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A suppository of zonisamide (ZNS) was investigated from the viewpoint of pharmaceutical evaluation, pharmacokinetics and pharmacological effect. Two types of ZNS suppositories were prepared. One used Witepsol (H-15 : S-55=3 : 1) as a lipophilic base and the other polyethylene glycol (PEG, 4000 : 1500=4 : 1) as a hydrophilic base. The in vitro release rate of ZNS from the PEG suppository was significantly rapid compared with that of ZNS from Witepsol. Male Wistar rats were administered ZNS (20 mg/kg) using an intravenous, oral or rectal (PEG or Witepsol) route. The absorption of ZNS from the PEG suppository was more rapid than that of ZNS from the Witepsol suppository or from the oral preparation. The peak plasma concentration (Cmax) after a rectal administration of ZNS with Witepsol or PEG suppository was significantly higher than that after the oral administration of ZNS. However, the bioavailability of the three preparations was approximately 100%. Male ICR mice were administered ZNS (80 mg/kg) using the oral or rectal (PEG or Witepsol) route. A positive correlation was observed between the electroshock seizure (ES) threshold and ZNS concentration in plasma or brain. Further, there was no significant difference in the ES threshold or the ZNS concentration in plasma or brain among the three preparations. These results indicate that a ZNS suppository is a very useful preparation from the viewpoint of both pharmacokinetics and pharmacological action.

We estimated the benefits of a transdermally applicable 10% lidocaine gel mixture with absorption promoter (glycyrrhetinic acid monohemiphthalate disodium: GA MHPh 2Na) for the self-injection of human growth hormone (hGH) to reduce injection distress in eight children with growth hormone deficiency (GHD). Pain rating scales upon both needle puncture and fluid injection of hGH were significantly lower with the lidocaine gel application than with the placebo. The use of the lidocaine gel application in hGH therapy can alleviate the pain of injection and accompanying anxiety, thus obtaining better compliance of children who need daily injections of hGH.

In order to estimate the penetration depth of transdermal 3% GA MHPh 2Na-10% lidocaine gel mixture, the following physiological functions of the skin were examined before and after a 60 min occulusive application of the gel in 16 adult volunteers. Thermal sweat expulsins ceased completely on the gel-treated ventral surface of one forearm in all the firs 5 subjects, though it continued on the untreated contrast area of the other forearm. Sympathetic skin response (SSR) was also no longer induced on the gel-treated middle finger in 1 of another 3 subjects and was severely depressed in the other 2 subjects, while the SSR on the untreated index finger appeared constantly. Vasomotion of the skin circulation on another 3 subjects, remained unaffected on both the gel-treated and the untreated fingers. Extraction of a leg-hair in the treated area did not induce pain sensation in all the last 5 subjects. In addition to the transcellular main roots, some of the transcutaneously applied gel seems to penetrate deeply into the skin through the appendageal roots such as the eccrine sweat glands and the pilosebaceous glands.

The promoting effect of sodium guaiazulene-3-sulfonate (AZ) on nasal absorption of insulin and calcitonin was studied in rats. The promoting effect of AZ was compared with two established nasal absorption promoters i. e. sodium caprate(Na Cap) and glycyrrhetinic acid 3-O-monohemiphthalate disodium (GA-MHPh 2Na). The nasal absorption of insulin was estimated from plasma immunoreactive insulin and changes in glucose levels. Plasma glucose level was decreased by intranasal administration of 10 U/kg insulin with 1% AZ, The extent of total decrement of glucose level to control was 51% and comparable to that with 1% Na Cap. The addition of 1% AZ to the nasal formulations enhanced insulin bioavailability from 3.7% to 27.6%. The nasal absorption of salmon calcitonin was evaluated from serum calcitonin and changes in calcium levels. Serum calcium levels were de-creased by intranasal administration of 10 U/kg salmon calcitonin in the presence of two already known promoters as effectively as intramuscular administration of the same dose, The addition of 1% AZ also showed the same extent of decrease as these ; the extent of total decrement of serum calcium level to control was 26.6%. The optimum concentration of AZ was about 1%. Intranasal administration of 1% AZ alone hardly changed plasma glucose level and serum calcium level from control. Hence, promoting effect of AZ on nasal absorption of insulin and calcitonin was proved. These findings indicate that AZ can be safe and effective nasal absorption promoter of peptides.

