HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a.

Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite the extensive research, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. Loss of GABAergic tone may have an important role in the neuropathic pain state. Glutamic acid decarboxylase 67 (GAD67) is one of the isoforms that catalyze GABA synthesis. Here, we used recombinant herpes simplex virus (HSV-1) vectors that encode gad1 gene to evaluate the therapeutic potential of GAD67 in peripheral HIV gp120-induced neuropathic pain in rats. We found that (1) subcutaneous inoculation of the HSV vectors expressing GAD67 attenuated mechanical allodynia in the model of HIV gp120-induced neuropathic pain, (2) the anti-allodynic effect of GAD67 was reduced by GABA-A and-B receptors antagonists, (3) HSV vectors expressing GAD67 reversed the lowered GABA-IR expression and (4) the HSV vectors expressing GAD67 suppressed the upregulated mitochondrial superoxide and Wnt5a in the spinal dorsal horn. Taken together, our studies support the concept that recovering GABAergic tone by the HSV vectors may reverse HIV-associated neuropathic pain through suppressing mitochondrial superoxide and Wnt5a. Our studies provide validation of HSV-mediated GAD67 gene therapy in the treatment of HIV-related neuropathic pain.

Spasmolytic agents. 2. 1,2,3,4-Tetrahydro-2-naphthylamine derivatives.

N-[(Benzoyloxy)alkyl]-1,2,3,4-tetrahydro-2-naphthylamine derivatives were synthesized from 1,2,3,4-tetrahydro-2-naphthylamines and evaluated for their spasmolytic. Some of these compounds showed a nerve-selective effect on colon rather than stomach in anesthetized dogs and were found to be equal to or more active than the reference drug (mebeverine). The biological data have indicated some structure-activity relationships. Among these compounds, N-ethyl-N-[6-(3,4-dimethoxybenzoyl)oxy]hexyl]-1,2,3,4-tetrahydro-6-methoxy-2- napththylamine hydrochloride (63) was found to be the most active spasmolytic agent.

Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.

A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.

Thromboxane A2 synthetase inhibitors. 2. Syntheses and activities of tetrahydronaphthalene and indan derivatives.

A series of 1-imidazolylalkyl-substituted or 5-thiazolylalkyl-substituted tetrahydronaphthalenecarboxylic acid and indancarboxylic acid derivatives were prepared and tested for the inhibitory activities of thromboxane A2 (TXA2) production in vitro and ex vivo. Most of the compounds showed potent TXA2 synthetase inhibitory activities in vitro and had long duration of inhibition of TXA2 production in rats when orally or intravenously administrated. The imidazole analogues had slightly less potency in vitro than the thiazole analogues, but the activities of the imidazole analogues in ex vivo models were equal or superior to the activities of the thiazole analogues. 6-(1-Imidazolyl-methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride hemihydrate (47a, DP-1904) was chosen for clinical studies.

A novel pharmacokinetic method for analysis of placental transfer of latamoxef in humans.

A novel pharmacokinetic method was developed for analysing the behaviour of a drug in tissues. The absolute transfer ratio of a drug to a tissue was defined using the pharmacokinetic parameters obtained by this method. Composite data of latamoxef (moxalactam) concentration in maternal blood, umbilical cord blood and amniotic fluid following a 2g intravenous injection to pregnant women at delivery were analysed by this method to study the drug behaviour in pregnant women, fetuses and amniotic fluid. Latamoxef kinetics in pregnant women at full term were generally similar to that in previously reported healthy subjects. The concentration of latamoxef in umbilical cord blood peaked about 2 hours after dosing then decreased in parallel with the maternal blood concentration. The amniotic fluid concentration peaked about 7 hours after administration, then decreased slowly. The absolute transfer ratios to fetus and amniotic fluid were calculated to be about 2.5 and 0.37% respectively.

[Pharmacokinetic and clinical studies on ceftizoxime in the perinatal period].

