Influence of Alpha-Adrenoceptor Blockade with Thymoxamine on Changes in Pupil Diameter and Accommodation Produced by Tropicamide and Ephedrine

Summary

In a study in 12 healthy volunteers, local instillation of thymoxamine eye-drops (0.2 %) completely reversed the mydriasis produced by ephedrine (5 %) but not that produced by ephedrine (5%) together with tropicamide (0.5%). Small but significant changes in accommodation were found with ephedrine and reversed by thymoxamine, suggesting that they were mediated through alpha-adrenoceptor activity. The thymoxamine eyedrops were well tolerated.     

Reversal of tropicamide-induced mydriasis by thymoxamine eye drops

In a study in 12 healthy volunteers, local instillation of thymoxamine eye drops (0.5%), completely reversed the mydriasis produced by tropicamide (0.5%), but only incompletely that by tropicamide (1.0%). The difference between these effects was statistically significant (p less than 0.025). The thymoxamine eye drops were well tolerated.     

Comparison of blockade at α-adrenoceptors by thymoxamine and phentolamine in peripheral arteries and veins of man

1. The antagonism at alpha-adrenoceptors by thymoxamine and phentolamine of the response to noradrenaline was investigated in the limb veins and arteries of man.2. Brachial artery infusions of thymoxamine (40 mug/min) produced rises in resting arterial flow of up to 100%. When infused mixed with noradrenaline, thymoxamine (40 mug/min) attenuated the blood flow response to noradrenaline. Blockade was of a similar degree to that which occurred following a 10 min infusion of phentolamine (40 mug/min).3. Local intravenous infusion of thymoxamine (400-2,000 ng/min) mixed with noradrenaline attenuated the venoconstrictor response to noradrenaline. The degree of attenuation was similar to that seen after a 10 min infusion of phentolamine (500 ng/min). Blockade after thymoxamine did not last longer than 16 minutes. Neither thymoxamine nor phentolamine altered resting venous compliance.4. Local intravenous infusions of thymoxamine (500 ng/min) and phentolamine (500 ng/min) abolished the sympathetically mediated venoconstriction produced by overbreathing.5. Systemic injection of thymoxamine (0.1 mg/kg) did not block the reduction in forearm arterial flow produced by locally infused noradrenaline. In two out of three experiments, however, it produced some antagonism of noradrenaline induced venoconstriction. Systemic phentolamine (5 mg) blocked the effect of noradrenaline in the arterial bed, but antagonized its actions in the veins in only one out of three experiments.     

The effect of isoprenaline on adrenoceptors in human saphenous vein

1. The order of potency of sympathomimetic amines in causing contraction of strips of human saphenous vein was (-)-adrenaline>(-)-noradrenaline>(-)-phenylephrine>(+/-)-isoprenaline.2. The competitive alpha-adrenoceptor blocking drugs tolazoline, phentolamine, and thymoxamine and the irreversible blocking drug phenoxybenzamine all blocked noradrenaline and isoprenaline contractions.3. Contractions produced by 5-hydroxytryptamine were also blocked by phentolamine and thymoxamine. Fenfluramine-induced contractions were not blocked by thymoxamine or phenoxybenzamine.4. ED50 contracting doses of isoprenaline did not cause consistent relaxation of noradrenaline-contracted strips.5. It is concluded that human saphenous vein contains a dominant population of alpha-adrenoceptors which can be stimulated by high doses of isoprenaline, but the occurrence of beta-adrenoceptors mediating relaxation is rare.     

