Masako Oishi

Long-Term Administration of Intranasal Oxytocin Is a Safe and Promising Therapy for Early Adolescent Boys with Autism Spectrum Disorders

OBJECTIVE Oxytocin (OT) has been a candidate for the treatment of autism spectrum disorders (ASD), and the impact of intranasally delivered OT on ASD has been investigated. However, most previous studies were conducted by single-dose administration to adults; and, therefore, the long-term effect of nasal OT on ASD patients and its effect on children remain to be clarified. METHODS We conducted a singled-armed, open-label study in which OT was administered intranasally over the long term to eight male youth with ASD (10-14 years of age; intelligence quotient [IQ] 20-101). The OT administration was performed in a stepwise increased dosage manner every 2 months (8, 16, 24 IU/dose). A placebo period (1-2 weeks) was inserted before each step. The outcome measures were autism diagnostic observation schedule--generic (ADOS-G), child behavior checklist (CBCL), and the aberrant behavior checklist (ABC). In addition, side effects were monitored by measuring blood pressure and examining urine and blood samples. RESULTS Six of the eight participants showed improved scores on the communication and social interaction domains of the ADOS-G. However, regarding the T-scores of the CBCL and the scores of the ABC, we could not find any statistically significant improvement, although several subcategories showed a mild tendency for improvement. Caregivers of five of the eight participants reported certain positive effects of the OT therapy, especially on the quality of reciprocal communication. All participants showed excellent compliance and no side effects. CONCLUSIONS Although our results on the efficacy of long-term nasal OT therapy still remain controversial, to the best of our knowledge, this is the first report documenting the safety of long-term nasal OT therapy for children with ASD. Even though our data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, promising, and worthy of a large-scale, double-blind placebo-controlled study.

Inhibition of Experimental Abdominal Aortic Aneurysm in the Rat by Use of Decoy Oligodeoxynucleotides Suppressing Activity of Nuclear Factor κB and ets Transcription Factors

Background—Two phenomena, inflammation and matrix degradation, contribute to the progression of abdominal aortic aneurysm (AAA). Importantly, the inflammation is regulated by the transcription factor nuclear factor (NF)–&kgr;B, whereas the destruction and degradation of elastin fibers by matrix metalloproteinases (MMP) are regulated by ets. Thus, we developed a novel strategy to treat AAA by simultaneous inhibition of both NF-&kgr;B and ets by using chimeric decoy oligodeoxynucleotides (ODN). Methods and Results—AAA was induced in rats by transient aortic perfusion with elastase, whereas transfection of decoy ODN was performed by wrapping a delivery sheet containing decoy ODN around the aorta. Gel-mobility shift assay at 7 days after treatment demonstrated that both NF-&kgr;B and ets binding activity were simultaneously inhibited by chimeric decoy ODN. Transfection of chimeric decoy ODN resulted in significant inhibition of the progression of AAA such as aneurysmal dilation at 4 weeks after treatment as compared with control, accompanied by a reduction of MMP expression. Moreover, the destruction of elastin fibers was inhibited in the aorta transfected with chimeric decoy ODN. Importantly, transfection of chimeric decoy ODN demonstrated potent inhibition of aneurysmal dilatation compared with NF-&kgr;B decoy ODN alone, whereas scrambled decoy ODN had no effects. Interestingly, the migration of macrophages was significantly inhibited by chimeric decoy ODN. Conclusions—We demonstrated that inhibition of the progression of AAA was achieved by a novel strategy with chimeric decoy ODN used against NF-&kgr;B and ets in rat model. NF-&kgr;B and ets are considered to play an important role in the pathogenesis of AAA.

