培养条件下肌腱中心区域腱细胞的增殖能力

目的　研究肌腱损伤后腱中心区域组织的愈合能力。方法　选用 8只白色纯种来亨鸡 ,在无菌条件下切取双侧最长趾 区趾深屈肌腱 ,切成 4 mm长的肌腱段 ,分为两组 ,每组 12条。实验组 :切除腱外膜和外膜下腱组织的肌腱中心区域组织 ;对照组 :仅剥除腱外膜组织的肌腱段。将两组肌腱组织进行体外培养 ,于培养第 9、18及 2 7天取标本进行大体观察及组织学检查。另取 4条肌腱作正常对照组 ,直接进行大体观察和组织学检查。结果　各时间点的腱细胞数 ,对照组均明显少于实验组及培养前 ,有统计学意义 (P<0 .0 1) ;实验组比培养前均明显增多 ,有统计学意义 (P<0 .0 1) ;但培养第 18天和 2 7天时 ,实验组腱细胞数较培养第 9天少 (P<0 .0 1)。结论　屈肌腱损伤后腱中心区域组织有良好的愈合能力。     

几丁糖对肌腱腱鞘和腱外膜以及腱内膜细胞增殖和胶原产生的影响

目的探讨兔屈趾肌腱腱鞘、腱外膜和腱内膜细胞增殖、胶原产生和几丁糖对细胞的增殖和胶原产生的影响方法从免屈趾肌腱分离腱鞘、腱外膜和腱内膜细胞并培养，在使用几丁精培养后，测量细胞的数量和胶原产生量，并与不使用几丁糖培养的对照组比较。另外，通过逆转录聚合酶链反应(RT—PCR)法测定使用儿丁糖前后腱鞘细胞Ⅰ型胶原基因的表达结果所有三种细胞均可以产生Ⅰ、Ⅱ、Ⅲ型胶原组织，几丁糖使培养的细胞数量降低，且能显著性地抑制Ⅰ、Ⅱ、Ⅲ型胶原组织产生和腱鞘细胞Ⅰ型胶原基因的表达。结论几丁糖能抑制肌腱腱鞘、腱外膜和腱内膜细胞增殖和胶原组织的产生，可能为临床上防止肌腱粘连提供新的途径。     

鞘内肌腱愈合细胞参与形态学的实验研究

目的：研究鞘内肌腱损伤修复后的愈合机制，以期为防止粘连提供一新的途径。方法：应用鸡趾鞘内屈肌腱横断修复模型，不同时间组取材，通过光镜和扫描电镜观察腱愈合细胞参与形态学的过程。结果：鞘内肌腱具有白愈能力，自身细胞可分裂增殖并分泌胶原及基质，腱内膜和束内细胞，术后即表现出桥接吻合口活性，腱外膜细胞５天开始迁移，１０天达高峰，１５天后吻合口出现成熟胶原纤维。两残端间距离小，以健内膜和束内细胞参与为主，否则以外膜细胞迁移充填占优，前者胶原纤维成熟早于后者。结论：若能增加腱内膜和束内膜细胞活性，抑制或降低外膜细胞活性，可能会有效地防止粘连形成。     

乳酸对肌腱腱鞘、腱外膜和腱内膜细胞增殖和生物学活性的影响

目的　探讨兔屈趾肌腱腱鞘、腱外膜和腱内膜细胞增殖、胶原产生和乳酸对细胞的增殖、胶原产生和对TGF β1、b FGF、IL 8分泌的影响。 方法　从兔屈趾肌腱分离腱鞘、腱外膜和腱内膜细胞并培养 ,在使用乳酸培养后 ,细胞的数量 ,胶原产生量和TGF β1、b FGF、IL 8分泌量被测量 ,并与不使用乳酸培养的对照组比较。结果　所有三种细胞均可以产生Ⅰ、Ⅱ、Ⅲ型胶原组织 ,乳酸使培养的细胞数量降低 ,但能显著性地增加Ⅰ、Ⅱ、Ⅲ型胶原组织产生 ,TGF β1、b FGF的分泌和减少IL 8的分泌。 结论　乳酸能增加腱鞘成纤维细胞、腱外膜细胞和腱内膜细胞的胶原产生量 ,而这种刺激作用可能与增加TGF β1、b FGF和减少IL 8的分泌量有关 ,通过对乳酸的调节可能为预防肌腱损伤修复后的粘连提供新的途径。     