Mechanisms underlying mechanical responses to Ephedra herb of isolated rabbit urinary bladder and urethra, a possible stress urinary incontinence therapeutic

To compare the mechanisms underlying mechanical responses to ephedrine and Ephedra herb, a main component of Kakkon-to, in isolated male and female rabbit urinary bladder and urethral strips, responses of isolated strips to the agents were recorded in organ bath systems. Ephedrine and Ephedra herb relaxed the female urinary bladder to the similar extent. These relaxations are reversed to contractions by timolol. In the presence of timolol, ephedrine produced less contraction of urethral strips in the female than those in the male; this contraction was abolished by prazosin. Ephedra herb contracted the female urethra less than that of the male, and the contraction was stronger than that by ephedrine. The contraction caused by Ephedra herb in strips treated with timolol was significantly inhibited by prazosin. The prazosin-resistant contraction of the female urethra was greater than that of the male. Quinacrine, a phospholipase A(2) inhibitor, indomethacin, and AA861, a 5-lipoxygenase inhibitor, inhibited the contraction. The contraction was inhibited by ZK 158252, a leukotriene (LT) B(4)-receptor antagonist. These findings suggest that Ephedra herb contracts the urethra via arachidonic acid metabolites together with alpha(1)-adrenoceptor stimulation. The metabolites produced by 5-lipoxygenase may stimulate LTB(4), but not CysLt(1), receptors. These contractile components induced by Ephedra herb and Kakkon-to might be effective for the treatment of stress urinary incontinence.     

Evaluation of the effect of thymoxamine solution 0.5% on mydriasis induced by ibopamine solution 1%

Summary The effects of thymoxamine 0.5% solution and of a placebo solution (mannitol) on the mydriasis induced by ibopamine 1% solution were evaluated in 8 healthy volunteers and 12 patients with eye diseases.One drop of ibopamine was instilled into each eye and 30 min later 1 drop of thymoxamine was instilled into one eye and 1 drop of placebo into the contralateral eye. Pupillary diameter was measured before and 30 min after the instillation of ibopamine, immediately before the treatment with thymoxamine and placebo and 30, 60 and 90 min after the instillation of thymoxamine or of placebo.Within 30 min of treatment, ibopamine had produced a statistically and clinically significant mydriatic effect. In eyes treated with thymoxamine, prompt reversal of mydriasis was observed, the baseline diameter being observed within 60 min.No difference in the time-course of the mydriatic effect was detected between healthy subjects and patients. The pupillary response to thymoxamine was not influenced by the colour of the iris. The tolerability of ibopamine and of thymoxamine was good. No local or systemic adverse events were seen or reported.     

Dopamine-like properties of ephedrine in rat brain.

1 Ephedrine (3.1-50 mg/kg) was given intraperitoneally to rats and was found to cause a marked increase in spontaneous locomotor activity. 2 In rats with a unilateral lesion in the substantia nigra made by stereotaxic injections of 6-hydroxydopamine, ephedrine (12.5-150 mg/kg i.p.) caused a dose-dependent turning towards the lesioned side. 3 Turning behaviour and increase in locomotion produced by ephedrine were antagonized by pretreatment of the animals with pimozide, amino-oxyacetic acid or reserpine plus alpha-methyl-p-tyrosine, but not by pretreatment with phenoxybenzamine, propranolol or methergoline. 4 In in vitro studies with synaptosomes prepared from rat brain, ephedrine blocked the uptake and caused the release of [3H]-dopamine. 5 Similar results with regard to locomotion and turning behaviour were obtained with (+)-amphetamine. 6 It is concluded that the increase in locomotion and turning behaviour produced by ephedrine is mediated through an indirect dopaminergic mechanism.     

