A survey on diarrhea and convenience of intake associated with a single-dose extended release formulation of azithromycin.

The development of a single-dose extended release formulation of azithromycin (AZ-SR) improves the adherence. However, gastrointestinal side effects such as diarrhea are frequent adverse drug reactions. The aim of the present study was to investigate the incidence of patient-reported in a diarrhea and the convenience of intake of AZ-SR in an Asian population. To assess the incidence of diarrhea and convenience of intake, patient-reported in a questionnaire about the incidence, onset, duration and severity of diarrhea, shape of stool, and patients' impression on taste. The drug was prepared and used in common with the hospital pharmacy and the community pharmacy. AZ-SR was prescribed in 96 outpatients, among whom 81 patients received the medicine and the questionnaire at the hospital pharmacy or one of five neighboring community pharmacies. The recovery of the questionnaire was 40.7%. Diarrhea occurred in 18 of 33 patients (54.5%), which was more frequent than in earlier reports, although the symptom was mild (grade 1-2) and occurred in most cases within 2 days. Approximately one third of patients reported inconvenience in taking the formulation in respect of the ease (36.4%), amount (42.4%), and unpleasant bitter taste (36.4%). We report here the importance of collaboration between hospital pharmacists and community pharmacists in providing accurate drug information, including the incidence of diarrhea, to patients receiving AZ-SR.

A quinol peroxidase inhibitor prevents secretion of a leukotoxin from Aggregatibacter actinomycetemcomitans.

BACKGROUND AND OBJECTIVE: Quinol peroxidase (QPO) catalyzes peroxidase activity using quinol in the respiratory chain as a substrate. Quinol peroxidase is essential for the secretion of leukotoxin (LtxA), which destroys leukocytes and erythrocytes in humans and is one of the major virulence factors of Aggregatibacter actinomycetemcomitans, which is associated with localized aggressive periodontitis. In the present study, we aimed to find a highly potent QPO inhibitor to attenuate the virulence of A. actinomycetemcomitans. MATERIAL AND METHODS: For screening of QPO inhibitors, QPO activity was measured kinetically by SpectraMax Plus with 96-well UV plates. Three hundred compounds in the Kitasato Institute for Life Sciences Chemical Library were screened. Secretion of LtxA in the culture supernatant was examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cytotoxicity against human promyelocytic leukemia cell line (HL-60) cells from the culture supernatant was measured by Trypan Blue exclusion test. RESULTS: The present study characterized ascofuranone as a highly potent inhibitor of QPO (K(i) = 9.557 +/- 0.865 nm). Ascofuranone inhibited secretion of LtxA by A. actinomycetemcomitans in a dose-dependent manner, making A. actinomycetemcomitans less pathogenic to HL-60 cells. CONCLUSION: Quinol peroxidase inhibitors are promising candidates as alternative drugs for the treatment and prevention of the onset of localized aggressive periodontitis. Using ascofuranone as a seed compound, further study of QPO inhibitors could provide novel chemotherapeutic strategies for controlling localized aggressive periodontitis.

Source of increased plasminogen activators during pregnancy and puerperium.

We investigated the increase of plasminogen activators (tPA and uPA) in the plasma during pregnancy. Both tPA and uPA antigens were found to increase after the third trimester of pregnancy and high levels of PAs persisted through the first stage of labor. The tPA antigen levels rose further for the first few hours post-partum, while the level of uPA antigen returned to normal immediately following childbirth. To clarify whether the uterus and/or placenta are involved in the increased levels of plasma PAs, the levels were measured in uterine venous blood in cases of caesarean sections. During the ante-partum period, the level of uPA antigen in the uterine venous blood was higher than that in the peripheral venous blood, while there was no significant difference between the levels of tPA antigen in peripheral blood and uterine venous blood. The level of tPA antigen in the uterine venous blood rose after delivery. In contrast, the level of uPA antigen declined immediately after delivery. These results suggest that (1) the placenta is the major source of the increased uPA antigen during pregnancy, (2) entire vascular system is involved in the increased tPA antigen during pregnancy, (3) a further increase in tPA after delivery is due to the release of this enzyme from the involuting uterus.

