Evaluation of Moisturizing Effect of Heparinoid Ointment (Hirudoid Soft Ointment) Diluted by White Petrolatum (Propeto).

Steroid ointments are frequently mixed with moisturizer. It was reported that steroid ointments mixed with moisturizer increase permeability. There are only few studies done on the permeability of the moisturizer. We researched moisturizing effect of heparinoid ointment (Hirudoid Soft ointment) diluted with white petrolatum (Propeto) on the dry skin models by measuring water content of stratum. Two to four fold dilution of Hirudoid to white petrolatum resulted in a significant decrease in the moisturizing effect of the active ingredient. There was no significant difference in moisturizing effect between four times diluted mixture and white petrolatum alone. This leads to the conclusion that steroid ointment mixture with moisturizer is frequently used, but we should take more caution regarding the decrease of moisturizing effect.

[Improvement of the Convenience of White Petrolatum].

White petrolatum is frequently used as an oleaginous base, but has a drawback of poor usability. In this trial, white petrolatum was prepared at a lower melting point to improve its usability. Characteristic pharmaceutical values such as melting point, yield, and consistency were compared between a conventional product and ophthalmic white petrolatum. Usability was compared by administering a survey questionnaire and evaluating the comparable moisturizing effect by conductivity in humans. The melting point and yield value of the improved product were significantly lower compared with other white petrolatum products. In the survey, the improved product was rated excellent in five criteria. On a scale of 1 to 5, the average values for the five criteria for the improved product were 4.7, while the conventional product and ophthalmic white petrolatum were rated 3.0 and 3.5, respectively. No difference in moisturizing effect was observed among all petrolatums after application, from day 1 to day 14. In conclusion, the improved white petrolatum demonstrated better usability, and the moisturizing effect was equivalent to conventional product, suggesting that the use of this improved product may lead to improved adherence.

The effect of a first-generation H1-antihistamine on postural control: a preliminary study in healthy volunteers.

First-generation H1-antihistamines are known to cause fatigue and drowsiness, due to their poor receptor selectivity and their high penetration rate of the blood-brain barrier. However, little is known about the effects of first-generation H1-antihistamines on postural stability. The purpose of this study was to evaluate the effects of d-chlorpheniramine on postural stability using posturography with and without foam rubber. A double-blind study with three parallel groups was conducted. Twenty-seven healthy young volunteers (mean age 21.9 years) were recruited and orally administered d-chlorpheniramine, 2 or 4 mg, or placebo. Postural sway was measured every hour up to 8 h after administration. Two-legged stance tasks were performed by each subject in four conditions: eyes open or eyes closed and with or without foam rubber. Inter-group comparisons showed that the group receiving 4-mg d-chlorpheniramine showed significantly larger sway in the eyes open with foam rubber condition (visual and vestibular information available, somatosensory information reduced). Inter-subject analysis in the 4-mg d-chlorpheniramine group showed that the effect of d-chlorpheniramine on postural control was variable. Our results suggest that among the three main sensory systems responsible for postural control (visual, vestibular, and somatosensory), d-chlorpheniramine may have a larger effect on the visual and/or vestibular systems in susceptible individuals.

[Fall risk and fracture. Drugs that affect the fall or fracture].

The relationship between the fall and types of hypnotics was studied. The incidence of falls on hypnotics was lower in subjects on ultra-short-acting type, such as Myslee tablet (1.6%) than in those on short-acting type (5.0 to 6.8%) drugs. For Myslee tablet, the incidences were similar in the daytime and the nighttime, but for short-acting hypnotics, the incidence was higher in the daytime than in the nighttime, suggesting a persistent diurnal effect. In order to prevent falls, we recommend to physicians prescribe Myslee tablet whenever possible. Afterwards, the number of patients who experienced falls decreased by 40%. The hypnotics was effected the severity of the injury after falling down. The odds ratios of different types of hypnotics to Myslee tablet on severe injury after falling as follows : Depas tablet having the highest odds ratioat 48, Rohypnol tablet coming in second at 38, respectively.

Evaluation of the degree of mixing of combinations of dry syrup, powder, and fine granule products in consideration of particle size distribution using near infrared spectrometry.

We used near infrared (NIR) spectroscopy to evaluate the degree of mixing of blended dry syrup (DS) products whose particle sizes are not specified in the Revised 16th Edition of the Japanese Pharmacopoeia, and also evaluated the degree of mixing when powder products or fine granule products were added to DS products. The data obtained were used to investigate the relationship between the particle size distributions of the products studied and the degree of mixing. We found that the particle size distribution characteristics of the 15 DS products studied can be broadly classified into 5 types. Combinations of frequently prescribed products were selected to represent 4 of the 5 particle size distribution types and were blended with a mortar and pestle. The coefficient of variation (CV) decreased as the percent mass of Asverin® Dry Syrup 2% (Asverin-DS) increased in blends of Periactin® Powder 1% (Periactin) and Asverin-DS, indicating an improved degree of mixing (uniformity). In contrast, in blends of Periactin and Mucodyne® DS 33.3%, mixing a combination at a 1:1 mass ratio 40 times resulted in a CV of 20%. Other mixing frequencies and mass ratios resulted in a CV by 50% to 70%, indicating a very poor degree of mixing (poor uniformity). These results suggest that when combining different DSs, or a DS with a powder or fine granule product, the blending obtained with a mortar and pestle improves as the particle size distributions of the components approach each other and as the ranges of the distributions narrow.