复方硫酸庆大霉素滴鼻剂的制备与质量控制

目的 :不经分离直接测定制剂中硫酸庆大霉素、盐酸麻黄碱、地塞米松磷酸钠3组分含量。方法 :利用Hantzsh反应使庆大霉素形成二氢砒啶衍生物 ,在紫外330nm波长处测定其含量 ;应用双波长原理 ,分别在紫外测定波长256.5nm、241.6nm ,参比波长228.4nm、266.4nm处测定盐酸麻黄碱、磷酸地塞米松含量。结果 :硫酸庆大霉素、盐酸麻黄碱、地塞米松磷酸钠3组分平均回收率分别为 (100.74±0.2) %、(100.15±0.66) %、(99.46±0.35) % ,n=5。结论 :方法简便、快速、准确、稳定 ,适用于该制剂的快速质量控制。     

An evaluation of l-ephedrine neurotoxicity with respect to hyperthermia and caudate/putamen microdialysate levels of ephedrine, dopamine, serotonin, and glutamate.

l-Ephedrine is an active ingredient in several herbal formulations with a mechanism of action similar to amphetamine and methamphetamine. However, its potential to damage dopaminergic terminals in the caudate/putamen (CPu) has yet to be fully evaluated. The studies here used in vivo brain microdialysis experiments to determine the systemic doses and extracellular brain levels of l-ephedrine necessary to produce similar increases in CPu extracellular dopamine and marked hyperthermia that were previously shown necessary for amphetamine-induced neurotoxicity in male Sprague-Dawley rats. At an environmental temperature of 23 degrees C, a single 40 mg/kg intraperitoneal (ip) dose of l-ephedrine produced marked hyperthermia (>/= 40 degrees C), peak microdialysate ephedrine levels of 7.3 +/- 1.2 microM, and a 20-fold increase in microdialysate dopamine levels. Twenty-five mg/kg produced a lesser degree of hyperthermia, peak microdialysate ephedrine levels of 2.6 +/- 0.4 microM, and a 10-fold increase in dopamine levels. Three doses of 40 mg/kg given at 3-h intervals or 4 doses of 25 mg/kg l-ephedrine given at 2-h intervals were compared with 4 doses of 5 mg/kg d-amphetamine given at 2-h intervals. Multiple doses of either ephedrine or amphetamine caused severe hyperthermia (>/= 41.3 degrees C) but striatal tissue levels of dopamine 7 days after dosing were reduced only 25% or less by ephedrine compared to the 75% reductions produced by amphetamine. The increases in CPu microdialysate levels of serotonin produced by either 4 x 25 mg/kg l-ephedrine or 4 x 5 mg/kg d-amphetamine did not significantly differ, but elevation of dopamine levels by d-amphetamine were over 2-fold times the level caused by l-ephedrine. Microdialysate glutamate levels were elevated to the same extent by either 25 mg/kg l-ephedrine or 4 x 5 mg/kg d-amphetamine. l-Ephedrine may not be as neurotoxic to dopaminergic terminals as d-amphetamine, because non-lethal doses of l-ephedrine do not sufficiently increase the CPu dopamine levels within nerve terminals or the extracellular space to those necessary for a more pronounced long-term dopamine depletion.     

麻黄碱与总皂苷对豚鼠气管平滑肌松弛的协同作用

目的　探讨麻黄碱与总皂苷在平喘作用方面有无协同作用。方法　将麻黄碱与总皂苷分成麻黄碱 +总皂苷组、总皂苷组和麻黄碱组进行离体豚鼠气管平滑肌松弛作用强度比较。结果　麻黄碱 +总皂苷组直接松弛豚鼠离体气管平滑肌的作用强度是麻黄碱组的 3 5倍 (P <0 0 5 ) ,总皂苷组无作用 (P >0 0 5 )。麻黄碱 +总皂苷组对氨甲酰胆碱(carbamylcholine,CCH)引起气管平滑肌收缩反应的解痉强度与麻黄碱组相同 ,但两者都比总皂苷组强 (P <0 0 5 )。麻黄碱 +总皂苷、麻黄碱和总皂苷组预先处理气管平滑肌均呈浓度依赖抑制CCH收缩反应 ,三者之间的作用强度无差异。结论　总皂苷对麻黄碱在直接松弛气管平滑肌和抑制CCH引起的气管平滑肌收缩方面具有明显的协同作用 ,但在解痉方面的协同作用不明显     

Thymoxamine: lack of antihistaminic effects in clinical doses in man.

