Biliary excretion and clinical efficacy of T-3262 (tosufloxacin tosilate) administered in the treatment of cholecystitis

T-3262 (tosufloxacin tosilate), a new oral pyridone carboxylic acid agent, was investigated for its biliary excretion and clinical efficacy and safety to evaluate its usefulness in the treatment of cholecystitis. T-3262 was administered to a total of 4 healthy volunteers for 2 days at a dose of 150 mg every 8 hours, and A-, B- or C-bile were collected using the MELTZER-LYON method at 10-11 hours after the final administration. Bile concentrations of T-3262 in 3 cases were 0.33-2.05 micrograms/ml (A-bile), 6.13-9.50 micrograms/ml (B-bile) and 1.11-2.70 micrograms/ml (C-bile). Thus, T-3262 levels in B-bile were 15-34 times higher than serum levels (0.28-0.41 micrograms/ml). Only a trace of serum concentration of T-3262 was detected in another case with the concentration in B-bile was 0.132 micrograms/ml. A total of 10 patients with cholecystitis were treated with T-3262 at a dose level of 150 mg per dose 3 times daily for 1 to 20 days. The clinical efficacy was excellent in 1 case, good in 5 cases and fair in 2 cases and unevaluable in 2 cases, thus the clinical efficacy rate was 75%. Bacteriologically, Klebsiella pneumoniae, Enterococcus faecalis and Haemophilus parahaemolyticus were isolated from biles of 3 patients before treatment. Upon the treatment, E. faecalis was eradicated and K. pneumoniae was unchanged. The fate of H. parahaemolyticus was not known because of examination was not done after treatment. Side effects were observed in 2 cases with diarrhea in 1 case and epigastric pain in another case. But those symptoms disappeared after cessation of administration of T-3262. Abnormal laboratory test values were not observed.     

Nephrotoxicity test on T-3262 in rats with experimental nephropathy

The present study was carried out to examine the effect of orally administered T-3262, a new synthetic antibacterial agent, on the kidney of male rats with experimental nephropathy. These rats had been treated with single intramuscular injection of mercuric chloride (HgCl2, 3 mg/kg) or daily subcutaneous administration of puromycin-aminonucleoside (PAN, 15 mg/kg) for 11 days. T-3262 was administered orally to these pretreated rats at a dose of 1,000 mg/kg/day for 2 or 6 days. Twenty-four hours after the second or the sixth day of T-3262 administration, the kidneys of these rats disclosed similar biochemical and pathological findings as observed in the kidneys of the rats treated with HgCl2 alone. Thus, no T-3262-related alterations were demonstrated in renal functional test, kidney weight or histopathological examinations at a dose of 1,000 mg/kg of T-3262. The HgCl2-induced nephropathy was not enhanced by the oral administration of T-3262. Twenty-four hours after the second or the sixth day of T-3262 administration, the kidneys of the PAN-pretreated rats disclosed the biochemical and pathological findings largely similar to those with PAN-induced nephropathy. Enhancement of PAN-induced nephropathy by the oral administration of T-3262 was hardly evident.     

Comparative study on salivary distribution of fluoroquinolones in rats

As a basic approach to identifying the distribution mechanism of quinolone antibiotics into saliva, salivary excretion of five fluoroquinolones, ciprofloxacin (CPFX), norfloxacin (NFLX), lomefloxacin (LFLX), ofloxacin (OFLX) and sparfloxacin (SPFX), was compared in rats. Blood, parotid and mandibular saliva were periodically collected from the anesthetized rats after bolus i.v. administration (10 mg/kg) of the quinolones. Quantification of the fluoroquinolones was performed by HPLC methods. The saliva-to-plasma unbound concentration (S/Pu) ratios of the fluoroquinolones in parotid saliva were larger than those of mandibular saliva. These five quinolones had considerably different S/Pu ratios from 0.014 to 1.497, while the S/Pu ratios theoretically calculated by the pH-partition theory were around 1.0 to 1.3, which showed no relationship to the corresponding measured ratios. Satisfactory linear correlations were observed in the plots of measured S/Pu ratios against 1-octanol-water partition coefficients of the fluoroquinolones in both types of saliva. These results indicate that fluoroquinolones possess different diffusibility in salivary distribution among the drugs and between parotid and mandibular glands. It was also clarified that the lipophilicity of the fluoroquinolones primarily determines the extent of salivary excretion.     

