Pharmaceutical Affairs Law In Japan Research Articles

Effects of Eculizumab Treatment on the Quality of Life in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated in Japan

Introduction: PNH is a hematopoietic stem cell disorder with the expansion of a PIGA mutated clone(s). PNH clones are deficient in the membrane expression of GPI-anchored proteins including CD55 and CD59, which leave erythrocytes susceptible to complement attack, resulting in intravascular hemolysis. Many symptoms experienced by PNH patients such as fatigue, dyspnea, and stomachache have been found to be associated with serum free hemoglobin (Hb) released from erythrocytes by intravascular hemolysis (JAMA. 2005;293(13):1653-1662). Eculizumab (Soliris®), a humanized monoclonal antibody against Complement Factor C5, has shown dramatic effect in blocking intravascular hemolysis. Previous reports have revealed that eculizumab has not only improved anemia but also patients' quality of life (QoL) (N Engl J Med. 2006; 355: 1233-1243, Blood. 2008; 111: 1840-1847, Int J Hematol. 2011; 93: 36-46). However, factors which may be associated with improvement of QoL have yet to be fully understood. To clarify the clinical significance of QoL improvement in PNH patients treated with eculizumab, we analyzed the change in QoL in 54 PNH patients treated with eculizumab based on the data from the post-marketing surveillance (PMS) of eculizumab in Japan.Methods: All PNH patients treated with eculizumab have been registered in PMS based on the revised Pharmaceutical Affairs Law in Japan since June 2010. Of 491 patients registered as at March 2017, QoL questionnaires were obtained from 225 patients. 54 patients who received both baseline and one-year assessment of QoL were analyzed in this study. QoL was assessed using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) instruments. Summary statistics were obtained from the figures of QoL scoring systems and the lab values, and paired Student's t-test was used for the change of the values in one year from the baseline. Canonical correlation analysis was performed among QoL variates (consisted of 16 items) and lab data variates (LDH, Hb, and platelets).Results: There was no bias in the baseline characteristics between the total (491) and the analyzed (54) patients. One-year administration of eculizumab improved serum LDH level (mean: from 1435.3 to 289.5 U/L), Hb level (mean: from 8.22 to 9.46 g/dL), and QoL in most of their items in comparison with the baseline. In particular, significant improvement of EORTC QLQ-C30 was shown in the items of fatigue, dyspnea, physical function, and global health status. Canonical correlation analysis revealed a high correlation between QoL variates and lab data variates (Canonical R=0.8393, p=0.004). Of the lab data variates, LDH (Canonical correlation coefficient: -0.91) and Hb (0.76) showed strong correlations with QoL improvement as expected. Interestingly, QoL improvement was independent of patient's baseline characteristics such as the coexistence of aplastic anemia and/or myelodysplastic syndrome and the degree of lactate dehydrogenase (LDH) (Fig. 1, 2).Conclusion: In this study, QoL improvement following treatment with eculizumab was statistically strongly correlated to the degree of hemolysis, which is consistent with the previous reports. Herein we also demonstrated, for the first time, that the degree of improvement was independent of the baseline serum LDH level before eculizumab treatment and of the presence or absence of bone marrow failure. Those PNH patients without eculizumab treatment due to mild hemolysis might benefit from eculizumab treatment regardless of the presence of bone marrow failure syndromes. [Display omitted] DisclosuresUeda:Alexion Pharma GK: Honoraria, Research Funding. Obara:Alexion Pharma GK: Honoraria, Research Funding. Yonemura:Alexion Pharma GK: Honoraria, Research Funding. Noji:Alexion Pharma GK: Honoraria, Research Funding. Matsuda:Alexion Pharma G.K.: Employment. Akiyama:Alexion Pharma G.K.: Employment. Chiba:Nippon Shinyaku: Honoraria, Research Funding. Kawaguchi:Alexion Pharma G.K.: Honoraria; Novartis,Pfizer: Consultancy, Honoraria. Shichishima:Alexion Pharma GK: Honoraria. Okamoto:Bristol-Myers K.K: Honoraria; Pfizer Japan: Speakers Bureau; Alexion Pharma G.K.: Honoraria; Astellas: Honoraria; Pfizer: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Novartis: Research Funding; Bristol-Myers K.K: Research Funding. Nishimura:Alexion Pharma GK: Honoraria, Research Funding. Kanakura:Fujimotoseiyaku: Research Funding; Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Shionogi: Research Funding; Chugai Pharmaceutical: Research Funding; Nippon Shinyaku: Research Funding; Pfizer: Research Funding; Bristol Myers: Research Funding; Toyama Chemical: Research Funding. Ninomiya:Alexion Pharma GK: Honoraria.

