The role of nitric oxide (NO)-containing nerves in adrenergic neurotransmission in hypertension was studied in mesenteric resistance arteries without endothelium in 2-kidney-1-clip renal hypertensive rats (2K-1C RHR) and sham-operated normotensive rats (Sham-R). Mesenteric vascular beds isolated from 2K-1C RHR and Sham-R were perfused with Krebs solution and changes in perfusion pressure were measured with a pressure transducer. Perfusion of a NO synthase inhibitor, N-ω-nitro-L-arginine methyl ester (L-NAME), markedly augmented vasoconstrictor responses to periarterial nerve stimulation (PNS) without affecting vasoconstriction induced by exogenously injected noradrenaline. L-NAME significantly increased the neurogenic release of NA evoked by PNS in both 2K-1C RHR and Sham-R preparations. The facilitatory effect of L-NAME based on the inhibition of NO production in 2K-1C RHR was less than that in Sham-R. These results suggest that the function of NO-containing nerves, which presynaptically inhibit adrenergic neurotransmission, is decreased in the renovascular hypertensive model rat.
Long-chain polyunsaturated fatty acids (LCPUFAs) are components of membrane phospholipids and they are abundant in the brain. LCPUFAs are supposed to be involved in several brain functions including emotion, learning and memory. However, the mechanisms of effects of LCPUFAs on brain functions at cellular and molecular levels remains unclear. Because LCPUFAs are insoluble in the intracellular compartment, specific transporters are required to deliver LCPUFAs for appropriate intracellular compartments. Fatty acid binding proteins (FABPs) are believed to play crucial roles as their cellular shuttles. Among various FABPs, heart-type fatty acid binding protein (H-FABP) is highly expressed in neurons of the mature brain and involved in arachidonic acid incorporation in the brain. Moreover, the association of H-FABP and dopamine D2L receptor has been documented by our studies. In this context, we here examined behavioral and molecular biological phenotype of H-FABP gene-ablated mice to clarify function of H-FABP in the higher brain functions.
The rate of smoking in patients with schizophrenia is higher than that in the general population. Nicotinic acetylcholine receptors (nAChR) are involved in the sensorimotor gating deficits in schizophrenia. We have revealed that nicotine ameliorates the disruption of the PPI, a model of sensorimotor gating, which is induced by apomorphine, a dopamine receptor agonist, but is not effective for the disruption of the PPI induced by phencyclidine, a glutamine NMDA receptor antagonist, in rats. Furthermore, the ameliorating effect of nicotine is antagonized by methyllycaconitine, a selective α7 nAChR antagonist. The effect of nocitine was also investigated in the stereotyped behavior induced by apomorphine, however, nicotine was found to have no significant effect. Considering these results, the ameliorating effect of the disruption of the PPI via α7 nAChR is therefore thought to be involved in dopaminergic systems. The dopaminergic systems involved in α7 nAChR may be different from the systems involved in stereotypy. In addition, this review describes the effects of the α7 nicotinic receptor agonists.
The fruits juice of Morinda citrifolia (Noni juice) is a well known healthy drink and has various pharmacological effects such as antioxidant. Here, we focused on the protective effect of Okinawa Noni juice (ONJ) against ischemic stress using cerebral ischemia-reperfusion model mice. We found that free intake of 10% ONJ for 7 days showed the protective effect on neuronal damage after ischemic stress, while 3% ONJ did not show such effects. It has recently reported that glucose intolerance might be induced by ischemic stress and controlling of the blood glucose levels in the early phase of ischemic stress seems to be important for good prognosis. Interestingly, we have found the glucose intolerance was developed on 1st day after ischemic stress, while it disappeared on 3rd day. On the other hand, neuronal damage gradually developed from 1st to 5th day after ischemic stress. These results indicate that development of glucose intolerance might be one of the exacerbating factors of neuronal damage after ischemic stress. Noteworthy, the development of glucose intolerance on 1st day after ischemic stress significantly suppressed by ONJ in a dose-dependent manner. These results suggest that protective effect of ONJ might be mediated by suppression of ischemic stress-induced glucose intolerance.