Immunohistochemical study on GABAergic system in salivary glands

Gamma-aminobutyric acid (GABA) and its receptors are found in the central nervous system and several peripheral tissues. The purpose of this study was to determine the expression and distribution of GABA and glutamate decarboxylase (GAD), a GABA biosynthetic enzyme, in rat salivary gland. Western blot and real time quantitative RT-PCR revealed that GAD67 was the major isoform of GAD in the salivary glands. Furthermore, both GABA and GAD were detected around the acinar cells in the submandibular glands by immunohistochemical analysis. When both sympathetic and parasympathetic nerves related to the submandibular glands were denervated, the immunoreactivities of GABA and GAD were dramatically depressed, and levels of GAD67 and GABA significantly decreased. However, no morphological changes in the glands were observed after denervation. These results indicate that GAD67 is present around acinar cells in the salivary glands, and suggest that the GABAergic system in the glands is closely related to the autonomic nervous system.     

A fundamental study on T-1982 (cefbuperazone) in the field of obstetrics a gynecology

T-1982 (cefbuperazone) concentrations in antecubital venous blood and pelvic dead space exudate were examined in 4 patients who had received radical hysterectomy due to uterocervical cancer. Data analysis for the transfer of T-1982 into pelvic dead space exudate was performed with the stimulation curves prepared from pharmacokinetic parameters by the three-compartment model. When T-1982 was given at a dose of 1 g, the peak level in the venous blood was 83.7 micrograms/ml at 1 hour after the start of administration. With regards to T-1982 concentration in pelvic dead space exudate, the peak level of 19.3 micrograms/ml was observed at 2.24 hours after the start of administration and relatively high concentration of about 6.1 micrograms/ml was observed even at 8 hours after the start of administration. From the above results, it is concluded that T-1982 is a useful drug for the treatment of infections in the field of obstetrics and gynecology.     

A subacute oral toxicity study of T-2588 in juvenile rats

A subacute toxicity study on T-2588 was carried out in juvenile rats (6 days-old 48 males and 48 females) by oral administrations at dose levels of 250, 500 and 1,000 mg/kg/day for 1 month. The results obtained were summarized below. During the study, there were no clinical signs considered to be related to the treatment. There were no T-2588-related abnormalities in urinalysis, hematological examinations, biochemical examinations and ophthalmological examinations. Slight increases in relative liver and kidney weights were observed in the 1,000 mg/kg-treated group and slight increases in relative kidney weight were detected in the 500 mg/kg-treated female group. Histologically, however, T-2588-related abnormality was not observed. The maximum safety dose of T-2588 was estimated to be 250 mg/kg/day. In addition to the above examinations, male reproductive performance was examined in the group administered with a dose level of 1,000 mg/kg/day. No adverse effects were observed in male fertility and F1 generation.     

Segmental and intracellular distribution of lead in rat kidney and salivary glands

The segmental and intracellular distribution of lead (Pb) was studied in the kidney and salivary gland of Sprague-Dawley rats. Lead acetate was administered i.v. in a single dose (10 or 65 mg/kg body wt) or multiple biweekly doses (subchronic: 7 X 10 mg/kg over 3 months; chronic: 13 X 10 mg/kg over 6 months). Segments of cortical nephrons and salivary glands were separated following tissue slicing, incubation with collagenase and centrifugation on a Percoll density gradient medium. Subcellular fractions were obtained by differential centrifugation of renal and salivary tissue homogenates. Lead was predominantly localized in the renal proximal tubules, which contained at least twice as much of the metal as the distal tubules. Segment populations prepared from salivary tissues contained far less Pb than the renal fractions and showed no clear differences among themselves in their affinity for the metal. Intracellular Pb distribution was as follows: kidney nuclei (Nu) greater than mitochondria (Mt) greater than cytosol (Cy) greater than microsomes (Mc); salivary gland Cy greater than Mc greater than Mt greater than Nu. In most cases, 45Ca followed the same intracellular distribution as lead. Our data suggest that the proximal tubular segment may be the most likely renal target of chronic lead toxicity. The results point also to a much greater retention of Pb by the kidney than by salivary glands. The ability of the kidney to accumulate a great deal of lead to be released into tubular fluid over long periods, makes urinary lead a poor indicator of duration and frequency of exposure. On the other hand, the inability of salivary glands to retain this metal makes saliva lead concentration a potential indicator of current exposure.     

