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PubMed2004

Transdermal eperisone elicits more potent and longer-lasting muscle relaxation than oral eperisone.

Eperisone hydrochloride is widely used for the treatment of plasticity to relieve muscle stiffness and back pain. However, oral eperisone has a very low bioavailability and short muscle relaxant activity, because of the profound intestinal first-pass metabolism. To improve the efficacy and compliance of eperisone, we designed a new dosage form, a transdermal patch, and evaluated the efficacy of the eperisone patch with the muscle relaxant activity of rats. The muscle relaxant activity was assessed by the measurement of forelimb grip strength and hanging test in rats. The transdermal patch of eperisone showed significantly enhanced muscle relaxant activity at 0.5 1.5 and 3 cm2/200 g rat (1.39, 4.17 and 8.33 mg of eperisone hydrochloride/kg, respectively) in a dose-dependent manner and the effects lasted over 24 h. Even though oral eperisone hydrochloride showed significant muscle relaxant activity at 12.5, 25 and 50 mg/kg in a dose-dependent manner, the activity lasted only 1 or 2 h after administration. These results suggest that eperisone as transdermal patch form showed efficient absorption with more potent and longer-lasting muscle relaxant activity than oral solution. The transdermal patch form of eperisone will increase the efficacy and compliance in the clinical use of eperisone.

Administration, Cutaneous↗
PubMed1979

Binding of adrenaline and isoprenaline to plasma proteins of the dog.

Adrenaline was incubated with dog plasma in concentrations ranging from 50 to 1,000 ng/ml and binding to plasma proteins was found to be about 12% (8, 12 or 14%, as determined by spectrophotofluorimetric, liquid scintillation or Sephadex G-50 gel filtration methods, respectively). For isoprenaline, the binding to plasma proteins was of about 14-18%, as shown by liquid scintillation or Sephadex G-50 gel filtration methods. Cellulose acetate electrophoresis demonstrated that albumin does not play any significant role in this binding, in the case of both adrenaline and isoprenaline. These results show that adrenaline and isoprenaline are much less bound to proteins that noradrenaline (40%). It is concluded that the N substitution present in adrenaline and isoprenaline appears to be responsible for the different degrees of protein binding.

Animals↗
PubMed1977

Uptake and metabolism of noradrenaline by the mesenteric arteries of the dog.

Uptake and metabolism of tritiated noradrenaline by the mesenteric arteries of the dog and concomitant behaviour changes in endogenous noradrenaline are described. Posterior mesenteric artery strips were incubated for 30 min in Krebs solution containing (-)-7-3H-noradrenaline (1,084 muM); suitable pretreatments and/or preincubations were performed to study the influence of some drugs on these parameters. The atrial strips showed a high capacity to retain, accumulate and metabolize exogenous noradrenaline. At the concentration of noradrenaline studied, neuronal uptake and deamination represented the main inactivation mechanism, however, when neuronal uptake was blocked, extraneuronal deamination and o-methylation played a more important role, o-Methylation represented a vicarious enzymatic route when monoamine oxidase activity was inhibited. Iproniazid pretreatment increased markedly the endogenous noradrenaline content of the mesenteric arteries. During incubation with tritiated noradrenaline both an outflow of endogenous noradrenaline and an inflow of tritiated noradrenaline were observed.

Animals↗
PubMed1980

Uptake and O-methylation of isoprenaline in the rabbit ear artery.

Factors which influence uptake on O-methylation of 3H-isoprenaline (3HISO) by isolated segments of the rabbit ear artery were investigated. The tendency of the artery to accumulate unchanged amine was enhanced either when the O-methylation of ISO approached saturation at a high substrate concentration (6 mumol 1(-1) ISO), or when O-methylation was inhibited. Under these conditions, deoxycorticosterone acetate (DOCA) partially inhibited the accumulation of ISO. DOCA exerted a stronger inhibitory effect on O-methylation, but only at low ISO concentrations (0.2 and 0.8 mumol 1(-1)). The results are interpreted as evidence that (a)O-methylation in the intact artery is a saturable process which serves to limit the accumulation of 3HISO when the bathing concentration of the amine is low, and (b) DOCA exerts its effects by inhibiting extraneuronal uptake into the compartment possessing O-methylating activity. Analysis of the kinetics of efflux of 3HISO suggested that O-methylation was restricted to only one compartment, whereas unchanged ISO was accumulated within at least two compartments in addition to the extracellular compartment. Attention is drawn to a small but significant inhibitory effect of chronic sympathetic denervation on the accumulation, although not the O-methylation of ISO, raising the possibility that there may also be distribution of 3HISO within the sympathetic nerves.