Pharmacokinetic and clinical studies were carried out on the use of ceftizoxime (CZX) in the perinatal period. The results obtained are summarized below. 1. Mean maternal serum concentrations of CZX reached 57.3 micrograms/ml at about 15 minutes after a single intravenous injection of CZX 1 g and then gradually decreased to 13.1 micrograms/ml in 1 hour and 55 minutes, 3.59 micrograms/ml in 4 hours and 20 minutes and 0.11 microgram/ml in 17 hours and 51 minutes. CZX in umbilical cord serum was at detectable concentrations soon after administration and peaked to 23.5 micrograms/ml in 32 minutes. Although the concentrations in umbilical cord serum gradually decreased thereafter, they were higher than those in maternal serum at 3 hours and more after an injection and was 0.41 microgram/ml at 17 hours and 51 minutes. The CZX in amniotic fluid became detectable a little later than CZX in umbilical cord serum. The concentration of CZX in amniotic fluid was below 1.00 microgram/ml at 30 minutes after administration. Concentrations then gradually increased to 21.3 micrograms/ml in 1 hour and 55 minutes and, even in 17 hours and 51 minutes, they were as high as 9.44 micrograms/ml. 2. In the clinical evaluation, CZX was given to a total of 7 cases, i.e., 1 of amnionitis, 2 of puerperal endometritis, 1 of puerperal fever, and 3 of pyelonephritis. The treatment showed satisfactory results, i.e. excellent result was obtained in 1 case, good in 5 and poor in 1 with an clinical efficacy rate of 85.7%. Microbiological examinations resulted in the isolation of 5 bacterial strains of 4 species and 1 fungal strain from 5 cases.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical study of imipenem/cilastatin sodium in the perinatal period].

A clinical study was carried out on imipenem/cilastatin sodium (IPM/CS) in the perinatal period, and the results obtained are summarized as follows. IPM/CS was given to 5 cases with puerperal intrauterine infection and 2 with puerperal fever. The clinical efficacies were evaluated as good in 6 cases and poor in 1. The clinical efficacy rate was 85.7%. In a bacteriological examination, 9 strains were isolated from 6 cases, and 7 strains were eradicated with an eradication rate of 77.8%. No side effects were observed in any of the cases treated with IPM/CS.

[Clinical studies on cefodizime in the field of obstetrics and gynecology].

Clinical studies on cefodizime (THR-221, CDZM), a new injectable cephem antibiotic, were performed and the following results were obtained. Ten patients with obstetrical and gynecological infections such as intrauterine infections, pyometra, adnexitis, parametritis and lymphocystitis. The clinical results were evaluated as excellent in 1 case, good in 4 cases and poor in 5 cases. The efficacy rate was 50.0%. Bacteriologically, 10 organisms were isolated from 8 patients and the eradication rate was 44.4%. No side effects were observed in any of the cases treated with CDZM. In laboratory examinations, transient elevations of serum GOT, GPT and Al-P were noted in 1 case.

[Pharmacokinetic and clinical studies on ceftriaxone in the perinatal period].

The pharmacokinetics of ceftriaxone (CTRX) and its clinical efficacy in perinatal infections were studied. The obtained results are summarized as follows. 1. Concentrations of CTRX in maternal serum, umbilical cord serum and amniotic fluid were determined following intravenous injection with 1 g of CTRX. Maternal serum levels were not lower than 100 micrograms/ml immediately after administration, and gradually decreased to about 10 micrograms/ml in 12 hours, and to 4 micrograms/ml in 24 hours. The half-life of CTRX in maternal serum was 5.6 hours. CTRX levels in umbilical cord serum were about 7 micrograms/ml at 10 minutes after injection, increasing to 12 to 13 micrograms/ml in 12 hours and decreasing to 5 micrograms/ml in 24 hours. CTRX levels in amniotic fluid were slightly lower than those in the umbilical cord serum, and about 2 micrograms/ml at 10 minutes after injection, and they remained at 4 to 8 micrograms/ml thereafter for 28 hours. 2. CTRX (1 g) was intravenously administered twice daily to 9 patients with perinatal infections for 3 to 7 days. Clinical efficacies of CTRX were judged excellent in 2 cases and good in 7, suggesting that CTRX was effective in all cases. No side effects or laboratory abnormalities were observed in any case. As a result of these findings, CTRX may be considered a very useful antibiotic in perinatal infections.

[Fundamental and clinical studies on ceftazidime in the field of obstetrics and gynecology].

Fundamental and clinical studies were performed on ceftazidime ( CAZ ), a new cephem antibiotic. Following a single intravenous administration of 1 g dose of CAZ , the transfer of CAZ to the internal genital organs was good. The transfer of CAZ to retroperitoneal fluid was excellent. In a clinical trial, CAZ was given to 6 patients with obstetrical and gynecological infections. The efficacy was evaluated as excellent in 3 cases and good in the other 3 cases. No adverse effects were observed in any of the patients treated with CAZ .

[Fundamental and clinical studies on cefpiramide in the field of obstetrics and gynecology].

