Takao Aoyama

Experience with a strong bleaching treatment for skin hyperpigmentation in Orientals.

Although a variety of topical treatments have been used for skin hyperpigmentation, the effectiveness of each varies after prolonged treatment. In this study, 136 Oriental patients who were followed up for more than 12 weeks were analyzed. The treatment protocol was composed of two steps: bleaching (2 to 6 weeks) and healing (2 to 6 weeks); 0.1% to 0.4% all-trans retinoic acid aqueous gel was originally prepared and applied concomitantly with hydroquinone-lactic acid ointment for bleaching. After obtaining sufficient improvement of the hyperpigmentation, a corticosteroid was applied topically with hydroquinone and ascorbic acid for healing. Improvement was evaluated with a narrow-band reflectance spectrophotometer. The results were successful in more than 80 percent of cases of senile lentigines and postinflammatory hyperpigmentations, especially on the face. Sixty percent of cases of nevus spilus were also successfully treated. Although the transient adverse effects of this treatment may be more severe than conventional treatment, this strong bleaching protocol improves a variety of hyperpigmented lesions, including nevus spilus, with a higher success rate and a shorter treatment period than conventional protocols. (Plast. Reconstr. Surg. 105: 1097, 2000.)

Nonlinear kinetics of threo-methylphenidate enantiomers in a patient with narcolepsy and in healthy volunteers

SummaryWe have studied the pharmacokinetics of methylphenidate enantiomers after the oral administration of different doses of racemic methylphenidate to one patient with narcolepsy and to four healthy volunteers.The plasma concentrations of (+)-methylphenidate were much higher than those of (−)-methylphenidate after each dose in all subjects. In the patient the oral clearance (CL/f) of (+)-methylphenidate fell 3-fold and the area under the concentration-time curve (AUC) rose 7-fold when the dose was increased from 20 to 40 mg (from 0.27 to 0.53 mg·kg−1), in spite of the relatively constant terminal half-life of 2.6–2.7 h.Similar dose-dependency was also observed in the healthy volunteers in the dose range of 10–60 mg (0.12–0.77 mg·kg−1). The mean value of CL/f for the 40 mg dose was significantly lower than that for the 20 mg dose. The mean AUC of the (+)-isomer corrected to a dose of 10 mg increased significantly between the 20 mg and 40 mg doses.In the urine (+)- and (−)-ritalinic acid were excreted for 48 h after each dose as 32–37% and 34–40% of the dose respectively. The mean total recoveries (sum of enantiomers of methylphenidate and its metabolite, ritalinic acid) in the urine were relatively constant (63–78% of the doses), suggesting that the changes in AUC with dose may not be due to a change in the intestinal absorption of racemic methylphenidate.We conclude that the nonlinear kinetics of (+)-methylphenidate may be due to saturation of its presystemic elimination.

Pharmacokinetics and pharmacodynamics of methylphenidate enantiomers in rats

We investigated the relationships between methylphenidate (MPD) enantiomers and endogenous dopamine (DA) levels in striatal extracellular fluid, and that between DA level and locomotor activity, after intravenous administration of racemic MPD (2,5 or 10 mg/kg dose) or the individual enantiomers (2.5 mg/kg dose) to rats. MPD and DA levels in the extracellular fluid were measured by in vivo brain microdialysis. The maximum levels of MPD enantiomers in the striatal extracellular fluid were obtained within 15 min after administration. On the other hand, the mean maximum DA levels after administration of 2–10 mg/kg dose of racemic MPD were obtained within 10 min with values in the range of 3.0- to 8.6- fold higher than the basal DA level. The maximum DA level (4.2-fold of the basal level) after administration of (+)-MPD was greater than that (2.2-fold) of the same dose of (−)-MPD. A clockwise hysteresis was observed between MPD concentration and DA level in the extracellular fluid after MPD administration. Locomotor activity after administration of (+)-MPD was also greater than (−)-MPD. From these results, it was shown that the locomotor activity induced by MPD may be related to the increase of DA level in the extracellular fluid, and the degree of increase of the DA level by (+)-MPD was greater than that of the (−)-isomer.