转化生长因子-β1对肌腱腱鞘、腱外膜和腱内膜细胞增殖和胶原产生的影响

目的 探讨兔屈趾肌腱腱鞘、腱外膜和腱内膜细胞增殖、胶原产生和转化生长因子（TGF）-β1对细胞的增殖和胶原产生的影响。方法 从兔屈趾肌腱分离腱鞘、腱外膜和腱内膜细胞并培养，在使用TGF-β1培养后，细胞的数量和胶原产生量被测量，并与不使用TGF-β1培养的对照组比较。另外，通过逆转录-聚合酶链反应（RT-PCR）测定使用TGF-β1前后各种细胞Ⅰ型胶原基因的表达。结果 所有3种细胞均可以产生Ⅰ、Ⅱ、Ⅲ型胶原组织，TGF-β1使培养的细胞数量降低，但能显著性地增加Ⅰ、Ⅱ、Ⅲ型胶原组织产生和Ⅰ型胶原基因的表达（P〈0．05）。结论 调节TGF-β1的水平能调节胶原组织的产生，可能为临床上防止肌腱粘连提供新的途径。     

自体组织工程化肌腱预制的初步研究

目的：应用组织工程技术研究组织工程化肌腱体内形成的可行性。方法：取成年家鸡的趾深屈肌腱，用酶消化法分离，培养肌腱细胞，将在体外扩增到一定浓度的肌腱细胞接种到聚羟基乙酸（PGA）上，形成细胞－材料复合物，体外培养5d后，将此复合物回植至自体右翼皮下，左侧以单纯PGA作为对照，培养后第3，4，6，8周取材，从大体，组织学等方面进行分析。结果；术后8周见组织工程化肌腱呈白色，有光泽，组织学见胶原组织平行排列，但仍可见未降解的PGA及少量炎性细胞，对照组则无任何组织形成，结论：自体肌腱细胞与生物材料复合后在免疫功能正常的自体动物体内能够再生出肌腱样组织，新生的肌腱样组织在大体，组织学等方面均与正常肌腱相似。     

6-磷酸果糖对肌腱细胞TGF-β及其受体表达的影响

目的通过体外培养兔肌腱的腱鞘、腱外膜和腱内膜细胞,观察6-磷酸果糖对3种细胞TGF-β及其受体、TGF-β1及TGF-β1mRNA表达的影响,探讨6-磷酸果糖在肌腱愈合粘连防治中的作用机制提供实验依据。方法成年新西兰大白兔8只,雌雄不限,体重4.0～4.5kg。取兔前肢趾深屈肌腱分离培养腱鞘、腱外膜和腱内膜细胞。将每种细胞随机分为2组,实验组加入6-磷酸果糖培养,对照组不加入6-磷酸果糖。分别于培养3d及24h后采用酶联免疫吸附实验定量检测TGF-β及其受体的表达,原位杂交检测TGF-β1mRNA的表达;免疫组织化学染色观测TGF-β1的表达。结果酶联免疫吸附实验显示实验组各细胞TGF-β及其受体的表达均较对照组下降,差异有统计学意义(P0.05)。TGF-β1表达平均降低程度从大到小依次为腱鞘细胞(36.1%)、腱内膜细胞(31.2%)、腱外膜细胞(31.0%),TGF-β2依次为腱鞘细胞(37.9%)、腱外膜细胞(32.1%)、腱内膜细胞(27.0%),TGF-β3依次为腱内膜细胞(42.5%)、腱鞘细胞(41.2%)及腱外膜细胞(33.3%)。TGF-β受体1、2表达平均降低程度从大到小依次为腱外膜细胞(29.9%、26.2%),腱内膜细胞(27.8%、23.5%),腱鞘细胞(23.1%、20.0%);TGF-β受体3依次为腱内膜细胞(26.1%)、腱外膜细胞(19.2%)、腱鞘细胞(15.8%)。实验组各细胞TGF-β1mRNA阳性表达率及细胞内TGF-β1mRNA表达强度均较对照组明显降低,比较差异有统计学意义(P0.05)。免疫组织化学染色观察显示实验组各细胞TGF-β1表达均较对照组明显降低。结论6-磷酸果糖能显著降低肌腱细胞的TGF-β及其受体、TGF-β1及TGF-β1mRNA的表达,为肌腱愈合过程中调节TGF-β水平提供了一种新途径。     