Regression of Abdominal Aortic Aneurysms by Simultaneous Inhibition of Nuclear Factor κB and Ets in a Rabbit Model

Because current therapy to treat abdominal aortic aneurysm (AAA), and particularly to manage small AAA, is limited to elective surgical repair, we explored less invasive molecular therapy by simultaneous inhibition of the transcription factors nuclear factor (NF)&kgr;B and ets using a decoy strategy. Both NF&kgr;B and ets were shown to be markedly activated in human AAA. In addition, NF&kgr;B- and ets-positive cells were increased in the aneurysm wall, and a part of the expression of NF&kgr;B and ets was detected in migrating macrophages. Thus, we used chimeric decoy oligodeoxynucleotides (ODNs) containing consensus sequences of both NF&kgr;B and ets binding sites to treat AAA. Inhibitory effects of chimeric decoy ODNs on matrix metalloproteinase-1 and -9 expression were confirmed by ex vivo experiments using a human aorta organ culture. To examine the regressive effect in a rabbit already-formed AAA model, transfection by wrapping a delivery sheet containing chimeric decoy ODNs around the aneurysm was performed 1 week after incubation with elastase. Importantly, treatment with chimeric decoy ODNs significantly decreased the size of AAA. Interestingly, significant preservation of elastic fibers was observed with chimeric decoy ODN treatment, accompanied by a reduction of matrix metalloproteinase-2 and -9 and induction of macrophage apoptosis. Regression of AAA was also associated with an increase in elastin and collagen type I and III synthesis in the aneurysm wall. Minimally invasive molecular therapy targeted to the inhibition of NF&kgr;B and ets is expected to be useful for AAA through the rebalance of matrix synthesis and degradation.

Hypertension Accelerated Experimental Abdominal Aortic Aneurysm Through Upregulation of Nuclear Factor κB and Ets

In this study, we focused on the effect of hypertension on the transcription factors nuclear factor &kgr;B (NF&kgr;B) and ets in the mechanisms of abdominal aortic aneurysm (AAA), and we investigated how hypertension affects the progression of AAA. AAA was produced by elastase perfusion in hypertensive rats and normotensive rats. The size of AAA rapidly increased in hypertensive rats as compared with normotensive rats. Western blot analysis demonstrated that the expression of matrix metalloproteinase (MMP)-2, -3, -9, and -12, as well as intercellular adhesion molecule, was increased in hypertensive AAA rats, accompanied by upregulation of NF&kgr;B and ets. Moreover, in situ zymography showed that the activity of MMPs was increased in the aorta of a hypertensive AAA model as compared with that in a normotensive AAA model. Interestingly, transfection of chimeric decoy oligodeoxynucleotide (ODN) resulted in significant inhibition of aortic dilatation both in normotensive and hypertensive rats at 4 weeks after transfection. Destruction of elastic fibers was also significantly inhibited by transfection of chimeric decoy ODN in both hypertensive rats and normotensive rats. The expression of MMP-2, -3, -9, and -12, as well as intercellular adhesion molecule, was significantly attenuated by the chimeric decoy ODN, accompanied by inhibition of the migration of macrophages. Also, the effect of chimeric decoy ODN was confirmed in an organ culture. The present study demonstrated that hypertension accelerated the progression of experimental AAA through upregulation of NF&kgr;B and ets. Inhibition of NF&kgr;B and ets could be a novel therapeutic strategy to treat AAA in hypertensive patients.

Pharmacokinetic Behavior of Intravitreal Triamcinolone Acetonide Prepared by a Hospital Pharmacy

PurposeWe developed a new hospital pharmaceutical preparation of triamcinolone acetonide (TA) for intravitreal injections using sodium hyaluronate as the vehicle. The purpose of this study was to compare the pharmacokinetic behavior of this hospital pharmacy preparation of TA (HPP-TA) to that of a commercial preparation of TA (CP-TA) in rats.MethodsWe injected the two preparations of TA into the vitreous humor of male Wistar rats. The rats were killed between days 1 and 21, and the concentration of TA in the vitreous was measured by high-performance liquid chromatography to determine the pharmacokinetic parameters. We also examined the microscopic appearance of the TA particles in these preparations.ResultsThe elimination half-life was 6.08 days for the CP-TA and 5.78 days for the HPP-TA. A two-compartment model was suitable to approximate the pharmacokinetic behavior of HPP-TA in the vitreous body, but this model was not suitable for CP-TA, because its pharmacokinetic behavior was not sufficiently stable. The particle size of CP-TA was largest, followed by TA powder and HPP-TA. Many particles were agglutinated in the CP-TA preparation, whereas the TA particles were fine and dispersed in the HPP-TA medium.ConclusionsThe TA particle size and the suspension medium are likely important factors in the preparation of a safe and stable suspension of TA. HPP-TA satisfied these requirements and should be suitable for clinical use.

