Clinical therapeutic trial of sodium meclofenamate and naproxen in rheumatoid arthritis,with comments on the use of placebos in clinical trials

Summary

Forty patients with active rheumatoid arthritis were entered into a single-blind study of 12-weeks' duration to compare the efficacy and tolerance of 100?mg sodium meclofenamate 3-times daily and 250?mg naproxen twice daily. Disease activity was defined by the presence of a Ritchie Articular Index score of greater than 15. Patients were assessed at 4-week intervals. Analysis of variance of the data from those patients who completed 12 weeks in the trial showed that in the sodium meclofenamate group there was a significant improvement in articular index, left grip strength, pain severity and patients' global assessment over the course of the study. In the naproxen group, there was a significant improvement in articular index, grip strength and pain severity over the study. Pairwise comparisons showed that morning stiffness improved significantly from baseline to 12 weeks only, in both treatment groups. There were no significant differences between the two treatment groups for any of the measurements at any time period during the study. In the sodium meclofenamate group, there were 4 drop-outs due to inadequate efficacy and 6 in the naproxen group. Four patients in the sodium meclofenamate group and 2 patients in the naproxen group dropped out of the study because of side-effects, primarily nausea. These results suggest that sodium meclofenamate was equally well tolerated and as effective as naproxen in the treatment of rheumatoid arthritis in this group of patients.     

Release of prostaglandin E2 and leukotriene C4/D4 from airway segments isolated from rats after exposure to ozone for 20 months

Metabolites of arachidonic acid have been implicated as mediators of some of the pulmonary effects observed after acute exposure to ozone. Accordingly, recent studies have focused on the effects of acute ozone exposure on the arachidonic acid cascade, however, whether eicosanoid metabolism is altered after chronic exposure to ozone is unknown. To begin to address this issue, we examined the effects of near-lifetime exposure to ozone on release of prostaglandin E₂ (PGE₂) and leukotriene C₄/D₄ from airway segments isolated from exposed Fischer-344 rats. Airway segments representing approximately eighth to tenth generation airways were isolated from rats of both genders that had been exposed for 6 h per day, 5 days per week for 20 months to filtered air or 0.12, 0.5 or 1.0 parts per million (ppm) ozone. Basal and stimulated release of eicosanoids were measured in the medium surrounding airway segments using enzymoimmunoassay. Basal release of PGE₂ was detected in the medium surrounding airway segments and this release was unaffected by ozone exposure. Incubation of the segments with the calcium ionophore, A23187, increased the release of the prostaglandin; the A23187-induced release of PGE₂ was significantly enhanced in airway segments isolated from rats in the 1.0 ppm exposure group. Basal release of leukotriene C₄/D₄ was not detected in the medium surrounding airway segments regardless of ozone exposure. Measurable amounts of the leukotriene were released during incubation with A23187, however, ozone was without affect on these levels. The results suggest that the cyclooxygenase pathway of the arachidonic acid cascade appears to be affected by ozone exposure. Which of the processes of prostaglandin production and release are affected by chronic ozone exposure remains to be determined.     

Ketanserin stabilizes blood pressure in conscious spontaneously hypertensive rats

1. It has been demonstrated that blood pressure variability (BPV) is increased in hypertension and related to organ damage. It will be important to lower BPV in the treatment of hypertension. The present study was designed to investigate the effect of ketanserin, a 5-HT2A receptor antagonist with a weak alpha1-adrenoceptor blocking effect, on BPV in conscious spontaneously hypertensive rats (SHR). 2. It was found that ketanserin decreased blood pressure (BP) and BPV in SHR when administered intravenously (3 mg/kg, i.v.). Ketanserin decreased BPV, but not the BP level, when administered intracerebroventricularly (50 microg/rat, i.c.v.). 3. Prazosin, an alpha1-adrenoceptor antagonist, lowered BP but did not affect BPV when given either i.v. (0.5 mg/kg) or i.c.v. (30 microg/rat). Ritanserin (0.625 mg/kg, i.v.; 40 microg/rat, i.c.v.), a 5-HT2A receptor antagonist, decreased BPV only when administered i.c.v. and did not modify the BP level. 4. Ketanserin enhanced arterial baroreflex function in SHR when given either i.v. or i.c.v. 5. The stabilizing effect of ketanserin on BP was persistent when administered intragastrically. This administration route is similar to oral administration clinically. 6. It is concluded that ketanserin is an antihypertensive agent with an effect of reducing BPV. This effect is mainly mediated by central 5-HT2A receptors and is probably attributable to the restoration of arterial baroreflex function.     