Fundamental study on T-1982 (cefbuperazone) in obstetrics and gynecology

Following results were obtained from intravenous administration of T-1982 (cefbuperazone) 1 g by measuring its concentrations in uterine arterial serum, cubital venous serum, oviduct, ovary and several sites in uterine tissue. Endometrium showed the highest concentration among various uterine tissues by any administration (bolus injection, dripping infusion for 1 or 2 hours). Transfer concentrations about 1 hour after the end of 1 hour drip infusion proved to be almost the same as 2 hours drip infusion. In the field of obstetrics and gynecology, it was considered that T-1982 has good efficacy in infections especially caused by E. coli, Klebsiella and Proteus.     

A tion of drugs on denervated myoepithelial cells of salivary glands

1. The pressure in the ducts of the two submaxillary glands was recorded in anaesthetized dogs in which either the superior cervical ganglion had been removed or the chorda-lingual nerve had been cut on one side, 17-30 days earlier. Noradrenaline, adrenaline, phenylephrine, acetylcholine and methacholine were injected to produce pressure rises attributed to contraction of myoepithelial cells.2. After sympathectomy increased pressure responses were obtained with all the drugs, but particularly with noradrenaline. Cocaine increased the effect of noradrenaline on the normal gland but slightly less than sympathectomy.3. Parasympathetic decentralization increased the pressure effects of acetylcholine and methacholine, and in most cases also increased those of the sympathomimetic drugs.4. It is concluded that the myoepithelial cells of this gland normally receive motor impulses from both divisions of the autonomic nervous system, and that many, if not all, of the cells are innervated by both. Disconnecting the gland from the central nervous system by either pathway causes supersensitivity of the classical post-junctional type, and sympathetic ganglionectomy causes in addition a pre-junctional sensitization.     

The effect of Cinnamaldehyde on mucositis and salivary antioxidant capacity in gamma-irradiated rats (a preliminary study)

Background and purpose of the study

The aim of this study was to investigate the effect of cinnamaldehyde on mucositis and salivary total antioxidant capacity in gamma-irradiated rats.

Methods

The study was conducted on 28 male Wistar rats, 7–11 weeks of age and 160 ± 20 g body weight, divided into four groups of seven rats each. The first group receiving normal saline (S), the second group receiving saline and gamma radiation (SR), the third group receiving 50 mg/kg cinnamaldehyde 98% (C), and the fourth group receiving 50 mg/kg cinnamaldehyde 98% and gamma radiation (CR). SR and CR groups were exposed to 15 Gy gamma irradiation for 7 min and 39 s. Rats were intraperitoneally injected each day during the 10-day period of the experiment, and their tongues and lips were examined to assess the incidence and severity of mucositis. The saliva samples were taken from the animals three times on day zero, six, and ten.

Results

The mean mucositis incidence appeared to be delayed in the CR than the SR group (P = 0.024), and the severity was significantly higher in the SR compared to the CR group;the difference was statistically significant on the second day (P = 0.027). In the evaluation of salivary antioxidant capacity, salivary antioxidant concentration was significantly higher in the C than the S, SR, and CR groups on the tenth day of the experiment (p <0.05).