Differences in Investigator-Initiated Trials between Japan and Other Countries: Analyses of Clinical Trials Sponsored by Academia and Government in the ClinicalTrials.gov Registry and in the Three Japanese Registries.

BackgroundFollowing the amendment of the Pharmaceutical Affairs Law in Japan in 2003 researchers were permitted to begin investigator-initiated trials (IITs). In subsequent years, however, the number of IITs remained low. In other countries in Asia as well as in Europe, North America, and South Africa, the number of IITs has increased over the past decade. The differences in the characteristics of IITs between Japan and other countries are unknown. Some studies have analyzed the characteristics of all clinical trials according to registry databases, but there has been less research focusing on IITs.AimsThe purpose of this study is to analyze the characteristics of IITs in the ClinicalTrials.gov registry and in the three Japanese registries, to identify differences in IITs between Japan and other countries.MethodsUsing Thomson Reuters Pharma™, trials sponsored by academia and government as IITs in 2010 and registered in ClinicalTrials.gov were identified. IITs from 2004 to 2012 in Japan were identified in the three Japanese registries: the University Hospital Medical Information Network Clinical Trials Registry, the Japan Pharmaceutical Information Center Clinical Trials Information, and the Japan Medical Association Center for Clinical Trials, Clinical Trials Registry. Characterization was made of the trial purposes, phases, participants, masking, arms, design, controls, and other data.ResultsNew and revised IITs registered in ClinicalTrials.gov during 2010 averaged about 40% of all sponsor-identified trials. IITs were nearly all early-phase studies with small numbers of participants. A total of 56 Japanese IITs were found over a period of 8 years, and these were also almost nearly all early-phase studies with small numbers of participants.ConclusionThere appear to be no great differences between Japan and other countries in terms of characteristics of IITs. These results should prompt a new review of the IIT environment in Japan.

血管内治療で救命した顎動静脈瘻破裂症例

A 64-year-old woman with neurofibromatosis type 1 was admitted because of a sudden hematoma in her right neck and throat. To prevent an airway obstruction, tracheostomy was performed, but bleeding into the trachea persisted and was difficult to stop. Bleeding arose from a vessel lesion in the right parapharyngeal space, passed through the paratracheal space, and finally reached the tracheostomy wound. An arteriovenous fistula (AVF) in the maxillary artery was revealed by angiography. We diagnosed rupture of the varix resulting from venous high pressure caused by the AVF. The patient was treated by vascular interventional radiology (IVR). A large number of platinum coils were inserted and N-butyl-2-cyanoacrylate (NBCA) was embolized in the AVF and varix. Although innovative vascular IVR was better than surgery to treat AVF of the head and neck lesion, some problems were encountered. The cost for the provided medical services was high, and NBCA was not approved by the pharmaceutical affairs law in Japan.

Introducing Internet Retailing of OTC Drugs in Japan: Revision of the Pharmaceutical Affairs Law.

Only the low-risk category of over-the-counter (OTC) drugs was permitted to be sold via the Internet, which was stipulated by the ordinance of the Minister of Health, Labour and Welfare under the Pharmaceutical Affairs Law in Japan. Two Japanese retailers of OTC drugs, who want to retail OTC drugs via the Internet, launched proceedings against the rule, and the Supreme Court gave a decision that the ministerial ordinance is illegal and invalid. The Ministry of Health, Labour and Welfare immediately started discussion to make rules for Internet retailing of OTC drugs. Finally, a bill designed to enable Internet retailing of OTC drugs was passed by the Diet on December 5, 2013, and the act was promulgated on December 13. The act was enforced on June 12, 2014. This article briefly touches on the decision process and also illustrates the key points of the new rules for Internet retailing.