The purpose of this study was to investigate whether the alpha 1-adrenoceptor antagonist thymoxamine possesses antihistaminic activity in clinical doses in man, as has been reported on the guinea pig ileum in vitro. Five normal subjects were given on three separate occasions intravenous infusions of thymoxamine (0.15 mg kg-1 loading dose followed by 0.15 mg kg-1 h-1), chlorpheniramine (1.5 mg loading dose followed by 1.5 mg h-1) and normal saline (placebo). Intravenous bolus doses of histamine (1 and 2 micrograms kg-1) were given after pretreatment with propranolol 10 mg to block the beta-adrenoceptor agonist effects of the catecholamines released by the histamine injections. Histamine caused a dose-dependent reduction of FEV1 and FVC that was antagonised by chlorpheniramine but not by thymoxamine, suggesting that thymoxamine has no antihistaminic activity in the doses used in man. Thymoxamine caused a small enhancement of the bronchoconstrictor effect of the lower dose of histamine. The relatively selective action of thymoxamine makes it a suitable agent for the investigation of alpha 1-adrenoceptors.     

The stimulus effect of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline is similar to that of cocaine but different from that of amphetamine.

5,6,7,8-Tetrahydro-1,3-dioxolo[4,5-g]isoquinoline (TDIQ) is a conformationally restricted phenylalkylamine related in structure to amphetamine and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) that does not act as a locomotor stimulant. To further evaluate this agent, a group of six rats was trained to discriminate 5.0 mg/kg of TDIQ from vehicle and tests of stimulus generalization were conducted to define the stimulus. The TDIQ stimulus (ED(50)=0.9 mg/kg) failed to generalize to the central stimulants (+)amphetamine, methylphenidate or (-)ephedrine but, curiously, generalized to cocaine (ED(50)=1.5 mg/kg). When administered to rats (n=5) trained to discriminate 1.0 mg/kg of (+)amphetamine from vehicle, TDIQ produced a maximum of 7% (+)amphetamine-appropriate responding, whereas when administered to rats (n=7) trained to discriminate 4.0 mg/kg of (-)ephedrine from vehicle, TDIQ produced a maximum of 57% drug-appropriate responding. Administration of MDMA to TDIQ-trained animals resulted in 76% TDIQ-appropriate responding. Tests of stimulus generalization were also conducted with fenfluramine, nisoxetine, clenbuterol, imipramine and buspirone, and tests of antagonism were conducted with haloperidol and R(+)SCH-23390 using the TDIQ-trained animals. Results were inconclusive in that these agents either failed to completely substitute for or failed to completely antagonize the TDIQ stimulus. Nevertheless, the generalization seen with cocaine, the partial generalization seen with (-)ephedrine, MDMA, nisoxetine, clenbuterol and buspirone and the partial antagonism seen with haloperidol suggest that TDIQ might be acting through a mixed mechanism that involves adrenergic, dopaminergic and/or serotonergic systems. Given that TDIQ is an agent that seems to differentiate among the stimuli produced by amphetamine, methylphenidate, ephedrine and cocaine, it is proposed that further tests be undertaken, using animal models of cocaine abuse, to evaluate the potential usefulness of TDIQ as pharmacotherapy in cocaine dependence.     

The effect of thymoxamine on peripheral blood vessels as monitored by the 133Xe clearance technique

The rate of clearance of intra-articularly administred ¹³³Xe provides an indirect method for the measurement of synovial tissue perfusion. The effect of an intra-articular injection of thymoxamine, and of isoprenaline was to increase the clearance rate whereas the converse was seen with noradrenaline. The prior administration of thymoxamine did not affect the isoprenaline response. In suitable doses, thymoxamine both prevented, and reversed the noradrenaline effect.     