前列腺素E1经不同途径给药后的大鼠体内药效学比较

本文研究了前列腺素E₁(PGE₁)分别经不同途径给药后的大鼠体内药效学，旨在寻找目前PGE₁注射给药的替代途径。以PGE₁降压效应作为药效学指标，以静脉注射为对照，分别测定PGE₁经鼻腔、舌下、肌肉(im)、腹腔(ip)给药后的药效学参数，包括峰效应时间(Tmax)，血压下降最大百分数(Emax，%)，效应持续时间(T_d)以及血压下降百分数-时间曲线下面积(AUC，%·min)。研究结果表明，PGE₁经上述途径给药后，药效学参数Emax，T_d，AUC等均随给药剂量的增加而增大，提示存在明显的剂量-效应关系。根据所测Tmax值，推断上述给药途径其吸收速率的大小顺序为：鼻腔≈im>ip>舌下；依据所测药理生物利用度(PF)值，预测药物绝对生物利用度的顺序为：鼻腔>im≈ip>舌下。上述研究结果提示，PGE₁经鼻腔与舌下黏膜给药，有望替代目前的注射给药。     

Changes in blood pressure,urinary kallikrein,and urinary prostaglandin E2 in rats with streptozotocin-induced diabetes

Summary To reveal the mechanism of hypertension in diabetes mellitus, changes in blood pressure were measured in streptozotocin (STZ)-induced diabetes mellitus in male Wistar rats. Development of diabetes mellitus and elevation of blood pressure were observed in rats which received 60 mg/kg STZ, but not in rats which received 20 mg/kg STZ. In the rats which developed diabetes mellitus after STZ, the plasma renin activity, renal renin content, plasma aldosterone, and urinary kallikrein activity were all significantly reduced. The urinary excretion of prostaglandin E₂ (PGE₂) was significantly increased at 1 week after STZ in diabetic rats, but it gradually returned to control values and showed a tendency to decrease at 4 weeks after the treatment compared to the rats of the control groups. The pressor responsiveness to norepinephrine in the conscious unrestrained state in the STZ-induced diabetic rats was not remarkably changed compared to that of control rats. These results indicate that blood pressure gradually increases with the progress of diabetes. It is suggested that the changes in urinary excretion of PGE₂ and urinary kallikrein activity may be related to the regulation of blood pressure in STZ-induced diabetic rats. On the other hand, it is considered unlikely that the reninangiotensin system and vascular responsiveness play an important role in the occurrence of hypertension in diabetes mellitus.     

The distribution and chemical kinetics of prostaglandin E1 in lipid emulsions

The partitioning of PGE₁ in a lipid emulsion has been shown to be consistent with a three-phase model which assumes that solute may reside in the bulk aqueous and oil phases and at the oil-water interface. Ultrafiltration and dialysis techniques were used to estimate the relative percentages of PGE₁ in each phase at various pHs. The amount of PGE₁ present in the bulk oil phase of the emulsion was concluded to be insignificant. At emulsion pH values of less than five, PGE₁ resides preferentially at the interface. With increasing pH, the percentage of PGE₁ in the aqueous phase increases. A model which assumes that both the non-ionized and ionized PGE₁ species may be present at the interface, depending on pH, was shown to be consistent with the data. Estimates were made of the distribution coefficients of the ionized and non-ionized PGE₁ between the interface and the aqueous phase and their concentration dependence. The distribution coefficients were used to generate a distribution profile of the various PGE₁ species as a function of pH. The overall dehydration kinetics of PGE₁ in a lipid emulsion were found to fit a model whereby the k_apparent measured at each pH is simply the sum of the product of the fraction of the PGE₁ at the interface, f_i, and the rate constant at the interface, k_i, plus the product of the fraction of the PGE₁ in the aqueous phase, f_aq, and the rate constant in the aqueous phase, k_aq. The k_{aq and} k_apparent were experimentally determined as a function of pH. The k_i was indirectly determined from the stability data in the emulsion. Microscopic rate constants for dehydration of PGE₁ in the aqueous phase and interface were estimated from the experimental data. The dehydration kinetics were also shown to be affected by the addition of charged surface active agents.     