A synthetic cannabinoid FDU-NNEI, two 2H-indazole isomers of synthetic cannabinoids AB-CHMINACA and NNEI indazole analog (MN-18), a phenethylamine derivative N-OH-EDMA, and a cathinone derivative dimethoxy-α-PHP, newly identified in illegal products.

Six new psychoactive substances were identified together with two other substances (compounds 1–8) in illegal products by our ongoing survey in Japan between January and July 2014. A new synthetic cannabinoid, FDU-NNEI [1-(4-fluorobenzyl)-N-(naphthalen-1-yl)-1H-indole-3-carboxamide, 2], was detected with the newly distributed synthetic cannabinoid FDU-PB-22 (1). Two 2H-indazole isomers of synthetic cannabinoids, AB-CHMINACA 2H-indazole analog (3) and NNEI 2H-indazole analog (4), were newly identified with 1H-indazoles [AB-CHMINACA and NNEI indazole analog (MN-18)]. In addition, 2-methylpropyl N-(naphthalen-1-yl) carbamate (5) and isobutyl 1-pentyl-1H-indazole-3-carboxylate (6) were detected in illegal products. Compound 6 is considered to be a by-product of the preparation of NNEI indazole analog from compound 5 and 1-pentyl-1H-indazole. A phenethylamine derivative, N–OH-EDMA [N-hydroxy-3,4-ethylenedioxy-N-methylamphetamine, 7], and a cathinone derivative, dimethoxy-α-PHP (dimethoxy-α-pyrrolidinohexanophenone, 8), were newly identified in illegal products. Among them, compounds 1 and 8 have been controlled as designated substances (Shitei-Yakubutsu) under the Pharmaceutical Affairs Law in Japan since August and November 2014, respectively.

Installation of a Neuromate Robot for Stereotactic Surgery: Efforts to Conform to Japanese Specifications and an Approach for Clinical Use-Technical Notes.

The neuromate is a commercially available, image-guided robotic system for use in stereotactic surgery and is employed in Europe and North America. In June 2015, this device was approved in accordance with the Pharmaceutical Affairs Law in Japan. The neuromate can be specified to a wide range of stereotactic procedures in Japan. The stereotactic X-ray system, developed by a Japanese manufacturer, is normally attached to the operating table that provides lateral and anteroposterior images to verify the positions of the recording electrodes. The neuromate is designed to be used with the patient in the supine position on a flat operating table. In Japan, deep brain stimulation surgery is widely performed with the patient's head positioned upward so as to minimize cerebrospinal fluid leakage. The robot base where the patient's head is fixed has an adaptation for a tilted head position (by 25 degrees) to accommodate the operating table at proper angle to hold the patient's upper body. After these modifications, the accuracy of neuromate localization was examined on a computed tomography phantom preparation, showing that the root mean square error was 0.12 ± 0.10 mm. In our hospital, robotic surgeries, such as those using the Da Vinci system or neuromate, require operative guidelines directed by the Medical Risk Management Office and Biomedical Research and Innovation Office. These guidelines include directions for use, procedural manuals, and training courses.

Changes in the prevalence of new psychoactive substances before and after the introduction of the generic scheduling of synthetic cannabinoids in Japan

