Strategies for maximizing heart and lung transplantation opportunities in Japan.

INTRODUCTION: Because the donor shortage is extremely severe in Japan because of a strict organ transplantation law, special strategies must be established to maximize heart transplantation (HTx) and lung transplantation (LTx) opportunities. The purpose of this study was to review our strategies to identify and manage heart and lung donors. METHOD: Transplantation doctors themselves assessed their own donor heart and lung function before starting the procurement operation; skillful staff surgeons harvested the organs. Since November 2002, a special transplantation consultant doctor assessed donor organ function to identify useful organs and intensively cared for the donor to improve cardiac and lung function. RESULTS: Only 63 brain-dead donors have been available in Japan. However, 49 HTx (77.7%) and 39 LTx (19 bilateral and 20 single) were performed from 36 donors (57.1%). Thirty-six HTx donors were marginal, requiring sustained high doses of inotropes (n = 26), low left ventricular ejection fraction (n = 5), cardiopulmonary resuscitation (n = 15), and age older than 55 years (n = 6). Twenty LTx donors had infected sputa or showed pneumonia using chest X-ray. None of 49 HTx recipients died of primary graft failure (PGF). Patient survival at 3 years after HTx was 98.0%. Although 5/39 LTx died early, including 2 of PGF, patient survival rate at 3 years was 66.9%. CONCLUSION: Although the number of cases was still small, the availability of hearts and lungs has been high and the transplantation outcomes were acceptable. These strategies may be useful to maximize HTx/LTx opportunities.

Expression of thyrotropin-releasing hormone (TRH) receptor mRNA in somatotrophs in the rat anterior pituitary.

A response of growth hormone (GH) to thyrotropin-releasing hormone (TRH) is observed in lower mammals and patients with diseases such as a cromegaly, but not in normal subjects. We have previously demonstrated the existence of intact TRH receptor mRNA in GH-secreting adenoma. To examine whether intact somatotrophs in the anterior pituitary also express TRH receptor, we attempted to localize both TRHR mRNA and GH immunoreactivity simultaneously. In situ hybridization analysis revealed TRHR mRNAs specifically in the anterior pituitary, and 61.1% of the anterior pituitary cells expressed this transcript. Staining for GH and PRL on the same samples showed that the somatotrophs apparently expressed TRHR mRNA and approximately 62.3% and 30.9% of hybridization-positive cells were somatotorophs and mammotrophs, respectively. Moreover, TRHR mRNA level in the somatotrophs expressed as the number of silver grains per cell was equivalent to that in the mammotrophs. These findings demonstrated expression of the TRHR mRNA in somatotrophs in the rat anterior pituitary, and also showed that more than 50% of the TRHR mRNA detected in the anterior pituitary was derived from these cells.

Stimulation of the preprothyrotropin-releasing hormone gene by epidermal growth factor.

Regulation of the expression of the prepro-TRH (ppTRH) gene by epidermal growth factor (EGF) was investigated. The i.p. injection of EGF significantly stimulated hypothalamic ppTRH messenger RNA levels in rats. To clarify whether this stimulatory effect of EGF could be exerted at the level of gene transcription, the 5'-flanking region (-1893/+127) of the mouse ppTRH gene fused to a luciferase reporter gene was transiently transfected into pituitary GH4C1 cells, and the effect of EGF on gene transcription was measured by a luciferase assay. EGF stimulated ppTRH gene promoter activity in a time- and dose-dependent manner. Deletion analysis revealed that two different regions of the promoter, between -254 and -218 [EGF response element-1 (EGFRE1)] and between -130 and -84 (EGFRE2) were required for full stimulation by EGF. The two EGFREs possessed putative binding sequences for the transcription factor Sp1, and they functioned cooperatively in heterologous promoters. Nuclear extracts from GH4C1 cells specifically bound those two EGFREs in gel retardation assays. Two protein-DNA complexes were found on EGFRE1, whereas four complexes were observed on EGFRE2. Although the binding of nuclear extracts to EGFRE1 was competed for by the consensus Sp1 binding sequence, the complexes on EGFRE1 were not supershifted by an Sp1 antibody. Formation of the slower migrating protein complex on EGFRE1 was prevented by EDTA, suggesting that one of the EGFRE1-binding proteins might be an Sp1-related zinc finger protein. Competition and supershift experiments demonstrated that the EGFRE2-binding protein showing that the slowest migration possessed a characteristic similar to that of Sp1. Selective mutations of the Sp1-binding site in EGFRE2 markedly diminished the EGF-induced stimulation. These results suggest that EGF may function as a positive regulator of ppTRH gene expression, and that the stimulatory effect may be mediated through a cooperative interaction between Sp1 or Sp1-related proteins and additional factors that bind to two separate DNA regions.

