01). The urinary ornithine and arginine concentrations were at the lower exposure 1.4±0.4 and 1.5±0.8 mol/mmol creatinine, respectively (mean±SD,n=4), and they increased significantly (p<0.01) to 4.5±2.5 and 3.2±1.5mol/mmol (mean±SD,n=5), respectively, at the higher exposure. This might have been caused by the inhibitory effect of EHA on urea synthesis which was partially compensated for by elevated arginine and ornithine concentrations to drive the urea cycle more efficiently.     

Dose-dependent emergence of preneoplastic foci in rat livers after exposure to 2-nitropropane

Male and female Sprague-Dawley rats, 4–6 days old were exposed for 3 weeks (6 h/day, 5 days/week) to 2-nitropropane vapours of 0, 25, 40, 50, 80 and 125 ppm. One week later polychlorinated biphenyls (Clophen A50, 10 mg/kg body weight) were administered for promotion twice a week for 8 weeks. Thirteen weeks after starting the experiments the logarithms of the numbers of preneoplastic liver foci deficient in adenosine-5-triphosphatase were found to be linearly related to the exposure concentrations of 2-nitropropane. Male rats exhibited an approximately four times lower foci incidence than females.