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PubMed1988

Dopamine-mediated behaviour following chronic treatment with B-HT 920.

Following subchronic (5-day) dosing with B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo(4,5-d)azepine (1 mg kg-1 day-1 i.p.) in rats there was a significant increase in both apomorphine-induced motor activity and stereotypy. On continued B-HT 920 treatment, however, the enhancement of apomorphine motor activity faded into insignificance but the increase in stereotypy persisted beyond 15 days. The results are discussed in terms of dopamine autoreceptor tolerance, postsynaptic D2 supersensitivity and possible differential effects in different brain loci on the above two receptor sub-classes.

Adrenergic alpha-Agonists↗
PubMed1989

The effects of B-HT 920 and St 91 on venous haemodynamics in cats.

The present study reports the effects of 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepin dihydrochloride (B-HT 920) and 2-(2,6-diethylphenylimino)-2-imidazolidine hydrochloride (St 91) in autoperfused cat hindquarters since we have previously shown that clonidine lowered blood pressure, heart rate and vena cava blood flow (VCBF) but not hindquarters perfusion pressure, indicating a selective venodilator action of this drug (Bentley et al 1986). It was found that intravenous (i.v.) and intracisternal (i.c.m.) administration of B-HT 920 caused essentially identical effects to those of clonidine. St 91, given i.c.m. lowered blood pressure and VCBF but not perfusion pressure, while i.v. St 91 had little effect on these variables. Thus, parallel changes in blood pressure and VCBF occurred using both drugs, suggesting that these centrally-acting clonidine-like drugs also caused selective venodilatation.

Adrenergic alpha-Agonists↗
PubMed1989

Stimulation of postsynaptic D2- dopamine receptors by B-HT 958 is revealed by co-treatment with the D1- receptor agonist SKF 38393.

The motor activity of reserpine-treated mice was used to study effects of B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo-[5,4-d]- azepine) on postsynaptic dopamine and noradrenaline receptors. The motor activity was only slightly stimulated by B-HT 958 or by the D1- receptor agonist SKF 38393 but it was markedly increased by the two drugs given in combination. The effect of B-HT 958 peaked earlier following low rather than high doses. The enhanced motor activity was inhibited by the D2- receptor antagonist sulpiride or the D1- receptor antagonist SCH 23390, indicating that it was caused by stimulation of both receptor types. The results suggest that B-HT 958 stimulates postsynaptic D2- receptors in addition to D2- autoreceptors and that its blockade of postsynaptic alpha 2-adrenoceptors is of no importance for the motor activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Dopamine receptor mediated hypothermic action of B-HT 920 in rats.

The hypothermic action of the thiazoloazepine derivative B-HT 920, an alpha 2-adrenoceptor agonist has been investigated in rats. B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d)-azepine dihydrochloride) (0.25-1.0 mg kg-1 i.p.) induced a dose-dependent hypothermia. This peak effect was seen within 60-90 min and lasted up to 120 min. Its action was potentiated by the selective D1-dopamine agonist SKF 38393 and inhibited by the D2-antagonists haloperidol (1 mg kg-1) and sulpiride (100 mg kg-1). The hypothermic action of B-HT 920 was centrally mediated; i.c.v. administration of 10 micrograms produced a significant fall in rectal temperature which was sensitive to blockade by haloperidol. B-HT 920 also potentiated the hypothermic action of apomorphine (0.1 and 0.5 mg kg-1) in a haloperidol sensitive manner. Reserpine (5 mg kg-1 i.p.) pretreatment reduced the hypothermic response of B-HT 920 (0.5 mg kg-1) but sensitized the response due to the combination of B-HT 920 (0.5 mg kg-1) and apomorphine (0.1 mg kg-1). Neither the selective alpha 2-adrenoceptor antagonists, yohimbine (1 mg kg-1) or idazoxan (1 mg kg-1), the histamine antagonist mepyramine (10 mg kg-1) nor the 5-HT antagonist cyproheptadine (5 mg kg-1) inhibited B-HT 920-induced hypothermia. Similarly, the selective alpha 1-antagonist prazosin (1 mg kg-1) and the beta-antagonist propranolol (10 mg kg-1) failed to modify the hypothermic action of B-HT 920. These observations demonstrated hypothermia induced by B-HT 920 is mediated by postsynaptic D2-receptors and D1- and D2-receptor interplay is essential for the full expression of hypothermia in rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Alpha 2-adrenoceptor- and D2-dopamine receptor-mediated analgesic response of B-HT 920.

