Antidepressant and anxiolytic profiles of newly synthesized arginine vasopressin V1B receptor antagonists: TASP0233278 and TASP0390325.

BACKGROUND AND PURPOSE: Vasopressin V1B receptor antagonists may be effective for the treatment of depression and anxiety and the objective of this study was to characterize the pharmacological profiles of two newly synthesized arginine vasopressin receptor 1B (V1B receptor) antagonists, TASP0233278 and TASP0390325. EXPERIMENTAL APPROACH: We investigated the in vitro profiles of TASP0233278 and TASP0390325. In addition, the effect of TASP0390325 on the increase in plasma adrenocorticotropic hormone (ACTH) levels induced by corticotropin-releasing factor (CRF)/desmopressin (dDAVP) was investigated. We also investigated the antidepressant and anxiolytic profiles of TASP0233278 and TASP0390325 in animal models. KEY RESULTS: Both TASP0233278 and TASP0390325 showed a high affinity and potent antagonist activity for V1B receptors. Oral administration of TASP0390325 antagonized the increase in plasma ACTH levels induced by CRF/dDAVP in rats, indicating that TASP0390325 blocks the anterior pituitary V1B receptor in vivo. Oral administration of TASP0233278 or TASP0390325 also exerted antidepressant effects in two models of depression (a forced swimming test and an olfactory bulbectomy model). Moreover, TASP0233278 improved depressive-like behaviour induced by repeated treatment with corticosterone, a model that has been shown to be resistant to treatment with currently prescribed antidepressants. In addition to depression models, TASP0233278 or TASP0390325 exerted anxiolytic effects in several anxiety models (social interaction, elevated plus-maze, stress-induced hyperthermia, separation-induced ultrasonic vocalization and sodium lactate-induced panic-like responses in panic-prone rats). CONCLUSION: TASP0233278 and TASP0390325 are potent and orally active V1B receptor antagonists with antidepressant and anxiolytic activities in rodents.

Incidence of congenital rubella syndrome and influence of the rubella vaccination program for schoolgirls in Japan, 1981-1989.

In 1984, the authors first conducted a nationwide survey of deaf children with a history of maternal rubella (HMR) in special schools for the deaf in Japan. The survey showed that the incidence of congenital rubella syndrome in the Japanese mainlands was similar to those in the United States and Europe. In 1993, a second nationwide survey by the authors evaluated the efficacy of the vaccination program for schoolgirls begun in 1977. This second survey yielded 272 deaf children with HMR born between 1981 and 1989. Per 100,000 annual livebirths, the incidence rates were 1.56-9.95 in the epidemic years 1981-1982 and 1987-1988 and 0.20-0.72 in the interepidemic years. During the 1987-1988 epidemic, the incidence rates per 100,000 livebirths were 1.52 among mothers eligible for the vaccination program and 5.52-7.44 among mothers not eligible, and the difference was significant. However, only 21.7% of the women who delivered children during the 1987-1988 rubella epidemic were eligible for the vaccination program, and because the majority of deaf children with HMR were born to mothers not eligible, a decrease in the birth rate of deaf children with HMR was not observed. These data suggested the need to introduce a new vaccine program to suppress rubella epidemics.

Large scale preparation of PA-oligosaccharides from glycoproteins using an improved extraction method.

We have developed a new method for the large scale preparation of pyridylaminated (PA-) oligosaccharides from glycoproteins. Phenol/chloroform extraction was adapted for the removal of protein and excess 2-aminopyridine, improving the efficiency of preparation. From a 2.5 g sample of human apo-transferrin, 25-30 mu mol of agalacto biantennary PA-oligosaccharide could be obtained. By increasing the concentration of PA-oligosaccharide substrate, we were able to detect a very low level of N-acetylglucosaminlytransferase IV activity in CHO cell extracts.

Long-term sequential changes of antibody to p40tax in HTLV-I carrier mothers and children.

Antibody to p40tax (anti-p40tax) in serum specimens obtained sequentially from a human T cell lymphotropic virus type I carrier population of mothers and children were assayed. The prevalences of anti-p40tax at the initial sampling were 88% (7/8) in children and 55% (16/29) in mothers. Two of the seven positive children lost their anti-p40tax during the investigation period, resulting in a final prevalence of 63% (5/8) in children. However, anti-p40tax status was constant in all the 22 mothers with multiple serum samples (15 remained positive and seven remained negative). A decline in the absorbance value of EIA for anti-p40tax was observed in seven of the 15 anti-p40tax positive mothers. This decline may result in the disappearance of anti-p40tax in some of them.