Conclusion

The clinical effects in the CR group seem to be due to antioxidant, anti-bacterial and anti-inflammatory effects of cinnamaldehyde; this conclusion, however, requires further investigations. Delayed antioxidant effect in the CR group was evident in ip cinnamaldehyde injection, the exact mechanism is not clear.     

Clinical study on T-1982 (cefbuperazone) in the field of obstetrics and gynecology

A clinical investigation on the efficacy of T-1982 (cefbuperazone), a new cephamycin antibiotic, was performed in the field of obstetrics and gynecology. T-1982 was administered to 17 cases: 6 cases of parametritis, 3 cases of endometritis after artificial abortion, 3 cases of puerperal fever, 2 cases of febrile abortion, 1 case of Bartholin's abscess, 1 case of adnexitis and 1 case of infection of vaginal hematoma. Seventeen cases of these infections receiving in total 6 to 20 g of T-1982 demonstrated excellent results in 8 cases and good in the remaining 9 cases. Neither side effect nor clinical test abnormality was observed. From the present study, T-1982 is considered to have excellent efficacy and safety.     

Metabolism of carbohydrate in vitro of the submandibular salivary glands (SMG) from mice injected with isoproterenol

• 1.1. The effect of a single dose of isoproterenol, a β-adrenergic drug, on the metabolism of carbohydrate in vitro of SMG from mice was studied.
• 2.2. At the end of 30 and 60 min of incubation the slices of SMG from the experimental groups, sacrificed from 2 to 18 hr after injection of IPR, presented higher glucose uptake.
• 3.3. At the end of 60 min of incubation slices of SMG from mice injected with IPR and sacrificed from 2 to 28 hr after the stimulation, formed quantitatively more lactate.
• 4.4. After the incubation periods in the presence of glucose, glycogen content was higher for the SMG from the experimental groups.

     

A combined study on the distribution of oxytetracycline and polyvinylpyrrolidone in rats.

With the purpose of studying the influence of polyvinylpyrrolidone (PVP) on the disposition of oxytetracycline (OTC), OTC was administered i.v. to male rats in two formulations, one of which contained 14C-labelled PVP. From the rats, whole-body sections (30 mum) were taken which were subjected to three analytical procedures: autoradiography to determine the distribution of the PVP-14C, fluorography and bioautography to obtain information on the OTC-distribution. The experimental results suggest equilibrium complex formation between OTC and PVP, it being mainly the complex which is i.v. injected when both products are combined in an injection formulation. Such complex formation can explain the lower toxicity of OTC when injected in combination with PVP as well as the slower build-up of OTC-levels in some organs, compared with that after OTC administration without PVP. Beyond this kinetic effect of PVP on the fate of OTC no evidence was obtained for an influence of PVP on the OTC distribution pattern per se, or on its ultimate antibiotic activity in the different organs. Some details of the OTC and especially of the PVP distribution are discussed.     

不同剂量苦参碱给药后的药动学及其在唾液中的分布

目的探讨苦参碱不同剂量给药后苦参碱在大鼠体内的动态变化规律及其在唾液中的分布情况。方法大鼠静脉注射苦参碱注射液后,用反相高效液相色谱法测定苦参碱在血液、唾液中的浓度,采用药动学软件MULTI97V10进行数据处理,确定药动学参数。结果苦参碱不同剂量给药后在大鼠体内符合二室模型分布,其高、中、低剂量主要药动学参数分别如下：t1/2=2．38h,AUC=203．0g·h·L^-1,Ve=675．3mL,CL=190．6L·h^-1。t1/2=1．39h,AUC=70．7g·h·L^-1,Vc=489．4mL,CL=243．3L·h^-1;t1/2=1．66h,AUC=41．85g·h·L^-1,Ve=500．2mL,CL=208．4L·h^-1。结论通过高、中、低剂量及相应的AUC对比,可知苦参碱中、低剂量给药后在体内呈线性药动学消除过程,高剂量给药后呈非线性药动学消除过程,中、低剂量给药后,苦参碱腮腺中唾液药物浓度与血液药物浓度有一定相关性,可以考虑利用腮腺唾液代替血液进行苦参碱的药动学研究。