1．The Survey of Trends on Japanese Post-marketing Study after Enforcement of Revised Good Post-marketing Study Practice （GPSP) / 薬剤疫学

In Japan, a re-examination system was introduced in the 1970s, and Post-marketing surveillance (PMS) has been conducted in many cases after the launch of new drugs or the approval of new indications for existing drugs. The revised Good Post-marketing Study Practice (r-GPSP) was enacted in 1 April 2018, and more scientific approach has been required for PMS. The survey aims to identify what kinds of change occurred in the PMS planned after r-GPSP enacted. As for the study method, after confirming the review report of each product, Risk Management Plan (RMP), and the package insert, and extracting necessary items, tabulation and analysis were performed. As a result of analysis, Drug Use Investigations (DUI) still accounted for more than 60％ of the total in PMS. Regarding the target number of DUI, Fifty-eight out of 90 had a sample size of 500 or fewer, only 3 studies exceeded 3,000. Regarding the newly introduced Post-marketing database surveillance (DB study) after r-GPSP enacted, 13 products and 18 surveillances were confirmed, although the number was not as large as the number of DUI. The most used database was Medical Data Vision Co., Ltd. (MDV), which were used in twelve DB studies, and cardiovascular disease and interstitial pneumonia were set as survey targets for safety considerations in multiple studies. There was no Drug Use Comparative Investigation. Furthermore, there were two products which were approved on the condition with re-examination period but did not required additional Pharmacovigilance activities. In terms of sample size calculation, 88 out of 135 studies mentioned rationales for setting the number of samples. Of which, 58 studies had statistical rationales. In many studies, the sample size calculation method that was commonly used in conventional PMSs, called ‘Rule of three’ was described as the statistical rational. After r-GPSP enacted, newly introduced Post-marketing surveillance, including DB surveys, and the scientific approach recommended by PMDA have been adopted in companies gradually. In the future, in order to further promote the scientific approach, it is necessary to further improve the capability of human resources of companies involved in PMS.

Usefulness of the Endotoxin Activity Assay to Evaluate the Degree of Lung Injury

PURPOSE: It has been reported that the Pulse Contour Cardiac Output (PiCCO) is very useful mainly in the field of intensive care and treatment to grasp the pathophysiological conditions of pulmonary edema because of its capability of obtaining data such as Pulmonary Vascular Permeability Index (PVPI) and Extra Vascular Lung Water (EVLW). Furthermore, a high degree of usability of various markers has been reported for better understanding of the pathological conditions in cases with septicemia. MATERIALS AND METHODS: The correlation between the cardiorespiratory status based upon the PiCCO monitor (EVLW and PVPI) and inflammatory markers including C reactive protein, procalcitonin (PC), and Endotoxin Activity Assay (EAA) were evaluated in 11 severe cases that required treatment with a respirator in an intensive care unit. RESULTS: The EAA values were significantly higher in patients with abnormal EVLW at 0.46+/-0.20 compared to the normal EVLW group at 0.21+/-0.19 (p=0.0064). In a similar fashion, patients with abnormal PVPI values tended to have higher PC levels at 18.9+/-21.8 compared to normal PVPI cases at 2.4+/-2.2 (p=0.0676). On the other hand, PVPI was significantly higher in the abnormal EAA group at 3.55+/-0.48 in comparison with the normal EAA group at 1.99+/-0.68 (p=0.0029). The abnormal EAA group tended to have higher PVPI values than the normal EAA group. CONCLUSION: The EAA is a measurement method designed to estimate the activity of endotoxins in the whole blood. Our results suggest that the EAA value, which had the greatest correlation with lung disorders diagnosed by the PiCCO monitoring, reflects inflammatory reactions predominantly in the lungs.

Studies on Therapeutic Effects and Pathological Features of an Antithrombin Preparation in Septic Disseminated Intravascular Coagulation Patients

PURPOSE: Few reports have been made on the therapeutic effects as well as pathological features of an antithrombin preparation in patients diagnosed with septic disseminated intravascular coagulation (DIC) by the diagnostic criteria for acute DIC. MATERIALS AND METHODS: A total of 88 sepsis patients who had received inpatient hospital care during the period from January 2000 through December 2008 were divided into two groups, an antithrombin group and a non-antithrombin group, to study the outcomes. Furthermore, the relationship between sepsis-related factors and DIC in 44 patients was studied. RESULTS: The antithrombin group contained 34 patients, and the non-antithrombin group contained 54 patients. The outcomes were significantly better in the antithrombin group. The levels of protein C were low in DIC patients. CONCLUSION: Our results suggest that early administration of antithrombin might improve outcomes of septic DIC patients in the diagnostic criteria for Japanese Association for Acute Medicine acute DIC.

Effectiveness of Human Atrial Natriuretic Peptide Supplementation in Pulmonary Edema Patients Using the Pulse Contour Cardiac Output System

PURPOSE: Atrial natriuretic peptide (ANP) has a variety of pharmacologic effects, including natriuresis, diuresis, vasodilatation, and suppression of the renin-angiotensin system. A recent study showed that ANP infusion improved hypoxemia and pulmonary hypertension in a lung injury model. On the other hand, the pulse contour cardiac output (PiCCO(TM)) system (Pulsion Medical Systems, Munich, Germany) allows monitoring of the intravascular volume status and may be used to guide volume therapy in severe sepsis and critically ill patients. MATERIALS AND METHODS: We treated 10 pulmonary edema patients without heart disease with human ANP (HANP). The patients were divided into two groups: a group with normal Intrathoracic Blood Volume (ITBV) (900-1100 mL/m2) (n = 6), and a group with abnormal ITBV (n = 4), as measured by the PiCCOtrade mark device; the extravascular lung water (EVLW) and pulmonary vascular permeability index (PVPI) in the two groups were compared. RESULTS: The average patient age was 63.9 +/- 14.4 years. The normal ITBV group showed significant improvement of the EVLW (before, 16.7 +/- 2.7 mL/kg; after, 10.5 +/- 3.6 mL/kg; p = 0.0020) and PVPI (before, 3.2 +/- 0.3; after, 2.1 +/- 0.7; p = 0.0214) after the treatment. The abnormal ITBV group showed no significant improvement of either the EVLW (before, 16.3 +/- 8.9 mL/kg; after, 18.8 +/- 9.6 mL/kg; p = 0.8387) or PVPI (before, 2.3 +/- 0.8; after, 2.7 +/- 1.3; p = 0.2782) after the treatment. In both groups, the EVLW and PVPI were strongly correlated with the chest X-ray findings. CONCLUSION: We conclude that HANP supplementation may improve the EVLW and PVPI in pulmonary edema patients without heart disease with a normal ITBV. The PiCCO(TM) system seems to be a useful device for the management of pulmonary edema.