To counter the spread of the many analogues of psychoactive substances, the Pharmaceutical Affairs Law in Japan was amended in 2006 to establish a new category - Designated Substances - in order to more promptly control these drugs. As of March 2013, 106 substances (including one plant, Salvia divinorum) were listed in the category of Designated Substances, and 13 of them had had their category changed from Designated Substances into the much stricter category, Narcotics. However, new analogues of controlled substances, especially synthetic cannabinoids, appeared one-by-one since the new category was introduced. To avoid a cat-and-mouse game between regulators and illicit drug manufacturers, a comprehensive system (generic scheduling) for designating naphthoylindole-type synthetic cannabinoids, with particular substituents, was introduced into the Designated Substances in 2013. Since late 2012, the naphthoylindole-type compounds have been gradually replaced by other types of synthetic cannabinoids, such as cyclopropylmethanones, cannabimimetic carboxamide derivatives, adamanthoyl indoles, and cannabimimetic quinolinyl carboxylates. After the enforcement of the generic scheduling for designating naphthoylindoles in March 2013, these naphthoylindoles have been completely replaced by other types and have rarely been detected in the products. New types of psychoactive substances, including opioid receptor agonists (e.g. AH-7921, MT-45), hallucinogenic phenethylamines (e.g. NBOMe-type compounds), and thiophene derivatives (e.g. methiopropamine, α-PVT) have also appeared. The almost infinite possibilities of altered structures of chemicals make it difficult to carry out effective and exhaustive scheduling. To prevent the widespread distribution and abuse of these new psychoactive substances, continuous and dedicated monitoring for the emergence of these substances is necessary.

From an Illegal Drug (So-called Non-medically Used Psychoactive Drug) to the Designated Substance (Shitei-Yakubutsu) Controlled by the Pharmaceutical Affairs Law in Japan<br/>—Approach from the Laboratory Examination to the Regulation—

From an Illegal Drug (So-called Non-medically Used Psychoactive Drug) to the Designated Substance (Shitei-Yakubutsu) Controlled by the Pharmaceutical Affairs Law in Japan<br/>—Approach from the Laboratory Examination to the Regulation—

Prevalence of New Designer Drugs and Their Legal Status in Japan

In recent years, many analogs of narcotics have been widely distributed as easily available psychotropic substances and have become a serious problem in Japan. To counter the spread of these non-controlled substances, the Pharmaceutical Affairs Law in Japan was amended in 2006 to establish a new category; Designated Substances in order to more strictly control these substances. In April 2007, 31 compounds and 1 plant were first controlled as Designated Substances. Before 2007, the major compounds distributed in the Japanese illegal drug market were tryptamines, phenethylamines and piperazines. Alkyl nitrites, such as isobutyl nitrite and isopentyl nitrite, were also widely distributed. After they were listed as Narcotics or Designated Substances in 2007, these compounds, especially the tryptamines, quickly disappeared from the market. In their place, cathinone derivatives have been widely distributed, as well as different phenethylamines and piperazines. Additionally, in recent years, new herbal products containing synthetic cannabinoids have appeared globally. As at July 2012, 78 substances (including 1 plant; Salvia divinorum) were listed in the category of Designated Substances. They were 13 tryptamines, 17 phenethylamines, 11 cathinones, 4 piperazines, 23 synthetic cannabinoids, 6 alkyl nitrites, 3 other compounds and 1 plant. In this review, we show our survey of the spread of new designer drugs in Japan, focusing especially on synthetic cannabinoids and cathinone derivatives. Also, the prevalence and legal status of these substances in other countries will be presented.

Changes in the prevalence of synthetic cannabinoids and cathinone derivatives in Japan until early 2012

The changes in the prevalence of designer drugs and their legal status in Japan were investigated on the basis of the analyses of 686 different products containing synthetic cannabinoids and/or cathinone derivatives obtained from 2009 to February 2012. In the early stages of distribution of herbal-type products containing synthetic cannabinoids, cyclohexylphenols and naphthoylindoles were mostly found in the products. In November 2009, however, cannabicyclohexanol, CP-47,497 and JWH-018 were controlled as “designated substances” under the Pharmaceutical Affairs Law in Japan, and the cyclohexylphenols have since disappeared from the illegal drug market and been replaced by various analogs of the naphthoylindoles, phenylacetylindoles and benzoylindoles. These compounds, which have high affinities for the cannabinoid CB1 receptor, have become very popular, and the number of emergency hospitalizations associated with their use has dramatically increased from 2011. Other synthetic compounds with different structures and pharmacological effects, such as cathinone derivatives, have been detected together with the synthetic cannabinoids in herbal-type products since 2011. Moreover, many new types of synthetic cannabinoids, different from the four typical structures described, have also begun to appear since 2011. In addition to the synthetic cannabinoids, liquid or powdery-type products containing cathinone derivatives have been widely distributed recently. In 2009, the most popular cathinone derivative was 4-methylmethcathinone. After this compound was controlled as a designated substance in November 2009, cathinone derivatives, which have a pyrrolidine structure at the nitrogen atom and a 3,4-methylenedioxy structure, or analogs of 4-methylmethcathinone, became popular. In the present analysis, tryptamines were also detected in 31 % of the products containing cathinone derivatives. Local anesthetics such as procaine, lidocaine, benzocaine and dimethocaine were also frequently detected. In total, we identified at least 35 synthetic cannabinoids and 22 cathinone derivatives during this survey.