乳酸对肌腱细胞转化生长因子-β表达的调节作用

目的探讨乳酸对免屈趾肌腱腱鞘、腱外膜和腱内膜细胞转化生长因子（TGF）-β及其受体产生的影响。方法从兔屈趾肌腱分离腱鞘、腱外膜和腱内膜细胞并分别进行培养，在使用25mmol／L的乳酸培养后，酶联免疫吸附试验定量检测TGF-β及其受体的表达，同时应用原位杂交和免疫组织化学技术测量TGF-β的表达。结果乳酸能显著增加3种细胞所有TGF-β及其受体的表达（P〈0．05），其中腱鞘细胞的TGF-β1和TGF-β增加值最大，腱外膜细胞的TGF-β1和TGF-β的受体增加值最大，腱内膜细胞则为TGF-β增加值最大；乳酸还显著增加3种细胞的TGF-β表达。结论乳酸能显著增加肌腱细胞的TGF-β、TGF-β受体和TGF-β mRNA的表达，因此为肌腱愈合过程中调节TGF-β水平提供新的途径。     

兔骨髓间质干细胞修复肌腱缺损效果观察

目的　观察兔骨髓间质干细胞(MSCs)修复肌腱缺损的效果。　方法　分离培养家兔MSCs,检测CD44mRNA进行鉴定。6只家兔分为实验组和对照组,每组3只。在兔跟腱处造成3cm长的缺损,实验组家兔以自体MSCs为种子细胞、以胶原聚羟基乙酸(PGA)为生物支架构建肌腱并移植于跟腱缺损处,对照组家兔仅以PGA生物支架修复跟腱缺损。于术后4、8、12周对移植部位进行大体和组织学观察。　结果　MSCs培养11d时CD44mRNA显示阳性。实验组术后8周肉眼可见移植处形成腱样组织, 12周时组织学观察可见形态一致、顺应力学方向排列于胶原中的腱样细胞,类似正常肌腱组织。对照组所形成的新生组织较实验组细小且与周围组织粘连, 12周时组织学观察见细胞排列紊乱,胶原纤维呈松散网丝状。　结论　应用组织工程技术以自体MSCs修复肌腱缺损具有可行性。     

腱旁组织修复后对肌腱愈合方式影响的实验研究

为了观察腱旁组织对肌腱愈合方式的影响，选用雌性罗曼鸡２０只，取双侧第三趾手术，以鸡趾伸肌腱为模型，随机分为两组，每组１０只２０趾。Ａ组仅缝合趾伸肌腱；Ｂ组缝合趾伸肌腱后再修复腱旁组织。术后３周和６周，分别取标本进行大体形态和组织学观察。结果表明，术后３周，Ａ组粘连广泛，成纤维细胞增生紊乱；Ｂ组修复的肌腱形成规则而光滑的“梭形体”，粘连较轻，成纤维细胞增生有序。术后６周，Ａ组粘连较重，愈合处为瘢痕组织连接，形态不规则，纤维细胞排列紊乱，胶原纤维少而幼稚；Ｂ组粘连基本消失，肌腱及腱旁组织基本恢复正常，增生的纤维细胞及胶原纤维来自肌腱和腱旁组织，排列有序，有腱束形成趋势     

Vasopressor hormone response following mesenteric traction during major abdominal surgery