Mecamylamine attenuates ephedrine-induced hyperactivity in rats

Ephedrine is a central nervous system stimulant that has a pharmacological profile similar to amphetamines. Ephedrine induces hyperactivity after acute administration to rats and locomotor sensitization develops to ephedrine with repeated administration. Recent research suggests that nicotinic receptors (nAChRs) play a role in the development of locomotor sensitization to d-amphetamine and the goal of the present study was to determine if nAChRs similarly mediate the effects of ephedrine after acute and repeated drug injection. On 12 consecutive days, rats were pretreated with the nAChR antagonist mecamylamine (0.3-3.0 mg/kg) or saline followed by (-)-ephedrine (10-30 mg/kg) or saline injection and locomotor activity was measured. Ephedrine produced a dose-dependent increase in locomotor activity, and sensitization to ephedrine developed with repeated injection. Mecamylamine pretreatment attenuated the hyperactivity and sensitization produced by repeated, but not acute, ephedrine (10 mg/kg) injection. The inhibitory effect of mecamylamine was overcome at the higher ephedrine dose (30 mg/kg). The present results indicate that nAChRs play a mediating role in the development of locomotor sensitization to ephedrine.     

The effects of uptake1 on alpha-adrenoceptor antagonist potency in dog saphenous vein.

1 The effects of alpha-adrenoceptor antagonists on contractile responses to noradrenaline and methoxamine were examined in isolated saphenous vein strips of the dog. 2 Phentolamine, labetalol and thymoxamine antagonized responses to methoxamine to a greater extent than responses to noradrenaline. 3 Cocaine (3.0 x 10(-5) mol/l) increased the potency of noradrenaline by about eight fold, but had little or no effect on the potency of methoxamine. 4 In the presence of cocaine (3.0 x 10(-5) mol/l) the potency of the antagonists against noradrenaline was increased such that the pA2 values were then similar to those obtained against methoxamine. 5 It is concluded that the lower potency of phentolamine, labetalol and thymoxamine as antagonists of noradrenaline than of methoxamine is due to the presence of an avid saturable uptake1 process in the saphenous vein.     

Anorectic effect of ephedrine

1. Different doses of ephedrine (3.1-50 mg kg-1) were given intraperitoneally to rats and found to decrease food intake dose-dependently. 2. The anorectic effect of ephedrine was decreased by animal pretreatment with pimozide, but phenoxybenzamine, propranolol and methergoline did not decrease the response. 3. The results show that the anorexia produced by ephedrine may be due to indirect dopaminergic mechanism of the drug.     

Effects of some sympathomimetic drugs and their antagonists on afterdischarges elicited in chronically isolated slabs of cerebral cortex

1. The role of sympathomimetic agents in the maintenance and termination of induced cortical epileptiform activity was studied in chronically neuronally isolated slabs of cerebral cortex in the suprasylvian gyrus of unanaesthetized, unrestrained cats.2. The administration of the sympathomimetic agents (+)-amphetamine, methamphetamine, tyramine, and ephedrine resulted in a highly significant decrease in the duration of epileptiform afterdischarge (EADs).3. The alpha-adrenoceptor blocking drugs phenoxybenzamine, phentolamine and tolazoline did not significantly alter the duration of EADs but prevented the decrease in duration of EADs produced by the sympathomimetic drugs.4. The effect of atropine and arecoline on the duration of EADs, previously described, were not modified by the alpha-adrenoceptor blocking drugs, but atropine prevented and reversed the inhibitory action of amphetamine.5. It is suggested that (1) in the chronically neuronally isolated cortical slab there is normally no spontaneous adrenergic activity, (2) a cortical, cholinergic inhibitory mechanism, previously described, is modulated by ascending adrenergic influences, (3) adrenergic cholinergic linkages might be arranged in the cortex in an alternating network, as proposed by Feldberg.     