The involvement of D2-dopamine receptors in the antinociceptive action of B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-(4H) thiazolo-(4,5d)-azepine) has been investigated in mice. B-HT 920 (0.1-2.0 mg kg-1) and apomorphine (0.1-2.0 mg kg-1) produced a dose-dependent increase in tail flick latency. Analgesia induced by apomorphine was blocked by the D2-antagonist, haloperidol (1 mg kg-1) but not by the opioid antagonist, naloxone (1 mg kg-1). The antinociceptive action of B-HT 920 was potentiated by the D1-agonist SKF 38393 (5 mg kg-1), an action antagonized by haloperidol. The selective alpha 2-adrenoceptor blocking drug yohimbine (1 mg kg-1) and naloxone (1 mg kg-1) blocked the antinociceptive action of B-HT 920 (1 mg kg-1). Haloperidol, however, failed to modify the B-HT 920-induced increase in tail flick latency. B-HT 920 and apomorphine reversed reserpine (2 mg kg-1) 4 h-induced hyperalgesia. The reversing action of apomorphine was blocked by haloperidol but not by yohimbine. Thus, a role of alpha 2-adrenoceptors and D2-dopamine receptors is postulated in the antinociceptive action of B-HT 920.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

The synthesis and some pharmacological actions of the enantiomers of the K(+)-channel blocker cetiedil.

Cetiedil ((+/-)-2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1 H-azepin-1-yl) ethyl ester) possesses anti-sickling and analgesic, antispasmodic, local anaesthetic and vasodilator activities. A total synthesis and circular dichroism spectra of the enantiomers of cetiedil is described, together with a comparison of their effectiveness as blockers of the Ca(2+)-activated K+ permeability of rabbit erythrocytes; the contractile response of intestinal smooth muscle to acetylcholine; the Ca(2+)-dependent contraction of depolarized intestinal muscle; and the cell volume-sensitive K+ permeability (Kvol) of liver cells. The enantiomers did not differ substantially in their ability to block the Ca(2+)-activated K+ permeability of rabbit red cells or in their effectiveness as blockers of the contractile response of depolarized smooth muscle to externally applied Ca2+. There was a clear difference in the muscarinic blocking activity of the enantiomers, as assessed by inhibition of the contractile response of intestinal smooth muscle to acetylcholine; (+)-cetiedil was 7.7 +/- 0.2 (s.d.) times more active than the (-) from. The enantiomers also differed in their potency as blockers of the increase in membrane conductance which occurs when liver cells swell. The concentration of (+)-cetiedil needed to reduce the conductance increase by 50% was 2.04 +/- 0.54 (s.d.) microM; (-)-cetiedil was 2.6 +/- 0.8 (s.d.) times less active (IC50 of 5.2 +/- 1.2 microM). Differences in the biological actions of the enantiomers of cetiedil indicate that a more extensive study could be rewarding in relation to the use of the enantiomers both in therapeutics and in the study of K+ channels.

Animals↗
PubMed2003

Piribedil enhances frontocortical and hippocampal release of acetylcholine in freely moving rats by blockade of alpha 2A-adrenoceptors: a dialysis comparison to talipexole and quinelorane in the absence of acetylcholinesterase inhibitors.