Background : We investigated the vasopressor hormone response following mesenteric traction (MT) with hypotension due to prostacyclin (PGI₂) release in patients undergoing abdominal surgery with a combined general and epidural anesthesia. Methods : In a prospective, randomized, placebo-controlled study we administered 400 mg ibuprofen (i.v.) in 42 patients scheduled for abdominal surgery. General anesthesia was combined with epidural anesthesia (T4-L1). Before as well as 5, 15, 30, 45, and 90 min after MT we recorded plasma osmolality, hemodynamics and measured 6-keto-PGFlα (stabile metabolite of PGI₂), TXB₂ (stabile metabolite of thromboxane A₂) active renin, and arginine vasopressin (AVP) plasma concentrations by radioimmunoassay. Catecholamine levels were assessed by high-pressure liquid chromatography (HPLC) with electrochemical detection. Results : Following MT, arterial hypotension occurred along with a substantial PGI₂ release. This was completely abolished by ibuprofen administration. Although plasma levels of 6-keto-PGF_1α (1133 (708) vs. 60 (3) ng/L, median (median absolute deviation), P=0.0001, placebo vs. ibuprofen) remained significantly elevated, blood pressure was restored within 30 min after MT in the placebo group. At the same point in time plasma concentrations of TXB² (164 (87) vs. 58 (1) ng/L, P=0.0001), epinephrine (46 (33) vs. 14 (6) ng/L, P=0.001), AVP (41 ± (18) vs. 12 (7) ng/L, P=0.0004), and active renin (27 (12) vs. 12 (4) ng/L, P = 0.001) were significantly higher in placebo-treated patients. Conclusion : Under combined general and epidural anesthesia arterial hypotension following MT due to endogenous PGI₂ release is associated with enhanced release of AVP, active renin, epinephrine and thromboxane A₂, presumably contributing to hemodynamic stability within 30 min after MT.     

A Teaspoon Pump for Pumping Blood with High Hydraulic Efficiency and Low Hemolysis Potential

Abstract: Virtually all blood pumps contain some kind of rubbing, sliding, closely moving machinery surfaces that are exposed to the blood being pumped. These valves, internal bearings, magnetic bearing position sensors, and shaft seals cause most of the problems with blood pumps. The original teaspoon pump design prevented the rubbing, sliding machinery surfaces from contacting the blood. However, the hydraulic efficiency was low because the blood was able to "slip around" the rotating impeller so that the blood itself never rotated fast enough to develop adequate pressure. An improved teaspoon blood pump has been designed and tested and has shown acceptable hydraulic performance and low hemolysis potential. The new pump uses a nonrotating "swinging" hose as the pump impeller. The fluid enters the pump through the center of the swinging hose; therefore, there can be no fluid slip between the revolving blood and the revolving impeller. The new pump uses an impeller that is comparable to a flexible garden hose. If the free end of the hose were swung around in a circle like half of a jump rope, the fluid inside the hose would rotate and develop pressure even though the hose impeller itself did not "rotate"; therefore, no rotating shaft seal or internal bearings are required.     

Microspheres Based Detoxification System: A New Method in Convective Blood Purification

Abstract: A variety of protein-bound or hydrophobic substances, accumulating as a result of pathologic conditions such as exogenous or endogenous intoxications, are removed poorly by conventional detoxification methods because of low accessibility (hemodialysis), insufficient adsorption capabilities (hemosorption), low efficiency (peritoneal dialysis), or economic limitations (high-volume plasmapheresis). Combining advantages of existing methods with microspheric technology, a module-based system was designed. Major operating parameters of the latter can be modified to allow for adjustment to individual clinical situations. An extracorporeal blood circuit including a plasmafilter is combined with a secondary high-velocity plasma circuit driven by a centrifugal pump. Different microspheric adsorbers can be combined in one circuit or applied in sequence. Thus, a prolonged treatment can be tailored using specially designed selective adsorber materials. Comparing this system with existing methods (high-flux hemodialysis, molecular adsorbent recycling system), results from our in vitro studies and animal experiments demonstrate the superior efficiency of substance removal.     

Is the recovery profile of mivacurium independent of the rate of decay of its plasma concentration in patients with normal plasma cholinesterase activity?