The effects of kisspeptin-54 on blood pressure in humans and plasma kisspeptin concentrations in hypertensive diseases of pregnancy

AIMS

To investigate (i) if kisspeptin administration alters heart rate (HR) or blood pressure (BP) in healthy male and female volunteers, (ii) whether circulating plasma kisspeptin concentrations in healthy pregnant women and women with hypertensive diseases of pregnancy correlate with BP and (iii) whether women with hypertensive diseases of pregnancy have altered plasma kisspeptin concentrations.

METHODS

We have previously reported the effects of administration of kisspeptin-54 on gonadotrophin secretion in healthy male and female volunteers. In these studies, cardiovascular parameters were not a primary endpoint. However, data were also collected on BP and HR for 4 h post administration of kisspeptin-54. Blood samples were taken from 105 women in the third trimester of pregnancy (27 women with hypertensive diseases of pregnancy and 78 controls). Samples were assayed for plasma kisspeptin immunoreactivity (IR).

RESULTS

Administration of kisspeptin was not associated with significant changes in HR or BP in healthy men or women. There was no significant correlation between plasma kisspeptin concentration and BP in healthy pregnant women or in those with hypertensive diseases of pregnancy. No significant differences in plasma kisspeptin-IR concentrations were observed between women with hypertensive diseases of pregnancy and normotensive pregnant controls, plasma kisspeptin concentrations ± SE: controls 2878 ± 157 pmol l⁻¹; pregnancy-induced hypertension 2696 ± 299 pmol l⁻¹ (95% CI vs. controls −514, 878 pmol l⁻¹); pre-eclampsia 3519 ± 357 (95% CI vs. controls −1644, 362 pmol l⁻¹).

CONCLUSIONS

Elevation of plasma kisspeptin-IR is not associated with an alteration in BP in humans.     

New lipo-PGE1 using a stable prodrug of prostaglandin E1 (PGE1)

Lipo-PGE₁ is an excellent drug delivery system (DOS) of PGE₁ widely used in Japan since 1988 for the treatment of various vascular diseases. However, this preparation has two major disadvantages. One is PGE₁ chemical instability in the lipid microspheres (LM) and the other is PGE₁ rapid leakage from the LM in the blood, leading to a decrease in the targeting of this drug. Δ⁸-9-O-butyryl prostaglandin F₁ butylester (AS013) was readily hydrolyzed to PGE₁ in human serum. AS013 was stable as an LM preparation and more effectively retained in the LM after incubation with human blood or serum when compared to PGE₁. These results suggested that lipo-AS013 would be a far superior PGE₁ LM preparation than lipo-PGE₁, for clinical use.     

Role of Ca-activated K channels and Na,K-ATPase in prostaglandin E1- and E2-induced inhibition of the adrenergic response in human vas deferens