Examination of purification methods and development of intravitreal injection of triamcinolone acetonide.

PurposeIntravitreal injection of triamcinolone acetonide (TA) is used in ophthalmic treatment, but the reliability of commercially available TA preparations has still not been established. We evaluated two previously reported purification methods, and developed a more reliable TA injection which can be prepared in a hospital pharmacy.MethodsWe tested the two methods previously reported for purifying commercial TA preparations, the sedimentation and the filtration and backflushing methods. We developed a new TA injection made of pure TA suspended in 0.5% sodium hyaluronate. We measured the TA content in each preparation by high-performance liquid chromatography to evaluate the three methods.ResultsIn the sedimentation purification method, the TA content of a nominal 4-mg preparation varied from 1.43 to 7.37 mg, and the average recovery rate was 91.6%. In the filtration and backflushing method, TA content was 0.10–10.33 mg and recovery was 59.5%. In the TA injection we developed, the mean TA content was 102.5% (SD, 0.24; CV, 2.9%). The stability of this preparation was 99% after sterilization, and 97% after 3 months of storage.ConclusionsThe results of our investigation showed that the purification methods used for commercial preparations are simple and easy but not precise enough for an intravitreal injection. In contrast, the TA injection prepared by our method is reliable, stable, and safe enough for clinical use. Jpn J Ophthalmol 2005;49:384–387

The Environmental Assessment by the Air Cleanliness of the Drug Preparation Room in the Hospital Pharmacy and the Analysis of Influential Factors to Airborne Particle Number.

In this study, the present state of the air cleanliness in the drug preparation room at a hospital pharmacy was evaluated, and factors affecting airborne particle numbers (APN) such as the number and the movement of workers and the materials on working clothes and cloths were investigated. In addition, the effect of environmental conditions on air cleanliness on a clean bench was compared. APN was measured with an Aerosol Particle Counter.The maximum 0.5μm APN values while working in the aseptic preparation room were 3, 610, 1, 312 (less than 10, 000 in GMP) and the non-aseptic room were 8, 008, 2, 660 (less than 100, 000) respectively. The conditions of all rooms were sufficiently suitable for drug preparation according to the criteria of GMP.Concerning factors affecting APN, the movement of workers increased the APN much more than the number of workers. The degree of dispersing particles differed greatly depending on the materials of the working clothes and cloths. A decrease to less than 1 /100 can be obtained by the selection of suitable materials for working clothes such as Overall made of polypropylene non-woven fabric from which few of fibers disperse. It is remarkable that smaller particles are dispersed from clothes even after passing through an air shower. In addition, it was confirmed that the dispersing of particles from cloths and rags was also a problem.As long as prescribed methods were used for the clean bench, the air cleanliness inside the clean bench was kept sufficient even through the external air conditions or locations were not so clean.

Studies on dissolution behaviors of extended-release articles.

The dissolution behavior of fifteen commercial extended-release articles was examined by the dissolution test in order to characterize their behavior in vitro. The articles were classified into six groups according to the formation types. The paddle method for six hours was used for tests, and the media were the first solution (pH 1.2) and the second solution (pH 6.8) in JP XI.Five articles showed different patterns in the above two media, so that their dissolution seemed to depend on pH. A few articles were also effected by pH on the dissolution although they showed time-dependent behavior. The others showed pH-independent (time-dependent) dissolution. The dissolution curves of time-dependent articles approximated to zero-order or firstorder kinetic model. There was, however, no significant relation between the formation type of articles and their dissolution behavior.In addition, for time-dependent articles, simulation curves of dissolution were calculated by using “Weibull function” with the data obtained from the dissolution test up to six hours. Since most of all curves conformed to the observed curves, the parameters of the simulation curves were re-calculated only with the data up to three hours to obtain the prediction curves. The predicted rate fitted well to the observed rate after six hours in many articles. Therefore the prediction curves could be applicable to shorten time for the dissolution test.