This paper describes the history of discussions on ethnic differences at the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (ICH). The first part of this paper gives a short outline of the purpose, organization, history, decision making process of the ICH. The ICH process consists of five steps. Step 1: Consensus building by Expert Working Group (EWG); Step 2: Confirmation of six-party consensus; Step 3: Regulatory consultation and discussion; Step 4: Adoption of an ICH harmonized tripartite guideline and Step 5: Implementation. Ethnic factors in the acceptability of foreign clinical data (“Ethnic Difference”) was one of the 14 topics on Efficacy. The author being one of the members of ICH-E5 EWG took part in the discussion of Ethnic Difference. The second part of this paper, describes the history of the discussion on this topic (from its inception to the finalization of the guideline) focusing on Step 2. A retrospective survey on individual pharmacokinetic data of around 80 drugs approved or under development in the 3 regions was conducted. In drafts 2 and 3, acceptance of phase 1 study only was discussed. But the proposal was opposed by industry members from US and EU. In drafts 4 and 5, the concept of “triage” was introduced and several algorithms were proposed, but finally a consensus could not be reached because the proposal was not so pragmatic. In drafts 7 and 8, the concept of “bridging study” was discussed to solve the problem of conducting phase II and III studies. Again, a consensus could not be reached. After the discussion of the “complete clinical data package” as proposed in drafts 9-12, the bridging study was once again discussed in drafts 13-19. Finally, draft 20 was confirmed and the discussion then moved to Step 3.
It becomes the important issue for the medical supplies administration to solve the drug lag in our country. As means to overcome both the slow speed and high cost of clinical trial for new drug application in Japan, it seems useful to carry out clinical development simultaneously in East Asia countries such as China, Korea and Taiwan where it is thought that each country has similar ethnicity one another. When conducting simultaneous development with the same protocol in plural countries, it should be avoided that side effect develops abusively. In addition, both the effectiveness and safety expected after marketing should be secured in each country by a recommended amount of medicine for usage provided by simultaneous development between many countries. It is necessary for ethnic similarity to be shown so that development between the many countries in the same dosage is permitted at least. It is expected that the possibility of mutual utilization of clinical trial data of China, Korea and Japan will be shown by pharmacokinetics and pharmacodynamics examinations based on clinical test data of these countries by the Scientific Research funded by MHLW. On the other hand, it seems that it is meaningful and significant to examine the similarity at the gene level from various points of view. In order to give grounds for the validity of carrying out clinical trial in the same protocol in East Asia countries, it may be useful to examine genetic diversity of East Asia countries with plural heredity anthropological techniques such as heredity distance, and compare degree of the genetic diversity between the races of East Asia countries and that of other regions, for example, West Europe countries which have been recognized as one clinical trial field.
Intra- and inter-ethnic differences in pharmacokinetic and pharmacodynamic profiles of clinically relevant drugs are important issues not only for scenes of appropriate drug use in clinical settings but also for those of the drug development. Pharmacogenomics is extremely useful for understanding these racial differences. In this presentation, I will introduce pharmacogenomic concepts (e.g., single nucleotide polymorphisms (SNPs) and haplotype) for interpretation of racial differences in some drugs; pharmacogenomics of drug transporters such as OATP1B1 (organic anion transporting-polypeptide 1B1) and OCT1 (organic cation transporter 1) in pravastatin, metformin, and rosuvastatin will be discussed as model drugs.