We studied the role of K⁺ channels and Na⁺,K⁺-ATPase in the presynaptic inhibitory effects of prostaglandin E₁ (PGE₁) and PGE₂ on the adrenergic responses of human vas deferens. Furthermore, we determined the effects of increasing extracellular K⁺ concentrations ([K⁺]_o) and inhibition of Na⁺,K⁺-ATPase on neurogenic and norepinephrine-induced contractile responses. Ring segments of the epididymal part of the vas deferens were taken from 45 elective vasectomies and mounted in organ baths for isometric recording of tension. The neuromodulatory effects of PGEs were tested in the presence of K⁺ channel blockers. PGE₁ and PGE₂ (10⁻⁸ to 10⁻⁶ M) induced inhibition of adrenergic contractions. The presence of tetraethylammonium (10⁻³ M), charybdotoxin (10⁻⁷ M), or iberiotoxin (10⁻⁷ M), prevented the inhibitory effects of PGE₁ and PGE₂ on the adrenergic contraction. Both glibenclamide (10⁻⁵ M) and apamin (10⁻⁶ M) failed to antagonize PGE₁ and PGE₂ effects. Raising the [K⁺]_o from 15.8 mM to 25.8 mM caused inhibition of the neurogenic contractions. Ouabain at a concentration insufficient to alter the resting tension (10⁻⁶ M) increased contractions induced by electrical stimulation but did not alter the contractions to norepinephrine. The inhibition of neurogenic responses induced PGE₁, PGE₂ and increased extracellular concentration of K⁺ was almost completely prevented by ouabain (10⁻⁶ M). The results demonstrate that PGE₁ and PGE₂ inhibit adrenergic responses by a prejunctional mechanism that involves the activation of large-conductance Ca²⁺-activated K⁺ channels and Na⁺,K⁺-ATPase.     

A comparison of the vasodepressor effects of the cyclic endoperoxides PGG2 and PGH2 with those of PGD2 and PGE2 in hypertensive and normotensive rats

The vasodepressor actions of the cyclic endoperoxides PGG₂ and PGH₂ were compared with those of their products PGD₂ and PGE₂ using anaesthetised normotensive and genetically hypertensive rats. Given into the aortic arch of normotensives PGE₂ was approximately 6 times more potent than PGH₂ and 11 times more potent than PGG₂ and PGD₂. Hypertensive animals were 1.5–10 times more sensitive than normotensives to the depressor effects of PGG₂ and PGH₂, but their sensitivity to either PGD₂ or PGE₂ was similar. Thus in hypertensives the endoperoxides may be converted more readily to PGE₂ and other products.In both types of rat PGG₂ and PGH₂ given intravenously were as active or more active than after intra-arterial administration. Low but not high intravenous doses of PGE₂ were less effective than intra-arterial. Therefore PGG₂ and PGH₂ may be converted more readily to more active products during passage through the lungs but whereas small doses of PGE₂ are almost completely eliminated large doses may saturate pulmonary removal mechanisms.     

莫索尼定与可乐定对自发性高血压大鼠作用的比较

目的 :比较莫索尼定与可乐定对自发性高血压大鼠 (SHR)的作用特点。方法 :采用颈动脉直接插管测压和尾动脉间接测压法 ,一次或连续口服给药 ,分别测定清醒和麻醉SHR的血压及其心率变化。结果 :清醒SHR一次大剂量口服莫索尼定降压与心率减慢作用呈剂量依赖性 ,其 10倍剂量与可乐定作用相近 ;连续小剂量口服莫索尼定降压百分率与可乐定相仿 ,心率减慢弱而短暂 ;在麻醉SHR ,小剂量口服莫索尼定降压作用与剂量相关 ;等剂量莫索尼定与可乐定降压百分率无显著差异 (P >0 .0 5 )。结论 :大剂量一次口服给药 ,莫索尼定 10倍可乐定剂量对SHR的作用与之相当 ,小剂量连续口服给药 ,莫索尼定和可乐定等剂量对SHR的降压作用相当。     

Qi盐对肾性和自发性高血压大鼠血压的影响

目的观察Qi盐对肾性和自发性高血压大鼠(SHR)的降压作用.方法通过缩窄左肾动脉而制备2K1C夹的肾性高血压模型,同时选用16周龄的SHR,2种实验鼠均连续给予Qi盐0.4、0.2、0.1 g·kg-1,14 d(ig,qd),观察其对肾性和SHR BP的影响.结果Qi盐各剂量组及普通盐组对肾性高血压模型鼠BP在用药d 7、14均无明显的影响,而对SHR,Qi盐0.4、0.2 g·kg-1给药7d后可显著降低BP,与对照组相比,P<0.05,但14 d后BP有所回升.结论Qi盐对肾性高血压模型无明显的治疗作用,但在给药7 d后能显著地降低SHR的BP.     