Stereoselective high-performance liquid chromatographic determination of ketamine and its active metabolite, norketamine, in human plasma

A stereoselective high-performance liquid chromatographic method for the determination of the enantiomers of ketamine and its active metabolite, norketamine, in human plasma is described. The compounds were extracted from plasma by liquid-liquid extraction three times in a combination of cyclohexane with 2.5 M NaOH, 1 mM HCl and 1 M carbonate buffer. Stereoselective separation was achieved on a Chiralcel OD column with a mobile phase of n-hexane-2-propanol (98:2, v/v). The detection wavelength was 215 nm. The lower limits of the determination of the method were 5 ng/ml for ketamine and 10 ng/ml for norketamine. The intra- and inter-day coefficients of variation ranged from 2.9 to 9.8% and from 3.4 to 10.7% for all compounds, respectively. The method was sensitive and sufficiently reproducible for stereoselective monitoring of ketamine and norketamine in human plasma during pharmacokinetic studies after the administration of ketamine for analgesia.

Usefulness of a narrow-band reflectance spectrophotometer in evaluating effects of depigmenting treatment.

Abstract. As a depigmenting treatment, combined topical applications of all-trans retinoic acid (atRA) aqueous gel and 5% hydroquinone, 7% lactic acid ointment were used for Oriental patients with hyperpigmented skin lesions such as senile lentigines and nevus spilus. A narrow-band reflectance spectrophotometer and a tristimulus colorimeter were used to evaluate objectively the intensity of pigmentation and erythema at each clinical visit. L*, a*, and b* values measured with a tristimulus colorimeter (Chroma Meter CR-300) enabled the evaluation of erythema but not pigmentation. On the other hand, the melanin and hemoglobin values measured with a narrow-band reflectance spectrophotometer (Mexameter MX-16) expressed both erythema and pigmentation well. It was revealed that, in our bleaching protocol, the narrow-band reflectance spectrophotometer was quite useful for estimating accurately the intensity of pigmentation and erythema and determining the best time point for the cessation of atRA treatment.

Pharmacokinetics and pharmacodynamics of (+)‐threo‐methylphenidate enantiomer in patients with hypersomnia

The pharmacokinetics of (+)‐methylphenidate after oral administration of 20 mg racemic methylphenidate hydrochloride and the relationship between clinical effects of plasma (+)‐methylphenidate concentration were investigated in 15 patients with hypersomnia and four healthy volunteers. The elimination half‐life of (+)‐methylphenidate in patients was within the range of 2.6 to 3 hours, and the time to reach the peak concentration ranged from 1 to 3 hours. The values of half‐life and time to reach the peak concentration in the patients were almost the same as the values in healthy subjects. The plasma (+)‐methylphenidate concentration profiles after repeated administration of racemic methylphenidate were similar to those after single administration. No correlation was observed between the plasma (+)‐methylphenidate concentration and the subjective sleepiness as measured by Stanford Sleepiness Scale. On the other hand, a significant correlation was found between the sleep latency as measured by the multiple sleep latency test and the plasma concentrations of (+)‐methylphenidate (r = 0.850). The time course of the sleep latency after repeated administration was similar to that after single administration. The sleep latency of more than 10 minutes was achieved by maintaining the plasma (+)‐methylphenidate concentrations above 3 ng/ml.

A new bleaching protocol for hyperpigmented skin lesions with a high concentration of all-trans retinoic acid aqueous gel.