われわれの施設で独自に開発した局所麻酔剤含有外用剤を使用する機会を得た。本剤は局所麻酔薬としてlidocaineを10%含有するゲル状の物質で, 経皮吸収の促進と局所刺激の抑制を目的としてグリチルレチン酸モノヘミフタレートジナトリウム塩他が配合されている。今回本剤の除痛効果および安全性について若干の検討を加えた。パッチテストでは局所, 全身共とくに問題となるような所見は認められなかつた。経皮吸収量の指標として末梢血中のlidocaine濃度の測定を行つた結果, 薬剤の貼付部位や個体によりその数値に差を認めた。さらに臨床応用として凍結療法に際し同一個体の同一部位に使用した例では, 貼付部位の皮膚の状態により血中濃度がかなり大きく変動することが認められた。このように安全性や適応について検討の余地があるものの, 本剤は密封包帯法による使用で充分な除痛効果が得られ, 今後凍結療法やverrucaの処置など皮膚外科領域での有用性が期待された。

Rhabdomyolysis is a severe adverse effect of hypolipidaemic agents such as statins and fibrates. We evaluated this muscular cytotoxicity with an in-vitro culture system. Cellular apoptosis was determined using phase-contrast and fluorescein microscopic observation with Hoechst 33342 staining. L6 rat myoblasts were treated with various statins and bezafibrate under various conditions. With statins only, skeletal cytotoxicity was ranked as cerivastatin > fluvastatin > simvastatin > atorvastatin > pravastatin in order of decreasing potency. Combined application of fibrates enhanced ator-vastatin-induced myopathy, which causes little apoptosis alone. These results suggest that statins and fibrates synergistically aggravate rhabdomyolysis.

The analgesic effects of transdermally applied 10% lignocaine aquagel containing 3% glycyrrhetinic acid monohemiphthalate disodium (as an absorption enhancer) and EMLA cream were compared on the forearms of 34 adult volunteers in a double-blind fashion. The mean pinprick pain scores (graded by noting the number of painful pinpricks out of five) at 30, 60 and 90 min after application and 30 min after removal of the anaesthetics were 3.3 (0.3) (mean SE), 1.2 (0.3), 0.3 (0.1) and 0.3 (0.1) respectively, in the lignocaine gel group. Corresponding scores were 3.5 (0.3), 1.5 (0.3), 0.7 (0.2) and 0.1 (0.1) respectively, in the EMLA group. Insertion of a 26-gauge needle into the treated skin to a depth of 1 mm at 90 min after application was not painful in 91% of the volunteers in the lignocaine gel group and 88% of those in the EMLA group. There was no significant difference in any of the corresponding pain scores between the two groups.

Clinical application of dermal patch anesthesia to relieve pain at venous cannulation of blood-access was studied in hemodialysis patients. Aqueous gel of 10% lidocaine base with 3% glycyrrhetinic acid monohemiphthalate disodium (GA MHPh 2Na) was applied for 60 minutes to the skin of the patients. Degree of pain was expressed as a pain score. Analgesic effect of the lidocaine gel was evaluated in 16 patients in a placebo-controlled, double-blind, cross-over design by comparing the gel with lidocaine with a placebo gel without lidocaine. The mean pin-prick pain score (1.0 +/- 0.5) in the lidocaine gel patch (n = 16) was significantly lower than that (2.3 +/- 0.3) in the placebo gel patch (P0.01). In 8.8% of the patients, blood pressure was elevated after venous cannulation, but this tendency was modified by dermal patch anesthesia with the lidocaine gel. Plasma concentration of lidocaine was under the detection limit of assay (0.05 micrograms/mL) after dermal patch anesthesia in six subsequent dialysis treatments.

Summary The clinical efficacy of transdermal 10% lignocaine gel mixture containing 3% w/w glycyrrhetinic acid monohemiphthalate disodium as an absorption promoter was evaluated at venous cannulation in 17 paediatric (6–11 years) and 17 adult (29–65 years) patients. After about 60 min of occlusive application, the mean (SD) pinprick pain score was 0.7 (0.7) in the paediatric group, compared with 1.4 (1.3) in the adults (p < 0.05). Twenty-five patients (14 children and 11 adults) who had a pinprick score of 0 or 1 underwent venous cannulation without intradermal local anaesthetic. The mean (SD) pain scores at venepuncture showed no significant differences between children and adults.

The clinical benefits of transdermal 10% lidocaine base gels with and without 3% glycyrrhetinic acid monohemiphthalate disodium (GAMHPh) for reduction of pain at venous cannulation were compared in a randomized, double-blind fashion in 24 surgical patients. After about 60 min of occlusive transdermal application, the mean pinprick pain score (1.3 +/- 1.5) in the GAMHPh group (n = 12), graded by noting the number of painful pinpricks out of five, was significantly less than that (2.5 +/- 1.7) in the control group (n = 12) (P less than 0.05). Twelve patients (eight in the GAMHPh group and four in the control group) who had a pinprick score less than 1 underwent venous cannulation without intradermal injection of a local anesthetic. The pain score at venipuncture, graded by the patients on a scale of 5, was significantly less in the GAMHPh group than that in the control group (1.9 +/- 1.1 vs 3.3 +/- 1.0, P less than 0.05). Erythema observed in 8 of the 24 patients was the only adverse local reaction. Addition of 3% GAMHPh to the lidocaine gel is useful in promoting transdermal lidocaine absorption.