In a dialysis procedure not requiring perfusate addition of acetylcholinesterase inhibitors to "boost" basal levels of acetylcholine (ACh), the influence of the antiparkinson agent piribedil upon levels of ACh in frontal cortex and dorsal hippocampus of freely moving rats was compared with those of other antiparkinson drugs and selective ligands at alpha(2)-adrenoceptors (ARs). Suggesting a tonic, inhibitory influence of alpha(2A)-ARs upon cholinergic transmission, the alpha(2)-AR agonist 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline tartrate (UK14,304), and the preferential alpha(2A)-AR agonist guanabenz reduced levels of ACh. They were elevated by the antagonists 2(2-methoxy-1,4 benzodioxan-2-yl)-2-imidazoline HCl (RX821002) and atipamezole and by the preferential alpha(2A)-AR antagonist 2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole (BRL44008). In contrast, trans-2,3,9,13b-tetrahydro-1,2-dimethyl-1H-dibenz[c,f]imidazo[1,5-a]azepine (BRL41992) and prazosin, preferential alpha(2B/2C)-AR antagonists, were inactive. The dopaminergic agonist and antiparkinson agent piribedil, which behaves as an antagonist at alpha(2)-ARs, dose dependently increased extracellular levels of ACh. This action was absent upon pretreatment with a maximally effective dose of RX821002. On the other hand, a further dopaminergic agonist and antiparkinson agent, talipexole, which possesses agonist properties at alpha(2)-ARs, dose dependently reduced levels of ACh. This action was also blocked by RX821002. In contrast to piribedil and talipexole, quinelorane, which interacts with dopaminergic receptors but not alpha(2)-ARs, failed to affect ACh levels. Finally, in analogy to the frontal cortex, piribedil likewise elicited a dose-dependent increase in extracellular levels of ACh in the dorsal hippocampus. In conclusion, in distinction to talipexole and quinelorane, and reflecting its antagonist properties at alpha(2A)-ARs, piribedil reinforces cholinergic transmission in the frontal cortex and dorsal hippocampus of freely moving rats. These actions may be related to its facilitatory influence upon cognitive function.

Acetylcholine↗
PubMed2003

SSR591813, a novel selective and partial alpha4beta2 nicotinic receptor agonist with potential as an aid to smoking cessation.

(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2',3':5,6]pyrano[2,3-d]azepine (SSR591813) is a novel compound that binds with high affinity to the rat and human alpha4beta2 nicotinic acetylcholine receptor (nAChR) subtypes (Ki = 107 and 36 nM, respectively) and displays selectivity for the alpha4beta2 nAChR (Ki, human alpha3beta4 > 1000, alpha3beta2 = 116; alpha1beta1deltagamma > 6000 nM and rat alpha7 > 6000 nM). Electrophysiological experiments indicate that SSR591813 is a partial agonist at the human alpha4beta2 nAChR subtype (EC50 = 1.3 micro M, IA =19% compared with the full agonist 1,1-dimethyl-4-phenyl-piperazinium). In vivo findings from microdialysis and drug discrimination studies confirm the partial intrinsic activity of SSR591813. The drug increases dopamine release in the nucleus accumbens shell (30 mg/kg i.p.) and generalizes to nicotine or amphetamine (10-20 mg/kg i.p.) in rats, with an efficacy approximately 2-fold lower than that of nicotine. Pretreatment with SSR591813 (10 mg/kg i.p.) reduces the dopamine-releasing and discriminative effects of nicotine. SSR591813 shows activity in animal models of nicotine dependence at doses devoid of unwanted side effects typically observed with nicotine (hypothermia and cardiovascular effects). The compound (10 mg/kg i.p.) also prevents withdrawal signs precipitated by mecamylamine in nicotine-dependent rats and partially blocks the discriminative cue of an acute precipitated withdrawal. SSR591813 (20 mg/kg i.p.) reduces i.v. nicotine self-administration and antagonizes nicotine-induced behavioral sensitization in rats. The present results confirm important role for alpha4beta2 nAChRs in mediating nicotine dependence and suggest that SSR591813, a partial agonist at this particular nAChR subtype, may have therapeutic potential in the clinical management of smoking cessation.

Animals↗
PubMed2004

Investigation into the potential anti-inflammatory effects of endothelin antagonists in a murine model of experimental monosodium urate peritonitis.