Animals↗
PubMed1983

Effect of inhibitors of neuronal and extraneuronal uptake on the accumulation and metabolism of 3H-l-norepinephrine in rabbit aorta.

In the isolated adventitia of rabbit aorta, blockade of neuronal uptake decreased the accumulation and deamination of 3H-l-norepinephrine (3H-l-NE) whereas blockade of extraneuronal uptake decreased O-methylation. Thus most of the O-methylation occurs in the extraneuronal elements. In the isolated media, blockade of extraneuronal uptake decreased metabolism but not accumulation of 3H-l-NE. If NE metabolism was prevented by pretreatment with pargyline and U-0521, 3H-l-NE accumulation in the isolated media increased markedly and now inhibitors of extraneuronal uptake could decrease this accumulation of 3H-l-NE by the isolated media. Thus when MAO and COMT are intact, NE does not accumulate in the extraneuronal compartment containing these enzymes, probably because it is metabolized as fast as it enters the compartment. Since the level of 3H-l-NE in the isolated media exceeded the sorbitol space when MAO and COMT are intact, some 3H-l-NE must have accumulated in a compartment which does not contain these enzymes.

Animals↗
PubMed1983

Two mechanisms of 3H-catecholamine accumulation in rabbit aorta media differentiated by sensitivity to temperature and corticosterone.

To characterize the extraneuronal accumulation of catecholamines (CA) in the media of rabbit aorta pieces of isolated media were incubated with 3H-CA (norepinephrine, isoproterenol or normetanephrine) plus 14C-sorbitol (to estimate the extracellular space) for varying periods at 37 or 0 degree C. The 3H-CA accumulation was 1.3 ml/g at 0 degree C and 2.2 ml/g at 37 degrees C. The sorbitol space was 0.6 ml/g at both temperatures. CA accumulation at 0 and 37 degrees C is significantly different from each other and from sorbitol accumulation. Corticosterone and phenoxybenzamine inhibit the temperature-sensitive component of CA accumulation. Accumulation of norepinephrine at 0 degree C is unaffected by corticosterone, phenoxybenzamine or oxytetracycline. The initial rate of NE accumulation at 37 degrees C, from steady state accumulation at 0 degree C, and the initial rate of accumulation at 0 degree C were linear functions of NE concentration between 10(-7) and 10(-2) M. Based on differences in sensitivity to corticosterone and temperature, we conclude that CA accumulation at 0 degree C is different from the accumulation at 37 degrees C.

Animals↗
PubMed1985

Antiarrhythmic drug therapy. Recent advances and current status.

A number of conventional and newer antiarrhythmic agents are available for the treatment and prophylaxis of ventricular tachycardia and sudden death. Using a multifaceted approach of programmed electrical stimulation studies, drug level determinations, exercise tolerance testing, and 24-hour ambulatory electrocardiographic monitoring, the physician can identify those patients who require therapy and then predict the likelihood of efficacy with each antiarrhythmic agent. This approach affords evaluation of both aspects of the sudden death equation-ectopy frequency (triggering mechanism) and vulnerability to development of sustained ventricular tachycardia (substrate). After institution of therapy, careful follow-up is necessary to document sustained drug efficacy and detect side effects. Serious adverse reactions necessitate a change in antiarrhythmic therapy, as opposed to lowering drug dosage to an ineffective level. The unacceptably high incidence of sudden death due to electrical instability can be reversed only by a rigorous and dedicated long-term approach to the management of serious ventricular arrhythmias.

Adrenergic beta-Antagonists↗
PubMed1987

Effect of solon on gastric mucus viscosity, permeability to hydrogen ion, and susceptibility to pepsin.