Background: The duration of action of muscle relaxants is poorly correlated to the rate of decay of their plasma concentration. The plasma concentration of mivacurium may rapidly decrease below its active concentration because of the extensive hydrolysis of mivacurium. By inflating a tourniquet on one upper limb for 3 min after the administration of atracurium, mivacurium or vecuronium, we studied the influence of the initial decline of their plasma concentration on their effect. Methods: In 50 patients anaesthetised with thiopental, isoflurane and fentanyl, the effect of bolus doses of 0.15 or 0.25 mg . kg^?1 mivacurium (MIV 15, MIV 25), 0.3 or 0.5 mg . kg^?1 atracurium (ATR 30, ATR 50) and 0.06 or 0.1 mg . kg^?1 vecuronium (VEC 06, VEC 10) were measured on both arms (evoked response of the adductor pollicis to train-of-four stimulation every 12 s), a tourniquet being applied on one arm just before and during 3 min after the muscle relaxant bolus. Results: Tourniquet inflation of 3 min almost abolished the neuromuscular effect of mivacurium. In the vecuronium groups and in the ATR 50 group, tourniquet inflation did not modify the maximum degree of depression of the twitch response. Also, the duration of action of vecuronium was unaffected by the tourniquet. In the ATR 30 group, times to return of the twitch response to 25% (duration 25%) and 75% (duration 75%) of control response were significantly shorter in the cuffed arm, 23 min vs 27 min, and 41 min vs 45 min, respectively. In the ATR 50 group, only duration 25% was significantly shorter in the cuffed arm (41 min vs 45 min). Conclusion: The results suggest that the rate of decline of the plasma concentration of mivacurium is so rapid, that a very low and almost clinically ineffective concentration is present as soon as 3 min after its administration. The results also indicate that the recovery from a mivacurium-induced neuromuscular blockade is not influenced by the rate of decay of its plasma concentration in patients with genotypically normal plasma cholinesterase.     

Membranes in Artificial Organs

Abstract: Membrane processes play a pivotal and enabling role in modern replacement therapy for acute and chronic organ failure and in the management of immunologic diseases. In fact, virtually all contemporary extracorporeal blood purification methods employ membrane devices, and the next generation of artificial organs and tissue engineering therapies are almost certain to be similarly grounded in membrane technology. In this short essay, we comment on the similarities and differences among synthetic membranes and their natural counterparts and also provide a critical overview of the demographics and technology of hemodialysis, hemofiltration, apheresis, oxygenation, and emerging membrane technologies and applications.     

Tissue perfusion in relation to cardiac output during continuous positive-pressure ventilation and administration of propranolol or verapamil

Background : Our objective was to determine whether administration of propranolol or verapamil modifies the hemodynamic adaptation to continuous positive-pressure ventilation (CPPV), in particular the regional distribution of cardiac output (CO).
Methods : General hemodynamics and regional blood flows assessed by microsphere technique (15 (μm) were recorded in 16 anesthetized pigs during spontaneous breathing (SB) and CPPV with 8 cm H₂O end-expiratory pressure (CPPV8) before and after intravenous administration of propranolol (0.3 mg · kg⁻¹ followed by 0.15 mg · kg⁻¹ · h⁻¹, n=8) or verapamil (0.1 mg · kg⁻¹ followed by 0.3 mg · kg⁻¹ · h⁻¹, n=8).
Results : CPPV8 depressed CO by 25% without shifts in its relative distribution with the exception of a noteworthy increase in adrenal perfusion. Propranolol increased arterial blood pressure, and due to a fall in heart rate, CO dropped by 25%. The kidneys and, to a lesser extent, the splanchic region and central nervous system received increased fractions of the remaining CO at the expense of skeletal muscle flow. Similar patterns were seen during SB and CPPV8 such that the combination of propranolol and CPPV8 depressed CO by 50%. The circulatory effects of verapamil were less evident but myocardial perfusion tended to increase.
Conclusions : The combination of propranolol or verapamil with CPPV does not result in any specific hemodynamic interaction in anesthetized pigs, except that the combined effect of propranolol and CPPV may severely reduce CO.     

Volatile anaesthetics reduce adhesion of blood platelets under low-flow conditions in the coronary system of isolated guinea pig hearts