Ephedrine: a postsynaptic depressant drug at the mammalian neuromuscular junction

The actions of ephedrine were studied using intracellular recording techniques in guinea pig intercostal muscle fiber. After application of ephedrine (10^?5 ?10^?4 M), miniature end-plate potential (MEPP) amplitude was decreased in a concentration-dependent manner. A greater depression in amplitude of end-plate potentials (EPP) was observed in preparations immobilized with d-tuboeurarine. In addition, ephedrine depressed the transient depolarization produced by iontophoretically applied acetylcholine (ACh).In normal Krebs solution and high Mg²⁺ solution, 10^?4 M ephedrine increased MEPP frequency but did not alter the quantal content of EPPs in high Mg²⁺ blocked muscle. In these preparations, EPP amplitude did not change significantly. These results suggested that in the absence of a postsynaptic receptor blocking agent, a slight presynaptic action of ephedrine may offset the decreased responsiveness of the postsynaptic membrane. In addition, no significant alterations of resting membrane potential or the electrical characteristics of the membrane were recorded.Pretreatment of a mouse phrenic nerve-diaphragm preparation with ephedrine did not protect against the irreversible blockade by α-bungarotoxin. These results suggested that ephedrine may depress ACh potentials, MEPPs, and EPPs in dTc-blocked muscle by acting postsynaptically at a site on or associated with the ACh receptor other than the ACh recognition site.     

Turning behaviour as an index of the action of amphetamines and ephedrines on central dopamine-containing neurones

1. Rats lesioned unilaterally in the substantia nigra show no obvious abnormalities after recovery from the operation but rotate towards the lesioned side after administration of drugs of the amphetamine and ephedrine groups.2. (+)-Amphetamine and (-)-amphetamine are equally potent in producing turning behaviour but (+)-methylamphetamine is considerably more effective.3. (-)-Ephedrine (with a beta-OH group on the ethylamine side chain) induces turning but only in doses approximately 20 times greater than (+)-methylamphetamine.4. (+)-Norpseudoephedrine was the most effective of the ephedrine isomers tested followed by (-)-ephedrine and (+)-pseudoephedrine.5. Turning produced by (-)-ephedrine and (+)-methylamphetamine is not reduced by FLA63 (50 mg/kg) 4 h previously, but is almost completely inhibited by alpha-methyl-p-tyrosine (150 mg/kg) 12 h previously.6. Reserpine pretreatment potentiates turning produced by (-)-ephedrine.7. Chlorpromazine (5 mg/kg) completely blocks turning induced by (+)-methylamphetamine although it concurrently increases exploratory activity. The level of exploratory activity after the (+)-methylamphetamine-chlorpromazine combination is more than 3 times that attained after saline alone.     

Urinary excretion of ephedrine after nasal application in healthy volunteers.

The urinary excretion of ephedrine after intranasal administration of the drug was studied in 8 healthy volunteers. Ephedrine (6 drops of a commercial 0.75% nasal ephedrine solution in each nasal cavity) was administered 4 times at intervals of 2 h (total amount applied equivalent to approximately 14 mg ephedrine), and urine was collected each hour for 10 h; the volunteers exercised on a bicycle ergometer at 50% of their VO2max for 2 h after the last ephedrine application. Ephedrine was detected in all urine samples. The urinary ephedrine concentration ranged from 0.9 to 16.5 micrograms mL-1; the number of urine samples with an ephedrine concentration exceeding 5 micrograms mL-1 ranged from 1/10 (volunteer 2) to 9/10 (volunteers 1 and 3). The mean percentage of dose recovered within 10 h was 33% (range 23-50%). There was a weak but significant negative correlation between urinary pH and amount of ephedrine in the urine; exercise did not consistently influence the urinary amount. These results illustrate the systemic availability of ephedrine upon intranasal administration and show that the therapeutic use of a nasal ephedrine formulation by an athlete on the day of a competition can lead to a urinary ephedrine concentration above 5 micrograms mL-1, which is considered positive in current doping regulations of the International Union of Cyclists.