Rapid, sensitive and simultaneous determination of fluorescence-labeled designated substances controlled by the Pharmaceutical Affairs Law in Japan by ultra-performance liquid chromatography coupled with electrospray-ionization time-of-flight mass spectrometry

A simultaneous determination method based on ultra-performance liquid chromatography (UPLC) with fluorescence (FL) detection and electrospray-ionization time-of-flight mass spectrometry (ESI-TOF-MS) was developed for 16 "designated substances" (Shitei-Yakubutsu) controlled by the Pharmaceutical Affairs Law in Japan. These substances were first labeled with 4-(N,N-dimethylaminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole at 60 degrees C for 2 h in 0.1 M borax (pH 9.3). The resulting fluorophores were well separated by reversed-phase chromatography using an Acquity UPLC BEH C(18) column (1.7 microm, 100 mm x 2.1 mm i.d.) by isocratic elution with a mixture of water and acetonitrile-methanol (20:80) containing 0.1% formic acid. The separated derivatives were sensitively detected by both FL and TOF-MS. However, the determination of several designated substances by FL detection showed interference from endogenous substances in biological samples. Therefore, the determination in real samples was carried out by a combination of UPLC separation and ESI-TOF-MS detection. The structures of the designated substances were identified from the protonated-molecular ions [M+H](+) obtained from the TOF-MS measurement. The calibration curves obtained from the peak area ratios of the internal standard (I.S.), i.e., 3-phenyl-1-propylamine, and the designated substances versus the injection amounts showed good linearity. The limits of detection (S/N = 3) and the limits of quantification (S/N = 10) in 0.1 mL of human plasma and urine for the present method were 0.30-150 pmol and 1.0-500 pmol, respectively. Good accuracy and precision (according to intraday and interday assays) were also obtained with the present procedure. This method was applied to analyses of human plasma, urine and real products.

ERRATA: Analytical Data of Designated Substances (Shitei-Yakubutsu) Controlled by the Pharmaceutical Affairs Law in Japan, Part I: GC-MS and LC-MS

ERRATA: Analytical Data of Designated Substances (Shitei-Yakubutsu) Controlled by the Pharmaceutical Affairs Law in Japan, Part I: GC-MS and LC-MS

Simultaneous determination of 11 designated hallucinogenic phenethylamines by ultra-fast liquid chromatography with fluorescence detection

To avoid the spreading of illegal drugs, a designated drug regulation system was introduced along with revision of the Pharmaceutical Affairs Law in Japan in 2006, and 32 substances including phenethylamine-type drugs were listed in April 2007. In this study, a new simultaneous determination method, based on ultra-fast liquid chromatography coupled with fluorescence detection (UFLC–FL), was developed for the 11 designated phenethylamine drugs. The phenethylamines were labeled with 4-( N, N-dimethylaminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole (DBD-F) at 60 °C for 2 h in 0.1 M borax (pH 9.3). The resulting 11 fluorophores were completely separated by reversed-phase chromatography using an ACQUITY UPLC BEH C 18 column (2.1 mm × 100 mm 1.7 μm) and fluorometrically detected at 550 nm (excitation at 450 nm). The calibration curves obtained from the peak areas versus the injection amounts of the phenethylamines showed a good linearity. The limits of detection (signal-to-noise ratio of 3: S/N = 3) on the chromatogram were in the range from 10 fmol (PMMA) to 2.5 pmol (MMDA-2). Good accuracy (%) and precision (CV) by intra-day assay and inter-day assay were also obtained using the present procedure. The method was applied to the qualitative and quantitative analyses of phenethylamine in real products obtained from the Japanese market. As the results, BDB (0.24 mg/mg), MMDA-2 (0.98 mg/mL) and 2C-I (0.016 mg/mg) were identified from the different products (powder, liquid and mushroom like). Because the procedure is simple, selective and sensitive, the present method seems to be useful for the qualitative and quantitative analyses of the designated phenethylamines in various samples including biological specimens.