Transcriptional down-regulation by epidermal growth factor of TRH receptor mRNA in rat pituitary cells.

To gain insight into the mechanism underlying the epidermal growth factor (EGF)-induced changes in responsiveness to TRH and in the numbers of TRH receptors (TRH-Rs) in the pituitary, we investigated the transcriptional regulation by EGF of the TRH-R gene in GH4C1 cells. Northern blot analyses and binding studies revealed that EGF reduced both TRH binding and TRH-R mRNA levels in a dose- and time-dependent manner, while no significant changes were observed in beta-actin mRNA levels. Addition of actinomycin D caused an acute increase in the basal TRH-R mRNA level, and the rate of decrease of the TRH-R mRNA was identical in control and EGF-treated groups, suggesting that the stability of the TRH-R mRNA was not significantly affected in EGF-treated cells. Incubation with cycloheximide also induced an increase in the basal TRH-R mRNA level and completely reversed the EGF-induced reduction of TRH-R mRNA levels. Furthermore, a nuclear run-on assay demonstrated that the rate of transcription of the TRH-R gene was significantly inhibited in cells treated with EGF. We conclude that (1) EGF decreases the expression of the TRH-R mRNA largely by reducing its rate of transcription, and this action requires the synthesis of new proteins, and (2) inhibitors of protein and RNA synthesis cause a significant increase in the basal TRH-R mRNA level, suggesting that there may be a short-lived protein suppressing the TRH-R mRNA level in the pituitary.

The appearance of noradrenaline and adrenaline and the developmental changes in the their concentrations in the gut of the chick.

1. The times of appearance and the concentrations of noradrenaline and adrenaline were determined fluorimetrically in the gut of the embryonic and developing chick. 2. In the duodenum and jejunum, noradrenaline was detected in embryos on the 12th day of incubation. The concentration continued to increase throughout the embryonic stage and attained a maximum within 3 days of hatching. Afterwards, it decreased to about one-third of the peak level. No adrenaline was detectable in most stages of development. 3. In the rectum, noradrenaline was detected in embryos on the 12th day of incubation; both noradrenaline and adrenaline were invariably found on the 15th day of incubation. The concentrations of both amines fluctuated after hatching, but the amount of adrenaline was always approximately 40% of the amount of noradrenaline, except in the adult.

Increased expression of c-jun gene during spontaneous hepatocarcinogenesis in LEC rats.

We have studied the expressions of nine proto-oncogenes (c-myc, N-myc, c-fos, C-jun, p53, H-ras, N-ras, c-raf, hst) and two other genes (PCNA, GST-P) during the spontaneous development of hepatocellular carcinomas (HCCs) in LEC rats. Expression of c-myc, H-ras, N-ras, C-raf, p53 and PCNA genes was detected, but this did not significantly change during the development of HCCs in LEC rats. Expression of N-myc and hst genes was not detectable. Expression of c-fos gene was detected in one HCC case out of four. Significantly increased expression of c-jun gene was observed in the liver tissues of LEC rats aged 8 months. This high expression was decreased with the development of HCCs. On the other hand, the expression of GST-P gene increased in parallel with the clinical course of the development of HCCs in LEC rats. The pattern of c-jun mRNA augmentation was different from that of GST-P mRNA. These observations suggest that c-jun gene may play a role in the spontaneous development of HCCs in LEC rats.

Pathological comparison between spontaneously developed and chemically induced liver cancers in LEC rats with hereditary hepatitis.

To investigate the pathological differences between spontaneously developed and chemically induced liver cancers in LEC rats with hereditary hepatitis, eight-week-old LEC rats were fed 0.06% or 0.03% of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) for 12 weeks, and then fed basal diet. Spontaneous liver cancers occurred in 60.4% of the LEC rats, while 3'-Me-DAB induced cancers in all LEC rats. The survival periods of chemically (0.06%) treated LEC rats were significantly shorter than non-treated rats. The chemically-induced cancers were strongly related to Edmondson classification. Metastasis and transplantability of the chemically-induced cancers were higher than spontaneous cancers. LEC rats are highly susceptible to the chemical carcinogen with the initiated status of hepatocarcinogenesis.