Effects of indomethacin and prostaglandins I2 and E2 on the tone of human isolated mesenteric arteries

The actions of indomethacin (IND), PGE₂ and PGI₂ were studied on the tone of isolated mesenteric arteries obtained from operated patients. The cyclooxygenase inhibitors IND (3 μ mol/l) and suprofen (0.58 μ mol/l) increased the resting tone and potentiated the contractile responses to electrical stimulation and noradrenaline. Low concentrations of PGE₂ (0.7?5.6 × 10^?9 mol/l) decreased the baseline tone and reduced the stimulation-evoked contractions whereas higher concentrations (from 5.7 × 10^?8 mol/l) increased the tone of the vessels. PGI₂ (0.7–10.8 × 10^?9 mol/l) also relaxed IND-treated arteries but, in contrast to PGE₂, it did not produce contraction even at a concentration of 10^?6 mol/l. Prostacyclin reduced the tone evoked and sustained by a high concentration of PGE₂ or PGE_2α, the IC₅₀ values being 46.2 or 7.9 × 10^?9 mol/l, respectively. The contractile responses to electrical stimulation and to noradrenaline were also inhibited by PGI₂ (IC₅₀ 5.6 and 6.8 × 10^?9 mol/l, respectively). These results suggest that the smooth muscle cells of human mesenteric arteries are just as sensetive to IND, PGE₂ and PGI₂ as are those from laboratory animals. Our observations may be of clinical importance.     

肾血管性高血压与原发性高血压患者动态血压的差异研究

目的 通过对比肾血管性高血压(RVH)与原发性高血压(EH)患者24h动态血压,以研究两者之间的差异.方法 应用动态血压监测仪测定30例RVH患者的24 h动态血压,同时选择30例年龄、性别与之相匹配的EH患者行24h动态血压测定,比较两者之间的差异.结果 RVH组患者24 h、白昼、夜间的收缩压、舒张压及脉压测定的平均值,均高于EH组(P ＜0.01);RVH组患者的24 h收缩压负荷、舒张压负荷分别为58.33％和38.41％,而EH组患者则为29.01％和22.38％,两组比较差异有统计学意义(P＜0.05)).EH组有63.30％的患者夜间血压下降率＞10％,血压曲线以杓型为主;而RVH组只有26.70％的患者夜间血压下降率≥10％,血压曲线以非杓型为主.结论 RVH患者动态血压均值和血压负荷增加明显,昼夜节律减弱.     

The effects of the 5 HT2 antagonist ritanserin on blood pressure and serotonin-induced platelet aggregation in patients with untreated essential hypertension

Summary We have given the selective 5 HT₂ antagonist ritanserin in a dose of 10 mg twice daily for 4 weeks in a double-blind, randomized, placebocontrolled, parallel group study of 18 patients with untreated essential hypertension.The fall in single platelet count due to 5 HT-induced platelet aggregation was significantly reduced by ritanserin compared with placebo (p<0.05).There were no significant changes in supine or erect blood pressure or heart rate after ritanserin compared to placebo. Forearm blood flow, measured by mercury-in-strain gauge venous occlusion plethysmography, was not significantly altered by ritanserin.Ritanserin caused prolongation of the QT_c interval by 41 (SEM 11) ms (p<0.05 compared to placebo) but had no detectable effect on QRS duration, features suggestive of Class III antiarrhythmic activity.These findings do not support an independent role of the 5 HT₂ receptor in maintaining raised arterial pressure in essential hypertension.     