As Japan becomes more integrated into the global market, pharmaceutical research and development (R&D) in Japan faces considerable challenges. While global simultaneous development including Asian countries has become a common strategy for multi-national pharmaceutical companies, Japan has been frequently set aside because of its provincial regulatory and clinical trial infrastructure. Meanwhile, many improvement programs in pharmaceutical area have been initiated in Japan. With this increased scrutiny, significant improvements in regulatory process, clinical trial costs, and site performance are anticipated over the next few years. RENAAL is the first multi-national clinical trial involving Japanese patients diabetic nephropathy associated with type II diabetes mellitus. In this article, issues which have been observed in the process of conducting multi-national clinical trial were discussed based on the experience with RENAAL. It is hoped that, as we gain more experiences in multi-national clinical trials, solutions for these issues are found in near future.
A randomized, double-blind, placebo- and active comparator-controlled study was conducted in 69 centers to compare detrusitol and oxybutynin with placebo in Japanese and Korean patients with an overactive bladder (OAB). Detrusitol had similar efficacy but was better tolerated than oxybutynin in Japanese and Korean patients with OAB. The study result was acknowledged as pivotal data in the clinical data package when NDA was filed and successfully approved both in Japan and Korea. Some differences were found in the efficacy and safety of the drug between the Japanese and Korean data, though. We therefore investigated the differences through stratified analysis; however exact causes could not be identified. This study is positioned as a first multinational clinical trial conducted in East Asia. From the aspects of utilization of interoperable data obtained from such multinational clinical trials for NDA filing and earliest possible registration of drugs in the participating countries, we believe it is important to accumulate more experiences in conducting multinational clinical trials. At this time, it is our prime task to minimize the “drug lag” in Japan; I think improving the speed of clinical trials is one of the factors to solve the issue. Global clinical trials involving Western and Asian countries make it possible to use the study data effectively and commonly in many countries. Moreover, from the viewpoint of revitalization of clinical trials, conducting global clinical trials is critically important; so we intend to continue accumulation of our experiences in global clinical trials.
The actual pharmacist workload is not always reflected in dispensing fees, while patients do not always understand the system of dispensing fees. In this study, the relation between the time required for dispensing and prescription details and that between the time required for instruction on drug administration and instruction details in nine pharmacies in Chiba prefecture were investigated. As a result of linear regression analysis, it was suggested that, compared with doses, the number of drug items more greatly affected the time required for dispensing. For oral drugs, the following relation was suggested in the study: [dispensing time (sec)]=29.3+27.5×[number of items]+0.7×[dosing days]+94.4×[number of items]+7.1×[dosing days]. Based on the actual dispensing fees claimed, fees per second of dispensing were estimated at 0.7 point. For drug administration instruction, it was considered reasonable to classify instructions into three categories according to the instruction details and set fees by the categories. When any further pharmaceutical expertise is required, fees should not be set according to the workload but additional fees should be provided to reward expertise.
The molecular status of a freeze-dried sample or a ground mixture of p-dimethylaminobenzonitrile (DMABN) with α-, β-, or γ-cyclodextrins (CDs) was examined using solid-state fluorescence measurements. A twisted intramolecular charge transfer (TICT) emission of DMABN crystals was shown at 475 nm. Emission peaks of freeze-dried samples were observed at 450, 380, and 393 nm in α-CD/DMABN, β-CD/DMABN, and γ-CD/DMABN systems, respectively. It was speculated that DMABN molecules existed as a twisted form in the cavity of α-CD, and as a plane structure in that of β-CD or γ-CD. On the other hand, fluorescence emission peaks of ground mixtures of DMABN with α-, β-, or γ-CD were observed at around 450 nm. When DMABN was ground together with microcrystalline cellulose, which cannot form an inclusion complex, only TICT emission was detected. These results suggest that the observed shift in the fluorescence peak could be due to inclusion phenomena. When the ground mixtures were crystallized under humid conditions, fluorescence emission peaks were observed at 450 nm in α-CD and of around 400 nm in β- and γ-CD systems. It is concluded that the conformation of the DMABN molecules in a crystalline CD/DMABN inclusion complex change depending on the size of the CD cavity.