Activation of the thyrotropin-releasing hormone (TRH) receptor by a direct precursor of TRH, TRH-Gly.

We studied the mechanism by which thyrotropin-releasing hormone (TRH)-Gly stimulated prolactin and thyrotropin (TSH) secretion in pituitary, using a pituitary mammotropic cell line, GH3 cells, and a cell line stably expressing a human TRH receptor (TRH-R). In GH3 cells expressing endogenous TRH-R, an addition of TRH-Gly evoked an immediate rise of intracellular calcium concentration, indicating that TRH-Gly reacted directly without converting from TRH-Gly to TRH. In order to determine whether this reaction might occur through TRH-R, we established a cell line stably expressing a human TRH-R, by transfecting a human TRH-R cDNA into Chinese hamster ovary cells (CHO cells). In this cell line, 10 nM TRH elevated intracellular calcium significantly; the Kd for MeTRH was 1.7 nM. One micromolar and 100 nM TRH-Gly also elevated intracellular concentration of calcium significantly, but not in CHO cells which were not transfected with the TRH-R cDNA. Competition studies further revealed that TRH-Gly displaced MeTRH binding (IC50, 12 microM). These data indicate that at high concentration, TRH-Gly interacts directly with TRH-R to activate signal transduction pathway, and that release of prolactin and TSH induced by TRH-Gly in vitro may be due, at least in part, to the direct effect of TRH-Gly on the TRH-R.

[A case of mucoepidermoid carcinoma underwent middle and lower sleeve bi-lobectomies with carinal reconstruction].

A case of mucoepidermoid carcinoma was successfully resected by bronchoplasty with carinal resection. A 36-year-old male complaining cough and sputum was admitted to our hospital. Bronchofiberscopical examination revealed a tumor mass occluding the truncus intermedius. The tumor seemed to invade the carina, but the orifice of the right upper lobe bronchus was intact. The results of the pathological examination of the biopsy specimen showed mucoepidermoid carcinoma. Sleeve middle and lower lobe bi-lobectomies with carinal reconstruction were successfully performed. The postoperative course was uneventful. The patient is alive 5 year and 5 months after operation without recurrent tumor.

Study of education program of in-hospital procurement transplant coordinators in Japan.

BACKGROUND: As the number of donated organs is still extremely small in Japan compared with other developed countries, in-hospital procurement transplant coordinators (In-Hp PTC) may play an important role in increasing organ donation and making the procurement procedure smoother. In this study, our education program of In-Hp PTC is described. MATERIALS AND METHODS: In May 2012, our department started the In-Hp PTC Education Program. In the first semester, a 2-hour lecture is provided every 2 weeks for 5 months to 15 In-Hp PTCs working near Osaka. In the second semester, 20 lectures were provided for 3 consecutive days to 31 In Hp PTCs, more than 80% of whom work far from Osaka. Lecture topics were the history and current status of organ donation in Japan, social regulation of organ donation, care of transplant recipients, overall procedures of organ donation, the role of In-Hp PTC, donor family care, donor indications, and donor assessment and management. Lectures also included simulations of the organ donation process. RESULTS: Participants were surveyed for their opinions after the program, Most participants were satisfied with the program, topics and duration. As most of them are not full-time In-Hp PTCs, they preferred to attend the 3-day program. Many participants are currently working as main In-Hp PTCs and establishing their own organ donation system in their hospital. CONCLUSIONS: In-Hp PTCs have an important role to play in establishing an organ procurement system and increasing organ donation in Japan. This program may help establish a systematic education program for this occupation in Japan.

Correlation between donor age and organs transplanted per donor: our experience in Japan.

The shortage of available organs for transplantation is a worldwide issue. To maximize the number of transplantations, increasing the number of organs transplanted per donor (OTPD) is widely recognized as an important factor for improving the shortage. In Japan, we have had 211 donors, 1112 organs transplanted, and 924 recipients receiving the transplants, resulting in 4.4 ± 1.4 recipients receiving transplants per donor and 5.3 ± 1.6 OTPD as of February 2013. Because donor age is a well-recognized factor of donor suitability, we analyzed the correlation between donor age group and OTPD. Only the age group 60 to 69 years and the age group 70 to 79 years were significantly different (P < .05) from adjacent age groups. We estimate that a donor under age 70 years has the potential to donate 4.6 to 6.7 organs.