The effect of a new antiulcer drug, solon (sofalcone), on gastric mucus viscosity, permeability to hydrogen ion and degradation by pepsin was investigated using an in vitro system. Preincubation of the isolated gastric mucus with solon produced a marked enhancement in mucus viscosity. This enhancement was concentration dependent and at 2.2 X 10(-1) M solon reached a value of 230%. Permeability measurements showed that 2.2 X 10(-2) M solon increased the retardation ability of mucus to hydrogen ion by 32%, while 43% increase was obtained with 2.2 X 10(-1) M solon. The drug had no effect on the viscosity and hydrogen ion retardation capacity of albumin. The results of peptic activity assay indicated that solon had an inhibitory effect on the rate of mucus and albumin proteolysis. The rate of inhibition of peptic activity was proportional to the solon concentration up to 1.0 X 10(-5) M, at which concentration the proteolysis of mucus was inhibited by 60% and that of albumin by 45%. The results obtained here under in vitro conditions suggest that solon, by inhibiting peptic erosion of the mucus layer, increasing its viscosity and enhancing the ability to impede the hydrogen ion penetration, strengthens the gastric mucosal integrity and thus could aid in ulcer healing.

Animals↗
PubMed1987

Enzymatic sulfation of mucin in gastric mucosa: effect of sofalcone, sucralfate and aspirin.

A sulfotransferase activity which catalyzes the transfer of a sulfate group from 3'-phosphoadenosine-5'-phosphosulfate to gastric mucus glycoprotein has been demonstrated in the rat gastric mucosa. Subcellular fractionation studies revealed that the enzyme activity was present in a Golgi-rich membrane fraction. Optimum enzymatic activity for sulfation of mucus glycoprotein was obtained with 0.5% Triton X-100 and 30 mM NaF at a pH of 6.8. The apparent Km of the enzyme for gastric mucus glycoprotein was 10.5 microM, and the sulfate ester was found incorporated into the carbohydrate chains of mucin. The sulfo-transferase activity of the Golgi enzyme was stimulated by sofalcone, while reduction in the rate of sulfation occurred in the presence of sucralfate and aspirin. The rate of enhancement of mucin sulfation by sofalcone was proportional to the drug concentration up to 5 X 10(-7) M, at which concentration a 17% increase in the glycoprotein sulfation was attained. The rate of inhibition of mucin sulfation was proportional to concentrations of aspirin up to 3 X 10(-4) M and of sucralfate up to 1 X 10(-4) M, at which concentrations about 50% reduction in sulfotransferase activity was obtained. The apparent KI values calculated from the double-reciprocal plots were 15.1 microM for aspirin and 19.6 microM for sucralfate. The results suggest that although both sucralfate and sofalcone are potent gastric mucosal strengthening agents, only sofalcone is capable of enhancement of the sulfotransferase enzyme involved in gastric mucin sulfation.

Animals↗
PubMed1988

Protection of gastric surface epithelial cells of rats by 16,16-dimethyl prostaglandin E2 and sofalcone, a synthetic flavonoid derivative of sophoradin, against ethanol.

We studied the effects of 16,16-dimethyl prostaglandin E2 (dm-PGE2) and sofalcone, a new antiulcer agent developed in Japan, on ethanol damage to isolated surface epithelial cells (SEC) in vitro and gastric mucosa of rats in vivo. Rats were given 5 micrograms/kg dm-PGE2, 30, 100, or 300 mg/kg sofalcone, or the vehicle, intraperitoneally. In the in vitro study, damage of the SEC isolated from rats given dm-PGE2 or sofalcone was significantly less after exposure to 15% ethanol than for the SEC from the control rats. In the in vivo study, the 15% ethanol did not induce gross visible damage, but did cause surface epithelial damage in the control rats as judged by scanning electron microscopy. This damage was inhibited by dm-PGE2 or sofalcone. Damage from absolute ethanol was inhibited by both of the agents as judged by the gross appearance, but the surface epithelium was damaged in all rats. We concluded that dm-PGE2 and sofalcone protect gastric mucosa from gross damage caused by absolute ethanol, and protect SEC both in vivo and in vitro from being damaged by ethanol when the concentration of ethanol is 15%.

16,16-Dimethylprostaglandin E2↗
PubMed1989

Lipolytic activity of Campylobacter pylori: effect of sofalcone.