Abstract. A new bleaching protocol for skin hyperpigmentation with a higher concentration of all-trans retinoic acid (atRA) aqueous gel than those commercially available is introduced. AtRA aqueous gel (0.1%) was applied topically twice a day along with 4% hydroquinone, 7% lactic acid ointment to oriental patients with hyperpigmented lesions such as senile lentigines, melasma, and postinflammatory hyperpigmentation. The clinical results of 39 patients treated with 0.1% atRA aqueous gel were compared to those of 22 patients treated with 0.1% atRA hydrophilic ointment. Better clinical results and subjective satisfaction were obtained through a significantly shorter period of treatment with 0.1% atRA aqueous gel than with 0.1% atRA hydrophilic ointment, although side effects such as erythema and irritation were seen at a higher frequency. It is suggested that our bleaching protocol with a high concentration of atRA aqueous gel in combination with hydroquinone and lactic acid has a strong bleaching ability and a potential as a standard therapy for various kinds of skin lesions with hyperpigmentation.

Pharmacodynamic Modeling for Change of Locomotor Activity by Methylphenidate in Rats

AbstractPurpose. The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed. Methods. MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis. Results. The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (Ki) of MPD for DA reuptake was estimated to be 41.3 ± 73.8 nM (mean ± SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model. Conclusions. The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may be useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine.

Stereospecific Distribution of Methylphenidate Enantiomers in Rat Brain: Specific Binding to Dopamine Reuptake Sites

To investigate the stereoselective distribution of methylphenidate (MPD) enantiomers in rats, the concentrations of each enantiomer were determined in plasma and brain regions (cerebellum, striatum, basal forebrain, brain stem, and cortex) after iv administration of racemic MPD and its individual enantiomers. The concentrations of MPD enantiomers in each brain region reached pseudo-steady state within 10 min after iv administration of racemic MPD (2 mg/kg dose). The influx clearances for MPD calculated from KPapp values in each brain region were not significantly different between MPD enantiomers and between the five brain regions. The mean KPapp values for (+ )-MPD in the striatum at 120 and 240 min after administration of racemic MPD were 10.1 and 10.5, respectively, and these values at each time were significantly larger than the KPapp values (7.5 and 7.0, respectively) for the (–)-isomer (P < 0.01). The KPapp value for (+ )-MPD in the striatum decreased by coadministration of mazindol as an inhibition of both dopamine and norepinephrine reuptake, but it was not changed by desipramine as a norepinephrine reuptake inhibitor. These results suggest that ( + )-MPD was bound specifically to the dopamine reuptake site in the striatum.

エトポシド(VP-16)注射液の持続注入時に発生したポリウレタン製カテーテル亀裂の要因に関する検討

We studied the cause of cracking of a clinically used polyurethane (PU) catheter during the constant infusion of etoposide (VP-16) injection (Lastet), administered without dilution to patients as a part of combination high-dose chemotherapy. After VP-16 injection was infused into the PU catheter at a constant infusion rate (30 ml/h) for 24 h, a decrease in the elasticity (36% of untreated) and on increase in the length of the catheter (3.7%) were observed. These changes were significantly higher than those treated with the control saline. The similar changes of the PU catheter were observed after treatment with a basal solution containing polyethylene glycol 400 (PEG 400), polysorbate 80 and ethanol, which is the vehicle of the VP-16 injection, and with ethanol alone. Moreover, obvious degeneration of the internal wall (occurrence of spots like melting) and cutting face (micro-cracking) of the catheter was observed with an electron microscope after treatment with the vehicle. On the other hand, the elasticity or extension of the PU catheter were not changed after treatment with saline or PEG 400. From these findings, it was suggested that the degeneration and subsequent cracking of the PU catheter during the infusion of VP-16 injection was caused by ethanol contained in its injection solution. No cracking or morphological changes of polyvinyl chloride (PVC) and silicone catheters were found after treatment with the vehicle solution. However, since it has been reported in previous reports that di(2-ethylhexyl)phthalate was leached from PVC bags, the high dose chemotherapy with the dilution-free VP-16 injection should be achieved safely and effectively using a silicon catheter, rather than the PU catheter.