Background : Inhibitory effects of volatile anaesthetics on platelet aggregation have been demonstrated in several studies. However, the influence of volatile anaesthetics on intracoronary platelet adhesion has not been elucidated so far.
Methods : Isolated hearts of guinea pigs were perfused with buffer in the absence or presence of volatile anaesthetics (0.5 and 1 MAC) at constant coronary flow rates of 5 ml/min for 25 min, then 1 ml/min for 30 min and again 5 ml/min for 10 min. Before, during and after low-flow perfusion, a bolus of human platelets was applied into the coronary system. To simulate thrombogenic conditions, 0.3 U/ml human thrombin was infused during low-flow perfusion and reperfusion. The number of platelets sequestered to the endothelium was calculated from the difference between coronary in- and output of platelets. The myocardial production of lactate and consumption of pyruvate and coronary perfusion pressure were also determined.
Results : At a flow rate of 5 ml/min only about 3% of the applied platelets did not emerge from the coronary system, in any group. In contrast, 13.1±1.2% (mean±SEM) of infused platelets became adherent in low-flow perfusion in the control group without anaesthetic. The adherence was reduced with each 1 MAC isoflurane (to 6.2±1.2%), sevoflurane (to 4.4±0.9%) or halothane (to 3.2±1.5%) (each P <0.05 vs. control). Volatile anaesthetic, 0.5 MAC, did not inhibit platelet adhesion to a statistically significant extent in any case. Perfusion pressure and metabolic parameters were not statistically different between the control and the hearts exposed to anaesthetics.
Conclusion : Volatile anaesthetics in a concentration of 1 MAC can reduce the adhesion of platelets in the coronary system under reduced flow conditions. This action does not arise from vasodilation or inhibition of ischaemic stress.     

Bariatric Surgery in Some "Central and East-European (former Eastern bloc)"Countries - Current Status and Prediction for the Next Millennium

Background: Obesity is increasing globallly, including in the formerly "Eastern Bloc" countries. Methods: A survey was made of obesity and bariatric surgery. Results: In the 8 East and Central European countries studied, with total population 300 million, roughly 43% of the population was overweight (BMI 25-30), 23% obese (BMI > 30), with about 15 million people morbidly obese (BMI > 40). From 0-10 morbidly obese individuals/100,000/year undergo bariatric surgery. Conclusion: Most countries were found to provide inadequate treatment for obesity.The majority of the morbidly obese are not treated effectively. However, health-care awareness of obesity and bariatric surgeons are slowly increasing.     

Dilemma of Membrane Biocompatibility and Reuse

Abstract: Numerous articles have been published on the multiple use of dialyzers and on the effect of different reprocessing chemicals and techniques on the dialyzer biocompatibility and performance. The results often appear contradictory, especially those comparing standard biocompatibility parameters. Despite this confusion, a discerning review of the published works allows certain limited conclusions to be drawn. Reprocessing of used hemodialyzers changes the biocompatibility profile of a dialyzer as defined by the parameters complement activation. leukopenia, and cytokine release. The effect of reprocessing depends on the chemicals and reprocessing technique applied and also on the type of membrane polymer being subjected to the reprocessing procedure. Reports of pyrogenic reactions indicate that the flux of the membrane also influences how suitable it is for safe reuse. An increased risk of allergic and pyrogenic reactions appears to be associated with dialyzer reuse. Furthermore, there has been a lack of investigations into the immunologic effect of the layer of adsorbed and chemically altered proteins that remains on the inner surface of reprocessed dialyzers. We conclude that the clinical benefit of dialyzer reuse cannot be generally accepted from a biocompatibility point of view.     

The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans

Background : Ketamine in sub-dissociative doses has been shown to have analgesic and phantom-Limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain-generating mechanisms are not well understood.
Methods : Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given sub-dissociative doses of 0.15, 0.30, or 0.45 mg/kg racemic ketamine and morphine 10 mg as a 5-min infusion on four separate days in a cross-over, double-blind, randomised protocol. Plasma levels of (S)- and (R)-ketamine and their nor-metabolites were analysed with an enantioselective high-performance liquid chromatography (HPLC) method. Pain levels were evaluated with a visual analogue scale (VAS).
Results : Individual pain levels were highly variable during and after all the infusions but the pooled pain levels showed a dose-dependent analgesic effect of ketamine with a transient but complete pain relief in all patients at the highest dose (0.45 mg/ kg). Side-effects, mainly disturbed cognition and perception, were pronounced and dose-dependent. Morphine 10 mg had an analgesic peak at 20 min and 5/8 patients had complete pain relief. The remaining 3 patients also had high baseline pain scores, indicating a higher analgesic potency for the 0.30 and 0.45 mg/ kg ketamine doses than for morphine 10 mg.
Conclusion : We have demonstrated a potent dose-dependent analgesic effect of racemic ketamine in clinical ischemic pain. Due to a narrow therapeutic window, this analgesic effect is probably best utilised in combination with other analgesics.