Heart donation in Japan before and after the revision of the Japanese Transplantation Act.

INTRODUCTION: After the revision of the Organ Transplant Act in July 2010, brain dead organ donation increased from 13 to 45 per year, and heart donation increased. The purpose of this study was to review 166 consecutive brain dead heart donors to evaluate our strategies to identify and manage organ donors. METHODS: This study reviewed 166 consecutive brain dead heart donors since the Act was issued. Whereas 69 heart donations were performed between October 1997 and July 2010 before the revision of the Act, 97 heart donations were performed for the 3 years after the revision. Since November 2002, special transplant management doctors were sent to donor hospitals to assess donor organ function and to identify which organs could be transplanted. They also intensively cared for the donors to stabilize hemodynamics and to improve cardiac function by giving intravenous antidiuretic hormones and by pulmonary toileting via bronchofiberscope. RESULTS: The mean heart donor age increased from 41.0 to 43.9 years after the revision. Notably, 11 hearts from donors more than 60 years old were transplanted successfully after the revision. Before the revision, the cause of death was 37 cerebrovascular disease (SAH 34, stroke 1, bleeding 2), 18 head trauma, 13 asphyxia, and 2 postresuscitation brain damage. After the revision, there were 49 cerebrovascular disease (SAH 37, stroke 2, bleeding 16, and other 4), 17 head trauma, 10 asphyxia, and 11 postresuscitation brain damage. A total of 58 donors had a history of cardiac arrest, 58 required a high dose of catecholamine drip infusion, and only 1 recipient died of primary graft dysfunction. Patient survival rate at 3 years after heart transplantation was not different before and after the revision of the Act (98.6% vs 92.2%). CONCLUSIONS: Although donor age was increased and donors who died of cerebral bleeding or postresuscitation after the revision of the Act increased, the outcome after heart transplantation was not changed.

Current status of in-hospital donation coordinators in Japan: nationwide survey.

OBJECTIVES: When the Japanese Organ Transplantation Act was issued, the Japanese Organ Transplantation Network (JOT) was established in 1997. JOT lists recipients, assesses and manages organ donors, and educates publics and headquarters for organ donations. JOT procurement transplant coordinators (PTC) play roles in obtaining consent from relatives for organ donation, donor evaluation and management, organ recovery management, organ transport, and care of donor families during and after donation. Every prefecture has at least one PTC who is mainly working in public education and hospital development. They also help the JOT PTC at the time of organ procurement. Most prefectures commission hospital staff in the procurement hospital to be an in-hospital PTC (In-Hp PTC), who make their hospital staff aware of organ donation and support organ procurement. Although the Act was revised in 2010 with brain-dead organ donation increased from 13 to 44 cases yearly, the number was still extremely smaller than other developed countries. In these circumstances, In-Hp PTC may play greater roles to increase donation and smooth procurement procedures Our primary aim was to describe the current status of In-Hp PTC in Japan. MATERIALS AND METHODS: Between December 15, 2011, and January 31, 2012, we invited 1889 In-Hp PTC to complete a letter survey using a self-designed questionnaire. In all, 56 In-Hp PTC (40%) completed and returned it. RESULTS: The occupation of the respondents was nurse (66%), physician (18%), or other (16%). Although 52% of respondents belonged to the hospital, which was designated for brain-death organ donation by the government, only 46% had any experience with a cadaveric donor. Only 2% were full-time In-Hp PTC. They mainly played a role in preparing their own manual for organ procurement (57%), providing in-hospital lectures (44%) or their own simulation exercise (29%), as well as coordinating donation cases. Although 77% had attended seminar about organ donation provided by JOT or the prefecture PTC, 93% wanted more professional education. However, it was difficult for them to attend these activities, to manage a rare and sudden donation case, and to find time to learn about organ donation because they had another post. The topics that they wanted to learn were donor family care (72%), overall organ/tissue donation procedures (65%), the role of In-Hp PTC (67%), simulations of donation (65%), legislation and social system of organ donation (61%), medical indications for donation (61%), current status of donation and transplantation in Japan (57%), donor management (56%), and case studies (49%). There were significant variations in the topics of interest among the occupations. As they had another post, they could find only a short period (1 or 2 days) to take professional education, such as lectures. Therefore, it was difficult for them to attend practical on-the-job training. CONCLUSIONS: To establish an organ procurement system and increase organ donation, In-Hp PTC have important roles in Japan. However, none is a full-time In-Hp PTC. Most In-Hp PTC require more professional education. A systematic education program for each occupation must be established soon.

