Lifecycle management of orphan drugs approved in Japan.

BACKGROUND: The development of orphan drugs (ODs) is challenging from both development and business perspectives because of their small patient populations. To overcome such business challenges, lifecycle management (LCM), which maximizes profits by increasing sales and extending product lifetimes, is important to overcome the business challenges arising from their small patient populations. To clarify the activities of the LCM of ODs, we investigated additional indications that contribute to market expansion and marketing exclusivity using the patent extension and re-examination system of ODs approved in Japan between 2004 and 2019. RESULTS: The 203 ODs consisting of 173 active ingredients were approved in Japan between 2004 and 2019. Sixty-eight (39%) of the 173 active ingredients have additional indications, of which 57 have at least one non-OD indication. Three-fourths of the 203 ODs had patent rights, and most of them included substance or use claims. Although the re-examination period for most ODs was 10 years after the approval, most patents had a longer duration than the re-examination period. CONCLUSIONS: Pharmaceutical companies were actively adding non-OD indications and were emphasizing the use of patent rights by registering extensions of substance or use patents for exclusive marketing periods. These results indicate that LCM through the addition of indications and registration of patent extensions is carried out as a strategy for many ODs in Japan, similar to the LCM of general non-ODs.

Patent production is a prerequisite for successful exit of a biopharmaceutical company.

Patents are especially important for the business of drug discovery; however, their importance for biopharmaceutical companies has not been revealed quantitatively yet. To examine the correlation between patents and long-term business outcome of biopharmaceutical companies we analyze annual number of patent families and business conditions of 123 public-listed biopharmaceutical companies established from 1990 to 1995 in the USA. Our results show the number of patent families per year correlates well with the business condition: average of the bankruptcy group is significantly smaller than those of the continuing and the merger and acquisitions (M&A) groups. In the M&A by big pharma group, the acquisition cost correlates with the number of annual patent families. However, patentability and strategy of foreign patent application are not different among the groups. Therefore, the productivity of invention is the key factor for success of biopharmaceutical companies.

[Effect of the active adult learning/patient oriented clerkship on affective reaction of students ∼ from the results of student survey].

We have previously reported the efficacy of the Patient Oriented Clerkship (POC) in the clinical clerkship in Showa University Hospitals, by a trial with old four-year pharmacy program students. In the unique clerkship, each student has a patient in charge, and follows his/her clinical conditions throughout the rotation. The aim of the POC is that having the students learn spontaneously (Active Learning) and actively (Adult Learning) promoted by student's commitment and responsibility by communicating with patients and health professionals in a team. As the POC requires students both Active Learning and Adult Learning, we define the POC as Active Adult Learning (AAL). Having a patient in charge for each student gives them many opportunities to participate in the medical team and foster their problem solving skills. Our previous study eventually showed positive results of the POC in the one-month short clerkship in the four-year program. On the other hand, the effect of the unique hospital clerkship in the new six-year program is not known. We conducted a student survey to clarify the learning effect in the new six-year education system which was revised and 2.5 month clinical clerkship was scheduled according to the model core clerkship curriculum. This report is the first report to show a challenge of the AAL/POC clerkship in the new six-year pharmacy education program.

Development of a novel fluorometric assay for nitric oxide utilizing sesamol and its application to analysis of nitric oxide-releasing drugs.

Nitric oxide (NO) is related to various physiological effects as well as to numerous diseases caused by accentuation of NO production. Measurement of NO in cells and tissues is difficult as NO readily reacts with other molecules; furthermore, its half-life as a radical is fleeting. Currently, many NO pharmaceuticals are marketed as therapeutic agents for ischemic disease. Consequently, the identification of NO radicals and determination of generation rate from pharmaceuticals is very important when the effect of the medicinal supply is estimated. In this study, we developed a fluorometric assay for NO employing sesamol (3,4-methylenedioxyphenol) as a fluorometric substrate. Sesamol is converted to a fluorescent derivative (ex. 365 nm, em. 447 nm), which is dimmer in the presence of NO. The detection limit of NO with this method is 400 fmol; moreover, NO generated from drugs can be measured.