A model system for the continuous production of a heterologous protein using a novel secretion promoting factor which operates in Escherichia coli.

The 'PAS factor' whose gene has been cloned from a species of Vibrio, is a novel protein secretion factor which is functional in Escherichia coli cells. To demonstrate that practical use of the PAS factor gene is possible, we have constructed a model secretion vector 'pAS23'. Using this system, beta-lactamase was produced and secreted into the medium of a continuous culture system, after optimization of culture conditions.

A novel protein secretion factor from a Vibrio species which operates in Escherichia coli.

A DNA fragment specific to a Vibrio species was found to promote extracellular secretion of proteins, when cloned into Escherichia coli. Cells harboring a plasmid carrying this fragment secreted significant amounts of periplasmic beta-lactamase and alkaline phosphatase into the medium, however most cytoplasmic beta-galactosidase was retained within the cell. The DNA sequence essential for this property was found to be a gene encoding 76 amino acids, which was designated as the 'PAS factor'. Highly expressed PAS factor is harmful to the cell, this may be due to a disruption of the membrane structure and/or function.

Cloning of eggplant hypocotyl cDNAs encoding cytochromes P450 belonging to a novel family (CYP77).

From eggplant hypocotyl tissues we have cloned two closely related cDNAs encoding cytochromes P450 (P450s) by PCR amplification using a primer designed based on the highly conserved sequence among the known eggplant P450s. One cDNA lacks the NH2-terminal short sequence that is present in the other, full-length cDNA. The two predicted protein sequences are 71% identical with each other and show less than 30% identity with any other known P450s. It is concluded that these P450s, which are termed CYP77A1 and -A2, belong to a hitherto unknown P450 family.

Trivalent cold recombinant influenza live vaccine in institutionalized children with bronchial asthma and patients with psychomotor retardation.

Twenty asthmatic children and 48 patients with severe psychomotor retardation were inoculated intranasally with trivalent cold-adapted recombinant (CR) influenza vaccine containing CR-125 (H1N1), CR-159 (H3N2) and CRB-117 (B). The vaccinees were mostly seropositive. Severe adverse reactions or asthmatic attacks were not observed, but 7 (15%) of 48 vaccinees with severe psychomotor retardation developed mild to moderate fever. Significant antibody responses in hemagglutination-inhibition tests were demonstrated in 33 (49%) vaccinees to CR-125, 20 (29%) to CR-159 and 8 (12%) to CRB-117. Two nosocomial outbreaks of influenza were observed in the subsequent winter. During an outbreak with H3N2 in one ward of severe psychomotor retardation patients, 2 (11%) of 18 vaccinees became infected compared with 10 (48%) of 21 placebo controls in the same ward (P < 0.05). In the other outbreak, with influenza B virus, 2 (14%) of 14 vaccinees and 13 (52%) of 25 controls in the ward for asthmatic children were infected (P < 0.05). The results indicate that trivalent CR vaccine is safe and effective against nosocomial outbreaks of influenza.

A case of congenital herpes zoster.

A 5 day old girl was transferred to the pediatric ward of Kyushu University Hospital because of papules noted since birth. The papules were distributed on her skin corresponding to the dermatomes innervated by the left Th1-Th3 and the left L1-L3. Varicella-zoster virus antigens were detected in scrapings of incised papules. The diagnosis of herpes zoster was made and acyclovir (ACV) was administered. She responded to ACV well, but she experienced a recurrence twice after discontinuation of ACV. This is the first report of 'congenital herpes zoster', which supports the hypothesis that varicella embryopathy is the sequelae of herpes zoster in utero.

Exanthema subitum and human herpesvirus 6 infection: clinical observations in fifty-seven cases.