Isolation of mitochondria from Plasmodium falciparum showing dihydroorotate dependent respiration.

Using N2 cavitation, we established a protocol to prepare the active mitochondria from Plasmodium falciparum showing a higher succinate dehydrogenase activity than previously reported and a dihydroorotate-dependent respiration. The fact that fumarate partially inhibited the dihydroorotate dependent respiration suggests that complex II (succinate-ubiquinone reductase/quinol-fumarate reductase) in the erythrocytic stage cells of P. falciparum functions as a quinol-fumarate reductase.

[Basic and clinical studies on cefminox in the field of obstetrics and gynecology].

Human pharmacokinetics and clinical studies of cefminox (CMNX, MT-141) were carried out and the following results were obtained. The concentrations of CMNX transferred to the uterus and its appendages after CMNX 1 g intravenous injection were maintained above 12.5 micrograms/g during first 3 hours or more. The concentrations of CMNX transferred to the pelvic dead space exudate were above 12.5 micrograms/ml during 6 hours or more. Those concentrations were sufficiently effective against the major pathogens (Gram-negative and anaerobic bacteria) demonstrated in the field of obstetrics and gynecology. We administered CMNX to 4 cases with postoperative infections at a dose of 2 g per day (twice a day) for a period of 4-6 days. The clinical effect was excellent in 3, good in 1 case. No side effect was observed.

[Transfer of cefotaxime to the pelvic organs (author's transl)].

The new antibiotic cefotaxime (HR 756, CTX) has been proved to be clinically effective against infections observed in the field of obstetrics and gynecology. The present study was intended to investigate the transfer of CTX to the internal genital organs and the dead pelvic space. The results were obtained as follows: 1. The concentrations of CTX transferred to the uteri and its appendages after CTX 1 g intravenous injection were sufficiently effective against the major pathogens (Gram-negative and anaerobic bacteria) demonstrated in the field of obstetrics and gynecology. 2. The concentrations of CTX transferred to the dead space of the pelvis were effective against almost all of the Gram-negative bacteria for 6 to 12 hours after CTX 1 g or 2 g intravenous injection. CTX was thus proved to be very effective for the prevention and treatment of infections of the dead pelvic space.

[The antibacterial activity of new cephem antibiotics against clinical isolates. A comparison of the antibacterial activity of cefotaxime with 6 other antibiotics].

During the period from May through July 1981, a comparative study was carried out on the antibacterial activities of cefotaxime (CTX) and ceftizoxime (CZX), cefoperazone (CPZ), latamoxef (LMOX), cefotiam (CTM), cefmetazole (CMZ) and cefazolin (CEZ). CTX and these other cephem antibiotics were tested against fresh clinical isolates which had been obtained from clinical materials by the laboratories of 14 participating medical institutions. 1. The clinical isolates were obtained from various clinical materials in the following decreasing order: urine, sputum and pus/discharge; 85.7% of the isolates came from these materials. 2. Concerning the sources of each species of clinical isolates, it was found that P. aeruginosa was isolated from the greatest number -9- of different clinical materials. This was followed by E. coli and E. cloacae, each isolated from 8 different clinical materials, and C. freundii and E. aerogenes, each found in 7 different clinical materials. 3. In relation to S. pyogenes, S. agalactiae and S. pneumoniae, CTX showed the best antibacterial activity; the second most potent antibiotic was CZX. CMZ and LMOX were found to show relatively high MIC values for those species. Against S. aureus, CEZ showed the best antibacterial activity, but 3 resistant strains had MICs of greater than 100 micrograms/ml. 4. With regard to Gram-negative bacteria, CTX and CZX showed the best antibacterial activities for all of the species, except for P. aeruginosa. These were followed, in order, by LMOX and CPZ. Compared with these 4 antibiotics, CTM, CMZ and CEZ were found to have inferior antibacterial activities against these bacteria. In relation to P. aeruginosa, the peak of the MIC distribution for CPZ was 6.25 micrograms/ml, and this was the best antibacterial activity detected with the various antibiotics tested. This was followed by CTX (25 micrograms/ml) LMOX (25 micrograms/ml) and CZX (50 micrograms/ml). CTM had an MIC of 100 micrograms/ml for 1 strain, and MICs of greater than 100 micrograms/ml for all of the other strains of P. aeruginosa, indicating them to be resistant to this antibiotic. All of the strains were resistant to CMZ and CEZ, showing MICs of greater than 100 micrograms/ml. 5. For each of the tested antibiotics, no correlation was found between the MIC and the serogroup for either P. aeruginosa or S. marcescens.