Gender differences in blood pressure and heart rate in spontaneously hypertensive and Wistar-Kyoto rats

1. In general, premenopausal women are known to have lower blood pressure than men and animal models have shown a similar sexual dimorphism. However, many studies in animals have been performed using anaesthetized or restrained models. Current experiments were conducted to investigate the relationships among resting heart rate, blood pressure and gender in conscious, unrestrained normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Biotelemetry transmitters were implanted in 6-month-old animals. Values for heart rate, diastolic blood pressure, systolic blood pressure and pulse pressure were recorded continuously at 10 min intervals after all animals recovered completely from surgery. 3. Normal circadian rhythms in heart rate were found in all rats, with no significant differences among the four groups; the circadian variation in blood pressure was evident in all groups, although much smaller. Heart rate was found to be higher in WKY female rats than in the other three groups. Male WKY rats, male SHR and female SHR had similar heart rates. Male SHR had significantly higher systolic and diastolic blood pressures than female SHR. Male and female WKY rats had similar diastolic blood pressure, but males had slightly higher systolic pressure than females. No significant difference in pulse pressure was found in WKY male and female rats. Male SHR showed significantly higher pulse pressure than female SHR at most times during the day. 4. In conclusion, these results indicate that hypertension is exacerbated in male SHR compared with females under conscious resting conditions and demonstrate that the higher heart rate observed in WKY female rats is not present in the SHR model.     

The effect of prostaglandins (PGE2 and PGF2α) on food intake in rats

Intracerebroventricular administration of PGF_2α and PGE₂ suppressed food intake in several feeding models. PGF_2α (20 μg) and PGE₂ (20 μg to 1 μg) suppressed food intake following a 24 hour starvation. PGF_2α (20 μg) and PGE₂ (20 μg) suppressed food intake following central administration of the feeding induces norepinephrine and muscimol. These prostaglandins also suppressed stress induced eating using the tail pinch model at doses of 20 μg, 10 μg and 5 μg with eating returning to control levels at the 1 μg dose. D-Ala Methionine Enkephalin failed to alter the suppressive effects of PGF_2α and PGE₂ at a dose of 1 μg but successfully reversed the effect of PGF_2α at a 10 μg dose while still having no effect on PGE₂ suppression of feeding.     

A comparison of the effects of prazosin and hydrallazine on blood pressure,heart rate and plasma renin activity in conscious renal hypertensive dogs

Prazosin, a novel antihypertensive agent, and hydrallazine have been compared in renal hypertensive dogs. I.v. prazosin (0.1 mg/kg) produced greater falls in blood pressure than hydrallazine (1 mg/kg i.v.) but, in contrast to hydrallazine, did not cause any significant alteration in heart rate or plasma renin activity in these animals. When given orally, prazosin (0.1 mg/kg) produced falls in blood pressure equivalent to those observed with i.v. hydrallazine (1 mg/kg) again without significant tachycardia or plasma renin activation.     

复方苦豆子对肾性高血压复合高脂血症大鼠血压和血脂的影响

目的:探讨复方苦豆子对肾性高血压复合高脂血症大鼠血压、血脂的影响及可能的机制。方法:建立肾性高血压复合高脂血症大鼠模型,随机分为模型组,复方苦豆子高、中、低剂量组,阳性对照组,每组12只。另取10只为假手术组。试验8周。每周末测定大鼠尾动脉收缩压(SBP);给药前及给药4,8周后测定大鼠血浆总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C);给药8周后测定大鼠血浆肾素活性(PRA)、AngII水平。结果:与模型组比较,药物高、中剂量组SBP,TC,TG,LDL-C及AngII水平明显降低(P<0.01);HDL-C,PRA水平明显升高(P<0.01)。结论:复方苦豆子可降低模型大鼠血压,调节血脂,其机制可能与肾素-血管紧张素系统的调节有关。     

前胡丙素对肾型高血压大鼠血压及尾动脉反应性的影响

目的：观察前胡丙素对肾型高血压大鼠血压及尾动脉反应性的影响。方法：两肾一夹ＳＤ大鼠，术后７ｗｋ始给予前胡丙素２０ｍｇ·ｋｇ－１·ｄ－１ｉｇ，给药第９周末测离体尾动脉反应性。结果：前胡丙素明显降低肾型高血压大鼠血压，用药９ｗｋ后血压较给药前下降４３％，较溶剂对照组下降４４％。尾动脉对ＮＥ和ＫＣｌ的反应性显著降低，量效曲线向右下移位。结论：前胡丙素的降压作用与其对血管平滑肌的松弛作用有关。