Effect of mixing method on the mixing degree during the preparation of triturations.

By using lactose colored with erythrocin, we investigated the effects of mixing methods on mixing degree during the preparation of trituration with a mortar and pestle. The extent of powder dilution was set to 4 to 64 fold in the experiments. We compared the results obtained by using two methods: (1) one-step mixing of powders after addition of diluents and (2) gradual mixing of powders after addition of diluents. As diluents, we used crystallized lactose and powdered lactose for the preparation of trituration. In the preparation of 64-fold trituration, an excellent degree of mixing was obtained, with CV values of less than 6.08%, for both preparation methods and for the two kinds of diluents. The mixing of two kinds of powders whose distributions of particle sizes were similar resulted in much better degree of mixing, with CV values of less than 3.0%. However, the concentration of principal agents in 64-fold trituration was reduced by 20% due to the adsorption of dye to the apparatus. Under conditions in which a much higher dilution rate and/or much better degree of dilution was required, it must be necessary to dilute powders with considering their physicality and to determine the concentrations of principal agents after the mixing.

Effect of particle size on mixing degree in dispensation.

By using lactose colored with erythrocin, we examined the effect of particle size on mixing degree during the preparation of triturations with a mortar and pestle. We used powders with different distributions of particle sizes, i.e., powder that passed through 32-mesh but was trapped on a 42-mesh sieve (32/42-mesh powder), powder that passed through a 42-mesh sieve but was trapped on a 60-mesh sieve (42/60-mesh powder), powder that passed through a 60-mesh sieve but was trapped on a 100-mesh sieve (60/100-mesh powder), and powder that passes through a 100-mesh sieve (> 100-mesh powder). The mixing degree of colored powder and non-colored powder whose distribution of particle sizes was the same as that of the colored powder was excellent. The coefficient of variation (CV) value of the mixing degree was 6.08% after 40 rotations when colored powder was mixed with non-colored powder that both passed through a 100-mesh sieve. The CV value of the mixing degree was low in the case of mixing of colored and non-colored powders with different particle size distributions. After mixing, about 50% of 42/60-mesh powder had become smaller particles, whereas the distribution of particle sizes was not influenced by the mixing of 60/100-mesh powder. It was suggested that the mixing degree is affected by distribution of particle sizes. It may be important to determine the mixing degrees for drugs with narrow therapeutic ranges.

Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers.

Ketamine is known to provide analgesic effects without an anesthetic when administered in a low dose. We previously reported that a tablet containing ketamine had analgesic effects in patients with neuropathic pain. In the present study, we compared the plasma concentration profiles of the enantiomers of ketamine and its active metabolite, norketamine, up to 8 h after the administration of 20 mg of ketamine by injection, after the administration of two tablets containing 25 mg of ketamine, after the administration of two sublingual tablets containing 25 mg of ketamine, after the insertion of a suppository containing 50 mg of ketamine, and after the application of a nasal spray containing 25 mg of ketamine to three healthy volunteers. The plasma concentration of ketamine biexponentially declined after the administration by injection; the value of T(1/2beta) for ketamine was approximately 120 min. The bioavailability of the tablet was estimated to be approximately 20%; the area under the plasma concentration-time curve, (AUC)(0-->8 h), of norketamine was approximately 500 ng h/ml in both enantiomers. The bioavailabilities of the sublingual tablet and the suppository were estimated to both be approximately 30%; the AUC(0-->8 h) of norketamine was 280-460 ng h/ml in both enantiomers. The plasma concentration profiles of the sublingual tablet and the suppository were almost similar to that of the tablet. The bioavailability of the nasal spray was estimated to be approximately 45%, which was the highest value among the preparations tested, and the AUC(0-->6 h) of norketamine was low (approximately 100 ng h/ml) in both enantiomers. These pharmacokinetic findings suggested that all of the ketamine preparations tested in this study may be useful for the alleviation of neuropathic pain. We propose that the type of ketamine preparation should be selected in accordance with the patient's disease condition and the required dosage amount of ketamine.

[Evaluation of the permeability of corticosteroid in hairless mouse and hairless micropig skin from admixture of commercially available corticosteroid ointments and/or creams].