Fundamental and clinical studies were performed on cefpiramide (CPM), a new cephem antibiotic, with following results. Following a single intravenous administration of 1.0 g dose of CPM, the average serum level of CPM was 129.5 micrograms/ml after 1 hour and the half-life in beta-phase was about 5.0 hours. The transfer of CPM to the internal genital organs was found to be good. the transfer of CPM to retroperitoneal fluid was moderate. In clinical trial, CPM was given to 9 patients with obstetrical and gynecological infection. Efficacy was excellent in 1 case and good in 6 cases (effectiveness rate: 77.8%). No side effects were observed. In laboratory findings, a mild elevation of S-GOT was noted in 1 case.

[Fundamental and clinical studies on T-1982 (cefbuperazone) in the field of obstetrics and gynecology].

Fundamental and clinical studies were carried out on T-1982 (cefbuperazone) a new cephamycin antibiotic, with the following result. Following a single intravenous administration of 1.0 g of T-1982, the transfer of T-1982 to the internal genital organs was found to be good. The transfer of T-1982 to retroperitoneal fluid was also good. In clinical trial, T-1982 was administered to 10 patients with obstetrical and gynecological infection. Efficacy was excellent in 4 cases and good in 6 cases. No side effects were observed. In laboratory findings, a transient elevation of alkaline phosphatase was noted in 1 case.

[Fundamental and clinical studies on cefuzonam in the field of obstetrics and gynecology].

Fundamental and clinical studies on cefuzonam (CZON, L-105), a new oxime type cephalosporin, were performed and the results obtained are summarized below: 1. Concentrations of CZON were determined in serum, internal genital organs and retroperitoneal fluid after a single intravenous administration of 1 g dose. The peripheral serum level of CZON was 74.0 micrograms/ml at 15 minutes after the administration. A sufficient transfer of CZON into internal genital organs and retroperitoneal fluid was demonstrated. 2. In clinical trial, CZON was given to 11 cases with obstetrical and gynecological infections. Efficacies were evaluated as good in 9 cases and poor in 2 cases. No side effects were observed in any of the cases treated with CZON. In laboratory examinations, transient elevation of serum GOT, GPT and alkaline phosphatase was noted in 1 case.

[Fundamental and clinical studies on cefotaxime in the field of obstetrics and gynecology (author's transl)].

Fundamental and clinical studies were made on cefotaxime (HR-756, CTX), a new cephalosporin antibiotic, with the following results. 1. Cefotaxime was given to 22 patients. Efficacy was excellent in 3 cases, good in 17 cases and poor in 2 cases. No side effects were observed in any cases. 2. Following a single intravenous injection of 1.0 or 2.0 g, the transfer of CTX to the internal genital organs was found to be good. The transfer of CTX to exudate of the dead space of pelvis was also good. 3. The above data demonstrated that CTX is a safe and effective drug.

[Fundamental and clinical studies on ceftazidime in the perinatal period].

Fundamental and clinical studies were carried out on ceftazidime (CAZ) in the perinatal period, and the results obtained were summarized below. Following bolus intravenous injection of CAZ 2 g, maternal serum concentrations of CAZ were as high as 145.3 +/- 17.2 micrograms/ml (mean +/- S.D.) at about 10 minutes, and then gradually decreased to 46.7 micrograms/ml at 2 hours, 5.31 micrograms/ml at 5 hours and 4 minutes, and 1.54 micrograms/ml at 11 hours and 10 minutes. The CAZ was detected in umbilical cord serum immediately after the administration, and concentrations were 31.0 +/- 1.54 micrograms/ml at about 10 minutes. Although the concentrations gradually decreased thereafter, they were higher than those in maternal serum at 3 hours and later and was 3.00 micrograms/ml at 11 hours and 10 minutes. The CAZ was detected in amniotic fluid a little later than in umbilical cord serum, and concentrations of CAZ in amniotic fluid were as low as 1.50 +/- 0.67 micrograms/ml at about 10 minutes after the administration. Concentrations then gradually increased to 12.8 micrograms/ml at 2 hours and 26.5 micrograms/ml at 5 hours and 4 minutes, and even at 11 hours and 10 minutes, they were as high as 14.2 micrograms/ml. The above results demonstrated that the transfer of CAZ through placental barrier was very rapid and satisfactory. Also, CAZ showed good transfer into amniotic fluid, as well as sufficient retention, and was considered to be an effective antibiotic for prophylaxis of both fetal infections and amniotic fluid infections.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetic and clinical studies of cefotiam in the perinatal period].