Analytical Data of Designated Substances (Shitei-Yakubutsu) Controlled by the Pharmaceutical Affairs Law in Japan, Part II: Color Test and TLC

Many psychotropic substances are readily available in Japan via the Internet. To avoid the spread of drug abuse, some drugs have been controlled as designated substances (Shitei-Yakubutsu) in Japan since 2007 by the Pharmaceutical Affairs Law. Twenty-nine designated substances (classified as tryptamine, phenethylamine and piperazine types) were analyzed using color tests and TLC. The color tests were examined with the Marquis, Ehrlich, Simon's, Liebermann-Burehard's, and Mandelin reagents. The color of beta-carbonyl-methylenedioxyphenetylamines produced by the Marquis reagent was yellow, and 4-halo-2,5-dimethoxy phenethylamines reacted with the Marquis reagent to a give deep yellow-green and/or a deep green color. Although all designated substances of the tryptamine type reacted with the Ehrlich reagent to give a brown color, only 1-(2,4,6-trimethoxyphenyl) propan-2-amine (TMA-6) among the phenethylamines showed a red color on treatment with the reagent. However, 3,4,5-trimethoxy and 2,4,5-trimethoxy isomers of TMA-6 were not colored with the reagent. Thus, TMA-6 could be distinguished from isomers using the Ehrlich reagent. We also analyzed the designated substances with thin-layer chromatography developed with two different solvent conditions. All substances were detected by UV(254 nm) and an iodoplatinate reagent. These results suggest that color tests and TLC, followed by GC-MS and LC-MS analyses, can be used for preliminary identification of designated substances.

Analytical Data of Designated Substances (Shitei-Yakubutsu) Controlled by the Pharmaceutical Affairs Law in Japan, Part I: GC-MS and LC-MS

In the last 10 years, many analogs of narcotic substances have been widely distributed in Japan as easily available psychotropic substances and this has become a serious problem. They have been sold as video cleaners, incense and reagents via the Internet or in video shops. They are not controlled under the Narcotics and Psychotropics Control Law because their pharmacological effects have not yet been proved scientifically. As a countermeasure to prevent the abuse of these substances, the Ministry of Health, Labor and Welfare amended the Pharmaceutical Affairs Law in 2006 so that 31 non-controlled psychotropic substances (11 tryptamines, 11 phenethylamines, 6 alkyl nitrites, 2 piperazines and salvinorin A) and 1 plant (Salvia divinorum) are now controlled as "Designated Substances (Shitei-Yakubutsu)" as of April 2007. Five other compounds (4 phenethylamines and 1 piperazine) were also added to this category in January 2008. In this study, we developed simultaneous analytical methods for these designated substances using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) and present retention times, UV spectra, electron ionization (EI), GC-MS, and electrospray ionization (ESI) LC-MS data.

Identification of Aloe species by random amplified polymorphic DNA (RAPD) analysis

Juice and integument of leaves of 3 Aloe species, Aloe vera, A. ferox and A. africana, are not allowed to be used as food according to the Pharmaceutical Affairs Law in Japan. On the other hand, whole leaves of A. arborescens can be used as food. The present study was designed to distinguish Aloe species by random amplified polymorphic DNA (RAPD) analysis. DNA was isolated from fresh and dried leaves of the 4 Aloe species. Five out of 32 different 10-mer primers examined were useful for analysis. By comparison of the characteristic bands of PCR products on agarose gel, it was possible to distinguish the 4 species. Thus, the botanical species of Aloe in commercial food products can be identified by RAPD analysis.