Yucatan hairless micropig (YHMP) skin has been shown to have histology and physiologic properties similar to human skin. To assess the relationship between the permeability of corticosteroid ointments and five types of commonly used admixtures of corticosteroid through hairless mice (HM) or YHMP skin and the clinical effects in humans, we conduct by in vitro experiments using HM and YHMP skin. The permeability of corticosteroid in admixtures with urea or heparinoid ointments across HM or YHMP skin was 1.5-4-fold greater than that of corticosteroid ointments alone. HM skin was found to have faster permeability than YHMP skin, but otherwise was similar to YHMP skin. These experiments demonstrated a close relationship between the permeability of HM or YHMP skin and vasoconstrictor activity in humans. These results suggest that the in vitro permeability of corticosteroid measurements across HM skin could be a useful, rapid, and easy method for assessing the vasoconstrictor activity of topical corticosteroids and the admixtures of commercially available ointments and/or creams in humans.

[Effect of grapefruit pulp on the pharmacokinetics of the dihydropyridine calcium antagonists nifedipine and nisoldipine].

The effect of the intake of 200 g of grapefruit pulp (corresponding to one grapefruit) on the pharmacokinetics of the calcium antagonists nifedipine (NF) and nisoldipine (NS) were investigated in 8 healthy Japanese male volunteers. A crossover design was used for the study: group I did not ingest any grapefruit (control group); group II ingested grapefruit 1 h after drug administration; and group III ingested grapefruit 1 h before drug administration. The intake of grapefruit pulp increased the plasma concentrations of both NF and NS, an effect that has previously been reported with grapefruit juice. The increase was most marked when grapefruit was eaten before drug administration. For both NF and NS, subjects who ingested grapefruit 1 h before drug administration exhibited a greater Cmax and AUC0-24 than did subjects in the control group. For NF, the Cmax was 1.4 times higher and the AUC0-24 1.3 times larger in group III than in group I. For NS, the Cmax was 1.5 times higher and the AUC0-24 1.3 times larger in group III than in group I. The increase in the AUC0-24 was significant for both drugs (p < 0.05). The finding that the ratios of Cmax and AUC0-24 for unchanged drug and metabolites did not vary greatly among the three groups for either drug suggests that the increase in serum concentration produced by grapefruit intake may be due to other factors than an inhibitory effect on drug metabolism. Also, the increases in Cmax and AUC0-24 of NS produced by grapefruit intake were smaller than those produced by grapefruit juice intake, indicating that grapefruit pulp and juice have different effects on the pharmacokinetics.

[Effect of admixture of commercially available corticosteroid ointments and/or creams on vasoconstrictor activity].

A commonly used admixture of commercially available ointments and/or creams was selected from the prescribed sheets in our hospital, and questionnaire to dermatologists. To assess the relationship between permeability of corticosteroid through murine skin and clinical effects in human, we attempted to investigate the vasoconstrictor activity of these admixtures of topical corticosteroid by double-blind controlled study. Test samples were occluded at random on the back of 20 healthy volunteers for 4 hours. The vasoconstrictor activity of corticosteroid creams (Lidomex) alone was significantly large as compared with that of ointments alone. The vasoconstrictor activity of corticosteroid in the admixture of Lidomex ointment and urea ointments or heparinoid ointment was 1.5-2 fold significantly larger than that from ointments alone. The extent of the stability of the emulsion after mixing was related to the vasoconstrictor activity. These experiments demonstrated a close relationship between the vasoconstrictor activity of human skin and permeability of hairless mice skin. These results suggested that the vasoconstrictor activity of topical corticosteroids mixed with commercially available ointments and/or creams depends upon their physicochemical characteristics.

[Effect of admixture of betamethasone butyrate propionate ointment on preservative efficacy].

Twenty percent of dermatologists have experienced a separation of water or deterioration of topical corticosteroids mixed with commercially available ointments and/or creams. However, few investigations of this deterioration of admixtures have been reported. To assess the effects of preservatives in preventing microbial contamination of these admixtures, we attempted to investigate the concentration of preservative agents in admixtures and the microbial contamination of these admixtures with a topical corticosteroid ointment (Antebate). The concentration of parabens was reduced by half using an admixture of corticosteroid ointment with four types of moisturizing creams, Urepearl, Pastaronsoft, Hirudoid, and Hirudoidsoft. After a further 3 months, no decrease in parabens was seen. No microbial contamination was found in any admixture stored at room temperature for 1 week and touched two times daily with a finger. The concentration and ratio of the parabens in the aqueous phase and oil phase were entirely different in the admixtures before being centrifuged. The aqueous phase of the admixtures of the oil/water (O/W)-type emulsions of Urepearl and Hirudoid was not found to have microbial contamination immediately after being centrifuged. All aqueous phases stored at room temperature or in a refrigerator for 1 week and touched with a finger twice daily exhibited microbial contamination. These experiments demonstrated that O/W-type emulsions, in which the water easily separates from the bases, should be thoroughly mixed to prevent microbial contamination.