Pharmacokinetic and clinical studies on cefotiam (CTM) in the perinatal period were performed and results obtained are summarized below. Concentrations of CTM in maternal serum, umbilical cord serum and amniotic fluid were examined after a bolus intravenous administration at a dose of 1 g. Data were analyzed using simulation curves drawn by the two- or three-compartment open model. The peak level of CTM in maternal serum was 86.6 micrograms/ml and the half-life of the beta-phase was 0.91 hour. Peak levels of CTM in umbilical cord serum and amniotic fluid were 20.8 micrograms/ml at 0.1 hour and 9.2 micrograms/ml at 3.2 hours after the administration, respectively. The concentration of CTM in amniotic fluid decreased after reaching the peak, but it was still as high as 1.6 micrograms/ml even at 12.0 hours after the administration. These results clearly demonstrated that the transfer of CTM to umbilical cord serum and to amniotic fluid was efficient in protection of perinatal infections. In a clinical trial, CTM was given to 11 patients with perinatal infections. Clinical efficacies were evaluated as excellent in 2 patients, good in 8 patients and poor in 1 patient. No adverse effects were observed in any of the patients studied. In conclusion, CTM was useful and safe antibiotic for the treatment of infections in the perinatal period.

[Fundamental and clinical studies on sulbactam/cefoperazone in the field of obstetrics and gynecology].

Fundamental and clinical studies on sulbactam/cefoperazone (SBT/CPZ), a newly developed combined beta-lactam antibiotics, were carried out and the following results were obtained. Each concentration of SBT and CPZ was examined in serum and internal genital organs after single intravenous administration of 2.0 g dose of SBT/CPZ. Each venous serum level of SBT and CPZ was 41.5 micrograms/ml, 122.3 micrograms/ml at 30 minutes after administration respectively. The transfer of SBT and CPZ to internal genital organs was similarly good. Each concentration of SBT and CPZ was examined in serum and retroperitoneal fluid after 1 hour drip infusion of 2.0 g dose of SBT/CPZ. The transfer of SBT and CPZ to retroperitoneal fluid was similarly excellent and the transfer ratio vs. serum level of the former was about 76.2 approximately 321.7%, and the latter was about 27.2 approximately 93.2% respectively. In clinical trial, SBT/CPZ was given to 10 patients with obstetrical and gynecological infections. The efficacy was evaluated as good in 9 patients and poor in 1 patient. As the side effects, diarrhea was appeared in 1 case. In laboratory findings, a transient elevation of serum transaminase was noticed in another one case. From the above results, it was concluded that SBT/CPZ was useful drug for infections in the field of obstetrics and gynecology.

[Fundamental and clinical studies on ceftriaxone in the field of obstetrics and gynecology].

Fundamental and clinical studies on ceftriaxone (CTRX, Ro 13-9904), a new cephalosporin antibiotic, were carried out with the following results. Concentration of CTRX was examined in serum, internal genital organs and retroperitoneal fluid after single intravenous administration of 1.0 g dose. The venous serum level of CTRX was 156 micrograms/ml at 5 minutes after the administration. The favorable transfer of CTRX to internal genital organs and retroperitoneal fluid was demonstrated. In clinical trial, CTRX was given to 10 cases with obstetrical and gynecological infections such as endometritis, adnexitis, pelvic peritonitis and parametritis. The efficacy was evaluated as excellent in 1 case, good in 8 cases and poor in 1 case. No side effects were observed in any of the cases treated with CTRX.

[The transfer of cefmenoxime into the retroperitoneal fluid after extensive panhysterectomy].

This study was to investigate the transfer of cefmenoxime (CMX) to the retroperitoneal fluid after extensive panhysterectomy. Twenty-two cases were examined and they were divided into 2 groups, 10 with 1.0 g and 12 with 2.0 g bolus intravenous administration of CMX. In 1.0 g group, CMX concentration in the retroperitoneal fluid was observed 42.0 +/- 9.59 micrograms/ml (Mean +/- S.D.) at 1 hour and thereafter decreased gradually, but it still remained 7.91 +/- 5.18 micrograms/ml at 6 hours after the administration. In 2.0 g group, its concentration was 33.4 +/- 34.5 micrograms/ml at 30 minutes and reached to the peak level of 45.1 +/- 24.6 micrograms/ml at 1 hour and then declined slowly, but it remained 13.3 +/- 8.28 micrograms/ml at 6 hours after the injection. The results demonstrated sufficient transfer of CMX to the retroperitoneal fluid.

[Clinical experience with fosfomycin sodium for bacterial infections in obstetrics and gynecology].

Fosfomycin sodium was administered to 36 cases with obstetrical and gynecological infection. Efficacy was excellent in 6 cases, good in 27 cases and poor in 3 cases and so effective ratio obtained was 91.7% in all. No side effects were observed in all patients except transient increase of serum transaminase in 2 cases.