Donor evaluation and management system (medical consultant system) in Japan: experience from 200 consecutive brain-dead organ donation.

PURPOSE: As the donor shortage is extremely severe in Japan because of a strict Organ Transplantation Act, special strategies must be established to maximize organ transplant opportunities. The purpose of this study was to evaluate our strategies to identify and manage 200 consecutive brain-dead organ donors. METHODS AND MATERIALS: We retrospectively reviewed the 200 donors procured since the Organ Transplantation Act was issued in 1997, including 118 males, a mean overall age of 45.1 years and cause of death being cerebrovascular disease (n = 119), head trauma (n = 37), and asphyxia (n = 44). DONOR EVALUATION AND MANAGEMENT SYSTEM: Since November in 2002, special transplant management doctors ("medical consultants") were sent to donor hospitals to assess organ function and identify transplantable organs. They also provided intensive care to stabilize hemodynamics and improve cardiac and lung functions by administering antidiuretic hormone intravenously and providing bronchofiberscopic pulmonary toilet. RESULTS: We obtained 146 heart, 1 heart-lung, and 154 lung (87 single and 67 bilateral), 175 liver (28 splitted liver), 142 pancreas (114 pancreas-kidney), 253 kidney and 12 small bowel grafts. Organs procured from 1 donor increased from 4.5 to 6.8 after applying these strategies. CONCLUSIONS: Although the number of cases was still small, the availability of organs and outcomes of transplantation have been acceptable.

Japanese strategies to maximize heart and lung availabilities: experience from 100 consecutive brain-dead donors.

OBJECTIVE: Because the donor shortage is extremely severe in Japan because of a strict organ transplantation law, special strategies have been established to maximize heart and lung transplantations (HTs and LTs, respectively). We reviewed 100 consecutive brain-dead donors to evaluate our strategies to identify and manage heart and lung donors. METHODS: We retrospectively reviewed all 100 consecutive brain-dead donors procured since the law was issued in 1997. There were 56 mens and the overall mean donor age was 43.5 years. The causes of death were cerebrovascular disease (n = 62), head trauma (n = 20), and asphyxia (n = 16): Since November 2002, special transplant management doctors were sent to donor hospitals to assess cardiac and lung functions, seeking to identify transplant opportunities. They stabilized donor hemodynamics and lung function by administering antidiuretic hormone intravenously and performing bronchofibroscopy for pulmonary toilet. RESULTS: Seventy-nine HTs, 1 heart-lung transplantations, and 78 LTs (46 single and 32 bilateral) were performed. By applying these strategies organs per donor were increased from 4.5 to 6.8. Among heart donors, 61/80 were marginal: high inotrope requirement (n = 29), cardiopulmonary resuscitation (n = 28), and/or >55 years old (n = 20). None of the 80 HT recipients died of primary graft failure (PGF). Patient survival rate at 10 years after HT was 95.4%. Among lung donors, 48/65 were marginal: pneumonia (n = 41), chest trauma (n = 4), and >55 years old (n = 9). Only 2/78 LT recipients died of PGF. Patient survival rate at 3 years after LT was 72.2%. After inducing frequent pulmonary toilet, lung procurement and patient survival rates increased significantly after LT. CONCLUSIONS: Although the number of cases was still small, the availability of organs has been greater and the outcomes of HT/LT acceptable.

Professional education and hospital development for organ donation.

Because of the strict Organ Transplantation Act, only 81 brain dead (BD) organ donations had been performed in Japan for 13 years since 1997. The Act was revised on July 17, 2010, allowing, organs to be donated after BD with consent from the family, if the subject had not denied organ donation previously. This act has lead to an expectation of a 6-7-fold increase in BD donation. The 82 organ procurement coordinators (OPC) in Japan include 32 belonging to the Japanese Organ Network (JOT) and the others to each administrative division. JOT has guideline manuals of standard roles and procedures of OPC during organ procurement from BD and cardiac death donors. To manage the increased organ donations after the revision of the act, we have modified the education system. First, we modified the guideline manuals for OPC to correspond to the revised Transplant Act and governmental guidelines. Second, all OPC gathered in a meeting room to learn the new organ procurement system to deal with the revised Transplant Act and guidelines. Third, a special education program for 2 months was provided for the 10 newcomers. Last, the practical training in each donor case for newcomers was performed by older OPC. Topics of the education program were the revised transplant act and guidelines, family approach to organ donation, BD diagnosis, donor evaluation and management, organ procurement and preservation, allocation system, hospital development and family care. In the future, each OPC will be divided into special categories, such as the donor family OPC, the donor management OPC, and the operating room OPC. Therefore, we need to construct separate special education programs for each category.