Evolution of subarachnoid space in normal fetuses using magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to measure the fetal subarachnoid spaces at different sites of the brain using magnetic resonance (MR) images and analyze them in relation to gestational age. METHODS: Fetal MR images were obtained from 158 fetuses between 18 and 39 weeks of gestation who later showed no neurological problems. We bilaterally measured the distance between the superoanterior gyrus and the cranium as the frontal subarachnoid space (FSS) and the distance between the cortex in the parieto-occipital sulcus and the cranium as the parietal subarachnoid space (PSS). We also measured the cisterna magna between the cerebellar vermis and the cranium. Each of these was analyzed in relation to gestational age. RESULTS: The width of the FSS began to decrease significantly at 32 weeks of gestation (P < 0.05). The width of the PSS started to decrease significantly at 34 weeks of gestation (P < 0.05). There was no difference between the right and left sides (P < 0.05). The size of the cisterna magna showed a positive correlation with gestational age (P < 0.05). CONCLUSION: Measurement of the subarachnoid space is potentially useful for evaluating fetal development.

Assessment of cortical gyrus and sulcus formation using magnetic resonance images in small-for-gestational-age fetuses.

OBJECTIVES: The purpose was to compare the development of gyrus and sulcus formation (GSF), an indicator of brain maturation, in small-for-gestational-age (SGA) fetuses using magnetic resonance (MR) imaging, with those of appropriate-for-gestational-age (AGA) fetuses. METHODS: The 160 infants with a normal neurological outcome were divided into two groups on the basis of their body weight at delivery; 37 SGA infants (Group SGA) and 123 AGA infants (Group AGA). Fetal MR images, which were obtained from 28 to 39 gestational weeks in Group SGA and from 18 to 39 gestational weeks in Group AGA, were classified into the 8 stages of development for GSF established by Abe et al. (2003), and comparison was made between the two groups retrospectively in their neurological development in relation to gestational age. RESULTS: In Group SGA, images were classified into stages 3 to 8 (P < 0.001). The gestational age of the cases determined for each stage between Groups SGA and AGA did not differ significantly, with respect to the development of GSF, despite differences in fetal estimated body weights. CONCLUSION: In SGA fetuses, evaluation of fetal GSF using MR images during the third trimester may be useful for predicting neurological prognoses postpartum.

Semiquantitative assessment of myelination using magnetic resonance imaging in normal fetal brains.

OBJECTIVES: To evaluate the development of myelination in normal fetuses quantitatively using magnetic resonance (MR) imaging in relation to gestational age (GA). METHODS: Fetal MR images were obtained from 101 fetuses between 26 and 39 weeks of gestation with no neurological problems. Regions of interest were designated in frontal lobe, corona radiata, optic radiation, thalamus, pons, cerebellar vermis, and vitreous body. The signal intensity ratio (SIR) was calculated by the signal intensity of each of these designated areas to that of the vitreous body and analyzed in relation to GA. RESULTS: The SIR of the frontal lobe did not vary significantly with GA. The SIR of the corona radiata and the optic radiation decreased significantly with GA (P < 0.05); after 34 weeks of gestation, they decreased sharply. The SIR of the thalamus, the pons, and the cerebellar vermis was significantly smaller than that of the cerebral white matter at 26 weeks of gestation (P < 0.05) and decreased significantly with GA (P < 0.05). CONCLUSION: Changes in the SIR approximately corresponded to the time-course of progression of myelination in the previous histopathological reports. Semiquantitative evaluation on MR images may allow prenatal diagnosis of a delay or deficit of myelination.

Assessment of cortical gyrus and sulcus formation using MR images in normal fetuses.

OBJECTIVES: The purpose of this study was to estimate the development of the gyrus and sulcus formation in normal fetuses on the basis of the neuroanatomical findings using MR images in relation to gestational age. METHODS: The MR images were obtained from 109 normal fetuses from 18 to 39 weeks of gestation with no neurological problems. The MR images were classified into 8 stages of development for the gyrus and sulcus formation in the frontal and temporal lobes on the basis of the neuroanatomical findings reported by Chi et al. (1977) and Dorovini-Zis and Dolman (1977). We examined retrospectively the relationship between our classification and gestational age in comparison with the five-stage classification proposed by McArdle et al. (1987). RESULTS: There were significant differences in the gestational age among the 8 groups (P < 0.001). Multiple comparison of individual groups revealed significant differences in the gestational age among the groups (P < 0.05). Images from 28 to 34 weeks of gestation were classified into 4 stages in our classification, while being covered by one stage in McArdle's classification. CONCLUSION: Our classification is useful for the assessment of fetal cerebral maturation during the third trimester of pregnancy and may contribute to the prenatal diagnosis of developmental delay of the gyrus and sulcus formation.