Endothelin (ET)-1 has been detected in many inflammatory pathologies, including rheumatoid arthritic patients, asthma, and ischemic-reperfusion injury. In this study, we have investigated the effect of a panel of different ET-1 antagonists displaying different selectivities for the receptors in a murine model of experimental inflammatory peritonitis. Systemic treatment of mice with the ETA antagonist C33H44N6O5, N-[N-[-N(hexahydro-1H-azepin-1-yl)carbonyl]-L-leucyl]-1-methyl-D-tryptophyl]-3-(2-pyridinyl)-D-alanine (FR139317) inhibited neutrophil accumulation. However, a greater degree of inhibition was observed with the ETB antagonist C34H51N5O7, N-cis-2,6-dimethylpiperidinocarbonyl-b-tBu-Ala-D-Trp(1-methoxycarbonyl)-D-Nle-OH (BQ-788) and the ET(A and B) antagonist C52H65N7O10, N-acetyl-alpha-[10,11-dihydro-5H-dibenzo-[a,d]cycloheptadien-5-yl]-D-Gly-Leu-Asp-lle-lle-Trp (PD145065); all these effects occurred without altering peripheral blood cell counts. Release of the CXC chemokine KC was significantly reduced by the FR139317 and PD145065 but not by BQ-788. Evaluation of the therapeutic potential of these antagonists showed that PD145065 inhibited neutrophil migration and KC release, whereas the others caused a nonsignificant reduction in these parameters. Parameters of endothelial cell activation showed that urate-stimulated interleukin-1beta release was inhibited by BQ-788 and PD145065 but not by FR139317, whereas ET-1 was only inhibited by the mixed antagonist. A different scenario was observed with respect to release of the CXC chemokine KC with FR139317 and PD145065 being effective, whereas with a marker of polymorphonuclear activation the ETA and mixed antagonist inhibited adhesion molecule expression. These data show that ET-1 antagonists elicit different mechanisms of actions in the way they display their antimigratory effects in a murine model of monosodium urate crystal peritonitis.

Animals↗
PubMed1984

Calcium channel activation in vascular smooth muscle by BAY K 8644.

BAY K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate) and CGP 28 392 (ethyl-4(2-difluoromethoxyphenyl)-1,4,5,7-tetrahydro-2-methyl-5-++ +oxofuro- [3,4-b]pyridine-3-carboxylate) are closely related in structure to nifedipine and other 1,4-dihydropyridine Ca2+ channel antagonists. However, both BAY K 8644 and CGP 28 392 serve as activators of Ca2+ channels. In the rat tail artery, responses to BAY K 8644 are dependent upon Ca2+ext and prior stimulation by K+ or by the alpha-adrenoceptor agonists, phenylephrine and BHT 920 (6-allyl-2-amino-5,6,7,8,-tetrahydro-4H-thiazolo[4,5-d]azepin dihydrochloride). Responses are blocked noncompetitively by the Ca2+ channel antagonists D-600 [-)-D-600 greater than (+)-D-600) and diltiazem, but competitively by nifedipine (pA2 = 8.27). This suggests that activator and inhibitor 1,4-dihydropyridines interact at the same site. BAY K 8644 potentiates K+ responses and Ca2+ responses in K+-depolarizing media. The leftward shift of the K+ dose--response curve produced by BAY K 8644 suggests that this ligand facilitates the voltage-dependent activation of the Ca2+ channel. The pA2 value for nifedipine antagonism of BAY K 8644 responses is significantly lower than that for nifedipine antagonism of Ca2+ responses in K+ (25-80 mM) depolarizing media (9.4-9.6), suggesting that the state of the channel may differ according to the activating stimulus.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1980

Centrally mediated hypotensive activity of B-HT 933 upon infusion via the cat's vertebral artery.

The acute hypotensive and bradycardic effects of the new compound B-HT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-[5,4-d]-azepin-dihydrochloride) were investigated in anaesthetized cats and rats. In spite of the molecular structure of B-HT 933, which differs considerably from that of clonidine, its cardiovascular reaction pattern is comparable, although the former is much less potent. B-HT 933 showed a central nervous origin for its acute hypotensive action in anaesthetized cats, since its effects on blood pressure after infusion via the left vertebral artery were much greater than after intravenous application of the same amounts. Pretreatment with the alpha-adrenoceptor-blocking drug, piperoxan (100 micrograms/kg), completely abolished the hypotensive response to B-HT 933 (30 micrograms/kg) injected subsequently via the left vertebral artery. It is concluded that B-HT 933 is a centrally acting hypotensive drug. Central alpha-adrenoceptors are involved in a similar manner as the mechanism of clonidine.