Modification of the education system for organ procurement coordinators in Japan after the revision of the Japanese Organ Transplantation Act.

BACKGROUND: From October 1997 to July 2010, only 86 brain-dead (BD) organ donations were obtained and no organs were retrieved from children under 15 years of age because of the strict Japan Organ Transplantation Act. The Act was revised on July 17, 2010, allowing organs to be donated after BD with family consent. OBJECTIVE: To manage the increased donations after the revision, the Japan Organ Transplant Network (JOT) employed 10 organ procurement coordinators (OPCs) and modified its education systems. We retrospectively reviewed the modified education programs to evaluate whether they were effective and whether the processes of organ donation were promptly performed after the revision of the Act. METHODS: The modifications of education program were: changing OPC to guideline manuals to correspond to the revised Transplant Act; OPCs were taught the new organ procurement system; and a special education program was provided for the 10 newcomers for 2 months. RESULTS: After 12 months of the revision, 58 BD organ donations were accomplished, whereas they had averaged 6.6 in a year before the revision. Two pediatric BD organ donations were accomplished without problem. One priority organ donation to a relative was performed uneventfully. After applying the modified education program, skilled JOT OPCs and leader JOT OPCs increased. CONCLUSIONS: To manage increased organ donations after the revision of the Act, the educational system was modified and 58 brain dead organ donations were performed safely.

High frequency region of the snore spectra carry important information on the disease of sleep apnoea.

Snoring is the most common symptom of obstructive sleep apnoea (OSA). Several researchers have reported differences between the power spectra of non-OSA and OSA snorers. The traditional approach over the years has been to record snore sounds at a bandwidth of < 5 kHz. Narrowing of the upper airways during OSA events and the resulting upward shift of snore frequencies also lend support to the idea of examining snore sounds beyond 5 kHz. In this paper, we compute the power spectra of snores in three different bands defined as: low-frequency band (LFB: < 5 kHz); middle-frequency band (MFB: 5-10 kHz) and high-frequency band (HFB: 10-20 kHz). We illustrate that there is a significant difference between non-OSA snorers (Apnoea Hypopnoea Index (AHI) < 10) and OSA snorers (AHI > 10) in the region > 5 kHz. We then develop a feature to diagnose OSA based on the spectral differences in the high frequency region and evaluate its performance on a database of 20 subjects. Our results strongly suggest that the high-frequency region of the snore sounds carry information, hitherto disregarded, on the disease of sleep apnoea.

Assignment of human thyrotropin-releasing hormone (TRH) receptor gene to chromosome 8.

The human gene encoding thyrotropin-releasing hormone receptor was assigned to chromosome 8, using human-Chinese hamster ovary somatic cell hybrids, analyzed by Southern hybridizations. Hybridization was carried out with a 32P-labeled fragment of the human TRH-R genomic DNA. Hybridization of this probe to a human specific 10.5-kb DNA fragment of EcoRI-digested WBC DNA was used to localize the human TRH-R gene. No hybridization, by contrast, was seen with this probe and hamster DNA after EcoRI treatment. Results from 18 somatic cell hybrids corroborated unequivocally that the human TRH-R gene can be assigned to human chromosome 8.

Antifungal activity of the new agent latoconazole in two tinea models.

In vitro and in vivo antifungal activities of the new imidazole derivative latoconazole ((+-)-(E)-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]-1- imidazolylacetonitrile, NND-318; CAS 101530-10-3) were studied in comparison with three major topical agents, clotrimazole, bifonazole and tolnaftate. The in vitro activity of latoconazole against dermatophytes was much stronger than that of any reference agent tested. Both the recently developed tinea pedis model and the conventional tinea model in guinea pigs were employed for evaluation of topical usefulness of latoconazole. The 1% solution or cream preparation of latoconazole was highly effective in both of the two tinea models and its 5 or more doses achieved almost complete mycological cure. However, both tinea models, especially the former, were considerably resistant to the therapeutic treatment of all of the reference drugs. These results suggest that latoconazole is a promising topical antifungal agent, probably applicable to the treatment of tinea pedis as well as other types of dermatomycoses.