Three types of skin pretreatments (stripping with adhesive tape, scrubbing with Skin-Pure jelly, and cleaning with benzine) were studied in 21 volunteers to determine whether the pretreatments could shorten the application period of transdermal 3% GA MHPh 2Na-10% lidocaine gel. Before application of the gel, each subject received skin pretreatment on the volar surface of one forearm. Then, the lidocaine gel soaked in a round sponge was applied on both the pretreated area of the forearm and the unpretreated contrast area of the other forearm. A pain score was obtained from each subject at 30, 45, 60, and 75 min after placement of the dermal patch by noting the number of painful pinpricks of five delivered. The mean pain scores on the pretreated side were significantly lower at 30, 45, and 60 min in the stripping study group and at 45 and 60 min in the cleaning study group, compared with the corresponding scores on the unpretreated side (P less than 0.05). Skin pretreatments, such as stripping and cleaning, are useful for shortening the onset of the dermal patch anesthesia.

The effect of oral administration of activated charcoal on serum elimination of 14C-M79175 injected intravenously in rats was studied. In situ single-pass perfusion studies showed that M79175 and/or its metabolites was transported into the small intestinal lumen. Total radioactivity expressed as equivalents of M79175 exsorbed in the perfusate and excreted in the bile juice was 3.2% and 2.0%, respectively, of dose. Oral administration of multiple doses of activated charcoal significantly decreased the serum concentration and serum half-life of 14C-M79175. The fecal excretion of 14C-M79175 after treatment with activated charcoal was increased when compared to that in the control. On the other hand, urinary excretion of 14C-M79175 after treatment with activated charcoal was decreased. However, there was no significant difference in the cumulative amounts of total excretion (fecal plus urinary excretion) between rats with activated charcoal treatment and rats without charcoal treatment. These results suggest that intestinal dialysis by oral activated charcoal is a reasonable method to enhance the elimination of M79175 from the serum in case of overdose of the drug.

The effects of some fibers on the in vitro and in situ rat small intestinal absorption of cadmium were studied. The fibers, such as cellulose, pectin, glucomannan, lignin, sodium alginate (Na alginate), and sodium carboxymethylcellulose (Na CMC), tended to depress the intestinal absorption of cadmium. The depressive effects of lignin, Na alginate, and Na CMC on the absorption of cadmium were much greater than those of cellulose, pectin, and glucomannan. In addition, the effects of these fibers on the in vitro intestinal transport of cadmium were examined in the presence of L-cysteine or L-histidine, a stimulator of transport of the metal. Lignin and Na CMC depressed the stimulation of transport of cadmium by L-histidine.

We studied the promoting effect of glycyrrhetinate and its derivatives on nasal absorption of insulin in rats. These derivatives can be divided into two groups based on mother structural skeleton. One group is 3-O-ester derivatives of glycyrrhetinate and the other group is 3-O-and 30-O-ester derivatives of a hydrogenated glycyrrhetinate analog. The former group consists of G2 2K, GA Na, GA-MHS 2Na and GA-HPh 2Ha and the latter group consists of DG-DHPh 2Na, HomAD-DHPh 2Na and HetAD-DHPh 2Na. These derivatives significantly promoted nasal absorption of insulin and decreased plasma glucose levels in rats. We found that the optimum concentration of these derivatives such as GA-MHS 2Na, GA-HPh 2Na and DG-DHPh 2Na was about 1%. The promoting effect of glycyrrhetinic ester groups on nasal absorption of insulin in rats is GZ 2K < GA Na < GA-MHS 2Na < GA-HPh 2Na. These results indicated that strength of the promoting effect differed by 3-O-ester groups. On the other hand, hydrogenated glycyrrhetinic ester analogs were more effective than the glycyrrhetinic ester group. Particularly, DG-DHPh 2Na and HomAD-DHPh 2Na were significantly promoted nasal absorption of insulin in rats, and bioavailability in the presence of these promoters was comparable to that following intravenous injection. It is indicated that glycyrrhetinate and its derivatives can be applicable to promotion of nasal absorption of insulin.