Animals↗
PubMed1989

A cyclic imine intermediate in the in vitro metabolic conversion of 1,6-diaminohexane to 6-aminohexanoic acid and caprolactam.

1. 3,4,5,6-Tetrahydro-2H-azepine is an intermediate in the enzyme-catalyzed conversion of 1,6-diaminohexane to 6-aminohexanoic acid and its corresponding lactam, caprolactam, by mammalian liver aldehyde oxidase. 2. Identification of metabolites was based on analysis by gas chromatography-mass spectrometry and confirmed by comparison with the properties of authentic standards. 3. The results indicate that the cell differentiating agent hexamethylene bisacetamide is converted into 1,6-diaminohexane, and its metabolism therefore involves diamine oxidase. 4. The metabolic fate of 1,6-diaminohexane is similar to that of putrescine and cadaverine in that a cyclic imine is an intermediate in the formation of metabolites with ring (lactam) and chain (amino acid) structures.

Aldehyde Oxidase↗
PubMed1991

Antagonistic effect of amiloride on alpha-2 adrenoceptor-mediated pigment aggregation: pharmacological heterogeneity between B-HT 920 and noradrenaline.

Pigment aggregation in melanophores from the cuckoo wrasse (Labrus ossifagus L.) has previously been shown to be mediated by alpha-2 adrenoceptors. In the present investigation, the effect of amiloride on pigment aggregation induced by noradrenaline and B-HT 920 was studied. Amiloride caused a parallel shift to the right in concentration-response curves for 5-allyl-2-amino-5,6,7,8-tetrahydrothiazolo-[4,5-d]azepine-dihyd roc hloride: (B-HT 920), with no change in the maximal response, indicating simple competitive inhibition. Subsequent Schild plot analysis gave a straight line with a slope of almost unity (0.95) and a KB of 5 x 10(-6) M. In contrast to the effect of amiloride on B-HT 920-induced pigment aggregation, only a very high concentration of amiloride (1 x 10(3) M) inhibited the corresponding effect of noradrenaline. Na+/H+ exchange has been suggested as a possible mechanism for alpha-2 adrenoceptors, and the amiloride analogs 5-(N,N-dimethyl)amiloride and 5-(N,N-hexamethylene)amiloride are known to be more specific than amiloride itself in this respect. However, these analogs inhibited the effect of B-HT 920 significantly less effectively than amiloride. Furthermore, manipulating the extracellular pH between 6.8 and 7.8 did not affect the concentration response curves of B-HT 920. Neither did the prostanoid pathway inhibitors, quinacrine or indomethacin, inhibit the pigment-aggregating effect of B-HT 920. The present results suggest that amiloride competes with B-HT 920 as receptor antagonist, and that Na+/H+ exchange is insignificant for the alpha-2 adrenoceptor-stimulated pigment aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1991

Concomitant D1 dopamine receptor activation (SKF 38393) unmasks D2 dopaminergic actions of B-HT 920 in mice.

The present study attempts to demonstrate D1/D2 dopamine (DA) receptor interactions during stereotyped behaviour in mice. B-HT 920 [2-amino-6-allyl-5, 6, 7, 8-tetrahydro-4H-thiazolo-(4, 5-d)-azepine] (0.05-1.0 mg/kg), a selective D2-DA agonist, induced mild per se stereotypy consisting mainly of sniffing and rearing responses. Apomorphine, a mixed D1/D2 agonist, also produced typical stereotypic response in mice. The stereotypic response of B-HT 920 was blocked by D2-DA antagonist, sulpiride (50 mg/kg). The effect of apomorphine was not influenced by co-treatment with SKF 38393. Simultaneous administration of B-HT 920 (0.1-0.5 mg/kg) with SKF 38393 (5 mg/kg), a selective D1-DA agonist, elicited dramatic increase in stereotyped behaviours in naive as well as in 24 hr reserpinised (2 mg/kg) mice. Co-treatment of apomorphine (0.5 mg/kg) with B-HT 920 (0.1, 0.25 mg/kg) also resulted in a clearly synergistic effect on stereotyped behaviour. These potentiated responses were reduced or blocked by haloperidol, a D2-DA antagonist. The data suggest that in presence of concomitant stimulation of D1-DA receptors. B-HT 920 exhibits full expression of postsynaptic D2-DA receptor mediated behavioural effects.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

The dopaminergic actions of B-HT 920.