Exanthema subitum had been speculated to be a viral disease although its pathogen is unknown. Human herpesvirus 6 (HHV-6), first isolated in 1986, was proved by Yamanishi et al. to be the causal agent of exanthema subitum. To evaluate the role of HHV-6 as the causal agent in clinically diagnosed exanthema subitum, we tested for HHV-6 antibody in 57 infants with clinical exanthema subitum and exanthema subitum-like rash without fever. Of the 53 patients with clinical exanthema subitum 43 showed seroconversion or a significant rise in antibody titer to HHV-6, 7 were seropositive without significant rise and 3 remained seronegative. The clinical manifestations of these 43 infants with serologically confirmed HHV-6 infection were consistent with the classical characteristics of exanthema subitum. The 4 patients with atypical exanthema subitum showed significant rises in antibody titer. Our results therefore show that the majority of cases with typical clinical manifestations of exanthema subitum had HHV-6 infection. Most cases with HHV-6 infection had the typical clinical course of exanthema subitum, and a few cases might show an afebrile exanthema subitum-like rash.

Mother-to-child transmission of human T-lymphotropic virus type I (HTLV-I): an extended follow-up study on children between 18 and 22-24 years old in Okinawa, Japan.

The significant difference observed between the seroprevalence of HTLV-I in adults and in children is as yet unexplained. To evaluate a hypothetical explanation of the existence of seroconversion cases of "seronegative carriers" for this phenomenon, 21 of 55 children who had been born to seropositive mothers and who remained seronegative until the age of 18 years were further followed up at the ages of 22 and/or 24 years. None of the 21 seronegative children born to seropositive mothers seroconverted, either at 22 years or at 24 years. In addition, the polymerase-chain-reaction (PCR) technique could not prove the existence of the HTLV-I provirus genome in peripheral mononuclear cells (PBMC) of 10 of these children. Our results fail to prove the possibility of viral latency of HTLV-I in mother-to-child transmission. Therefore, the hypothetical seroconversion of "seronegative carriers" after adulthood cannot be an explanation.

Immunization of institutionalized asthmatic children and patients with psychomotor retardation using live attenuated cold-adapted reassortment influenza A H1N1, H3N2 and B vaccines.

Live attenuated cold-adapted reassortant (CR) influenza virus vaccines were evaluated in institutionalized asthmatic children and severe psychomotor-retarded (SPR) patients. Almost all the vaccinees were seropositive to the vaccine strains before immunization. Trivalent CR vaccine (containing A H1N1 (CR-125), A H3N2 (CR-149) and B (CRB-117)), bivalent CR vaccine (CR-125 and CR-149) and monovalent CRB-117 were inoculated to 19 asthmatic children and 36 and 16 SPR patients, respectively. Overall 49, 22, and 11% of vaccinees were infected by A H1N1, A H3N2 or B vaccine viruses, respectively, as indicated by significant haemagglutination-inhibition (HI) antibody titre rises 4 weeks after inoculation. No severe adverse reactions associated with CR vaccination were observed in the handicapped patients. A nosocomial outbreak of influenza A H1N1 occurred in the ward with asthmatic children, but none of the 19 CR-trivalent vaccinees became infected. However, five of 20 non-vaccinees in the same ward, and ten of 30 vaccinees in another ward that received inactivated split vaccine became infected. The CR vaccines demonstrated significant protective effects against natural exposure to the A H1N1 virus, and were well tolerated and safe when given to patients with bronchial asthma and severe psychomotor retardation.

Perinatal viral infections.

Among the TORCH agents, the occurrence of rubella and human T-lymphotropic virus type 1 (HTLV-1) in Japan were studied. Rubella epidemics occurred throughout Japan from 1964 to 1969 and from 1975 to 1979. Low prevalences of CRS were observed in northeastern Japan, and high prevalences in southwestern Japan, with the highest in Okinawa. These conditions could be explained by the lower rate of rubella H1 antibody in the female population of southwestern Japan. Time of maternal rubella was in the gestational age interval from 26 to 57 days for cataract, from 25 to 62 days for heart disease and from 16 to 131 days for deafness. HTLV-1 is the causative agent of adult T-cell leukemia. Main route of transmission of this virus is mother-to-child transmission, through breast milk. Among the 311 mother-child pairs in Okinawa, 65 mothers (20.9%) and 10 children (3.2%) were seropositive for HTLV-1. Ten (15.4%) of the 65 seropositive mothers had seropositive children. These children had acquired their HTLV-1 antibodies by the age of 3 years. A significant difference existed between the prevalence rate of HTLV-1 antibodies in mothers and children.