The lipolytic activity of Campylobacter pylori capable of gastric mucosal lipid degradation was investigated. The colonies of bacteria, cultured from antral mucosal biopsy specimens of patients undergoing endoscopy, were washed with saline and passed through a sterilization filter; the filtrate was examined for lipase and phospholipase A activities, using glycerol trioleate and dipalmitoyl phosphatidylcholine as substrates. The obtained results revealed that both enzymes are present in the C. pylori filtrate. The enzymes exhibited optimal activity at 37 degrees C and the pH range of 7.0-7.4. The major product of the triglyceride degradation was glycerol monoleate, while lysophosphatidylcholine resulted from the degradation of phosphatidylcholine. The lipase activity of the C. pylori filtrate was inhibited by an antiulcer drug, sofalcone, which at a concentration of 200 micrograms/ml caused a 43% reduction in the triglyceride hydrolysis. The sofalcone, however, showed only marginal, if any, inhibitory activity toward C. pylori phospholipase A. The results suggest that C. pylori infection may be detrimental to the integrity of gastric mucosal lipids.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1989

Antitumor-promoting activity of eperisone.

Eperisone, a Ca2+ entry blocker, suppressed the action of tumor promoter in vitro and in vivo, inhibited tumor-promoter-stimulated 32Pi incorporation into phospholipids of cultured cells, and also proved to have antitumor-promoting activity in mouse skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene plus tumor promoter, 12-O-tetradecanoylphorbol-13-acetate.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Broad-spectrum photoprotection: the roles of tinted auto windows, sunscreens and browning agents in the diagnosis and treatment of photosensitivity.

Since window glass absorbs sunlight below 320 nm, it provides a means of assessing sensitivity to longer wavelengths, i.e. UVA and visible radiation. Positive responses to the query of whether symptoms develop in the auto with the windows up must now be interpreted with regard to the possible presence of tinted plastic film on side and rear windows. These films block nearly all UVA radiation, as does the plastic interleaf of windshields. Thus, occupants of an auto equipped with plastic film receive photoprotection from UVB radiation and well into the UVA region. We define three classes of topical sunscreens: (1) conventional UVB screens, (2) broad-spectrum preparations containing a UVB screen and a UVA absorber and (3) browning agents such as dihydroxyacetone (DHA) that produce a skin coloration that absorbs in the low end of the visible region, with overlap into long-wavelength UVA. By considering responses of photosensitive persons in autos with tinted or untinted windows, coupled with efficacy of appropriate sunscreens, we produced an algorithm defining three photosensitivity subsets. Persons sensitive to long-wavelength UVA and/or visible radiation will benefit from tinted auto windows. In particular, patients with lupus erythematosus (LE) have actively promoted legislation allowing tinted windows. Support for their position is documented by recent reports of induction of lesions in LE patients by exposure to UVA and visible radiation. The brown color produced by DHA is a useful adjunct to the screening action of broad-spectrum sunscreens. Development of a durable color overnight allows application of the DHA preparation in the evening, thus eliminating possible interference with sunscreen use during the day.

4-Aminobenzoic Acid↗
PubMed1983

Clinical pharmacology of propafenone.

We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships of propafenone, a promising new antiarrhythmic drug. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving four increasing doses, during drug washout and during a randomized double-blind placebo-controlled trial, to evaluate the optimal dose in each patient. A nonlinear relationship was found between propafenone dose and steady-state mean concentration with a 10-fold increase in drug concentration as dose increased threefold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 hr, range 2.4 to 11.8), steady-state mean concentration on 900 mg/day of propafenone (mean 1008 ng/ml, range 482 to 1812), and "therapeutic" plasma concentration (mean 588 ng/ml, range 64 to 1044). The interaction of these three parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 hr, range 4 to 22). There was a greater than 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in seven during double-blind crossover. Side effects requiring discontinuation of the drug occurred in three patients and included apparent worsening of arrhythmias in two. We conclude that propafenone effectively suppresses ventricular arrhythmias and that nonlinear drug accumulation and intersubject variability in elimination of half-life, steady-state mean plasma concentration, and therapeutic concentration indicate a need for individual therapy.

Adult↗