B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine), an alpha 2-adrenoceptor agonist has been reported to modulate dopamine (DA) receptor activity. Earlier studies speculated the DA autoreceptor action of B-HT 920. However, some recent studies have indicated that the stimulatory effects of B-HT 920 are sensitive to blockade by sulpiride and haloperidol, suggesting a postsynaptic D2-dopamine receptor action. The article briefly reviews the current concepts about DAergic actions of B-HT 920.

Animals↗
PubMed1989

Relation between density (maximum binding) of alpha adrenoceptor binding sites and contractile response in four canine vascular tissues.

In microsomal fractions from dog aorta, saphenous veins, mesenteric arteries and veins, both [3H]prazosin and [3H]rauwolscine displayed monophasic saturation in binding. The Kd for [3H] rauwolscine binding was similar for all these blood vessels, but the maximum number of [3H]rauwolscine binding sites was 3 to 7 times higher in veins compared to arteries. The Kd for [3H] prazosin was higher in saphenous vein than that in the arteries. The maximum number of binding sites for [3H]prazosin was similar, except for that in aorta, which was 3 times greater. Phenylephrine (alpha-1 adrenoceptor selective agonist) or norepinephrine (nonselective adrenoceptor agonist) produced similar maximal responses in all vessels. The alpha-2 adrenoceptor selective agonist, B-HT 920 (2-amino-6-allyl-3,4,7,8-tetrahydro-6H-thiazolo[5,4-d]-azepine)-induced contraction in veins but not in arteries. Prazosin (10(-6) M) inhibited completely the contractions to norepinephrine (3 x 10(-6) M) in mesenteric arteries and to phenylephrine (3 x 10(-6) M) in arteries and veins. Contractile responses of mesenteric artery were unaffected by rauwolscine. Rauwolscine (10(-7) M) caused a greater parallel rightward shift of the concentration-response curve to norepinephrine than did prazosin (10(-7) M) in saphenous veins, and a further rightward shift of responses to norepinephrine after 10(-7) M prazosin in mesenteric vein and saphenous vein and abolished B-HT 920-induced responses at alpha-2 adrenoceptors. The tissues responding to B-HT-920 correspond to those having the highest alpha-2 receptor density as measured by [3H]rauwolscine binding. The density of such sites required for contraction to be initiated in veins was much higher than with alpha-1 adrenoceptor sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

[Influence of laurocapram on ultrastructures of mouse skin and sarcoma 180 membrane].

Laurocapram (Lau), 1-dodecyl-hexahydro-2 H-azepin-2-one, (azone) is a new percutaneous penetration enhancer. However, the mechanism of its action for absorption promoter of other agents is still unknown. In this paper the effect of Lau on ultrastructures of skin surface and tumor cell membrane were studies. Lau (2%) suspension was applied to abdominal skin of ICR/JCL, C 57 BL mice or one side of abdominal skin of nude mouse with drug and other side with the vehicle solvent once daily for 2-3 d. The skin was excised at 4 h after the final medication for examination under scanning electron microscope (SEM). The results showed the numerous small infolding lines which divided the skin surface into small areas with vesiculation and peeled the epidermal surface to form a few minor holes. The cuticles of the hair shaft dropped off and became thinner. Numerous desquamated cells around the orifice of the hair were fractured, detached and widened. Sarcoma 180 cells were incubated with Lau 25 micrograms/ml at 37 degrees C for 4 h. The microvilli of some cells dropped off and the size of villi became thinner and shorter. The top of some villi of the cells appeared occasionally thick to make the profile as a bat. The surface of numerous naked cells became rugged and rough and showed many black minor holes in the area of denuded cell membrane or dropped microvilli. More than 100 holes in the exposed surface of the naked cell were seen. It seemed that the Lau drilled holes on the biomembrane and enlarged the orifice of hair follicles and thus enhanced the transdermal absorption.

Animals↗