We investigated the promoting effect of medium chain fatty acid salts such as sodium caprylate, sodium caprate (Na C10) and sodium laurate on rat nasal absorption of insulin. Further, we studied the possible mechanism of the absorption promoting effect by fatty acid salts in terms of hemolytic activity, osmotic pressure, chelating effect and inhibition of leucine aminopeptidase activity. Na C10 exhibited the strongest absorption promoting effect on insulin among these fatty acid salts. The promoting effect of Na C10 was very rapid reaching the maximum immunoreactive insulin level within 5 min and its optimum concentration was about 1%. The amount of insulin absorbed after a nasal administration with Na C10 was about 98% of one half subcutaneous dose. The absorption promoting effect of fatty acid salts on insulin was at least in part associated with the chelating ability for calcium ions and the inhibitory action on leucine aminopeptidase activity.

The effects of exogenous glucagon on a totally pancreatectomized patient were evaluated in both the acute postoperative and convalescent periods. In the acute postoperative phase, glucagon stabilized the blood glucose level and allowed the administration of an adequate amount of energy, while during the convalescent period, it proved useful in promoting the metabolism of lipids and amino acids and maintaining liver function. Moreover, we developed a glucagon aerosol which enabled frequent administration without causing major discomfort to the patient and raised the blood glucagon to satisfactory level.

Nasal absorption of insulin in rats was enhanced by addition of sodium glycyrrhetinate (GA Na), dipotassium glycyrrhizinate (GZ K2), and carbenoxolone (glycyrrhetinic acid hydrogen succinate) disodium salt (GAHS Na2). The latter agent was the most effective. On addition of 1% GAHS Na2, plasma immunoreactive insulin levels in rats showed a maximum level of 0.75 mU/ml at 15 min and plasma glucose levels were decreased to about 25 mg/dl after nasal administration of 10 U/kg insulin. In a comparison of the absorption rates of insulin by nasal and intravenous (i.v.) routes in rats, nasal absorptions of 10 U/kg insulin in the presence of 1% GAHS Na2, 0.5% GA Na and 1% GZ K2 were 26.5%, 13.2% and 14.5% of that in the case of a 5 U/kg i.v. dose, respectively. Hemolytic activies of GAHS Na2, GA Na and GZ K2 were milder than those of Na caprate and Na laurate, and nasal leucine aminopeptidase activity was more strongly inhibited by GAHS Na2 than by medium chain fatty acid salts, sodium glycocholate, GA Na or GZ K2. Therefore, it is suggested that GAHS Na2 is a very useful promoter which dose not irritate the nasal mucosal membrane or degrade insulin.

Bioequivalency of newly formulated digoxin powder containing mainly crystalline lactose, which is expected to improve the fluidity of powder, was compared with that of the previous formula containing non-crystalline lactose.The digoxin concentrations in serum of 8 healthy male volunteers were determined by Stratus Immunoassay System after oral administration of either new or old formulation of digoxin powders in a latin square crossover design.The extent and rate of bioavailability of the both digoxin powders were found to be bioequivalent.It was concluded that both formula had clinically equivalent bioavailability but the power of analysis in this bioequivalency test was lower than the guide-line valve given by the committee on bioequivalency test.

The enzymatic and chemical stability of three 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides has been studied. Chemical degradtion of the analogues was measured in the pH range of 1.0-9.0. 2',3'-Dideoxy-2',3'-didehydrocytidine (DDCN) degraded rapidly under acidic conditions, but the chemical stability was greater under basic conditions. The chemical degradation of 2',3'-dideoxy-2',3'-didehydrouridine (DDUN) and 2',3'-dideoxy-2',3'-didehydrothymidine (DDTN) was not pH dependent and was faster than that of cytarabine. Enzymatic degradation of DDCN, DDUN and DDTN was not observed in human plasma, though cytarabine was degraded enzymatically under the same conditions. DDCN was also not degraded in the presence of mouse kidney cytidine deaminase.

The effects of dietary fibers on the gastrointestinal absorption of cadmium were studied. The fibers, such as lignin, cellulose, and sodium carboxymethylcellulose (Na CMC), produced a slight decrease in the contents of cadmium in the tissues of rats following a single oral administration of cadmium. In addition, in rats fed continuously with the experimental diets containing cadmium together with fibers, lignin and Na CMC significantly decreased the contents of cadmium in the tissues. These results show that the fibers depressed the intestinal absorption of cadmium. It is suggested that the inhibitory effects of these fibers on the gastrointestinal absorption of cadmium were due to their intrinsic properties, such as ability to bind cadmium and effect on viscosity, and that the differences of inhibitory effects of the fibers on the intestinal absorption of cadmium were related to differences in such physical properties.