[Experimental and clinical studies of cefmenoxime in the field of obstetrics and gynecology].

The study group was organized to evaluate the usefulness of cefmenoxime (CMX) injection, a new synthetic cephalosporin, for the treatment of infections in the field of obstetrics and gynecology. Fundamental and clinical studies were made by the society and the following results were obtained. 1. The peak distribution of CMX's MIC for E. coli, Klebsiella sp., Enterobacter sp., Bacteroides sp. and Peptococcus sp. isolated from obstetrical and gynecological infections with relatively high frequencies area 0.1, less than or equal to 0.05, 0.2, 3.13, 1.56 micrograms/ml, respectively, with an inoculation of 10(6) cells/ml. 2. When 1 g of CMX is administered by intravenous drip infusion for 1 hour, the maximum concentrations in various tissues of female genital organs were as follows: 14.2 and 13.2 micrograms/g in ovary and oviduct, respectively, at 1.20 hours after the start of administration, and 16.9 and 26.3 micrograms/g in corpus uteri and cervix uteri, respectively, after 1 hour. As for the transfer to the exudate in the pelvic dead cavity, the peak concentration was 15.6 micrograms/ml after 2.13 hours. 3. In the clinical studies, CMX was given to 258 cases with female genital organ infections and others. As for the clinical effects, with exclusion of 3 cases in which other antibiotics are concomitantly used, responses were excellent in 76 cases, good in 162 cases and poor in 17 cases, among 255 cases in total. The efficacy rate was 93.3%. The efficacy rates by diseases were 97.1% (68/70) for intrauterine infections, 88.8% (79/89) for intrapelvic infections, 98.4% (62/63) for adnexitis, and 100% (23/23) for infections of external genital organs. As for the clinical effects on causative bacteria, the efficacy rates were 100% (19/19) for single infections due to Gram-positive bacteria, 94.8% (55/58) for single infections due to Gram-negative bacteria, and 88.2% (15/17) for single infections due to anaerobic bacteria. And its efficacy rates were 89.6% (69/77) for mixed infection cases. Side effects were observed in 2 cases (0.8%); 1 case with eruption, and 1 case with diarrhea and vomiting. As for abnormal laboratory findings, lower white blood cell count was observed in 2 cases and elevation of the values regarding hepatic functions in 9 cases. All cases were returned to the normal after the completion of the administration. Cefmenoxime showed a satisfactory clinical efficacy and a potent bacteriological effect in treatment of the infections in the field of obstetrics and gynecology, and it has been concluded that cefmenoxime will be useful addition to the antibiotics for the therapy of these infections.

[Clotting and fibrinolytic activities in acute alcoholic golden hamsters with or without ether anaesthesia].

Fluid cadaveric blood is generally known as a characteristic of sudden death. However, it has been reported that soft blood clots have been observed in a number of cases of sudden death after alcohol drinking. Such a tendency was also recognized on autopsy cases in our laboratory. This study was carried out to reveal the effects on clotting and fibrinolytic system in golden hamsters under acute alcohol intoxication. Furthermore, the influences of ether anaesthesia were also observed. Activities of clotting and fibrinolytic factors were measured with fluorogenic peptide substrate. Prothrombin and factor X activities began to decrease 1 hr after administration of alcohol. But thrombin-like and factor Xa-like activities significantly increased after 1 hr and then returned to the initial value 4 hr after administration. Plasminogen activity began to decrease 1 hr after administration, whereas plasmin-like and t-PA-like activities increased after 1 hr and returned to the initial values or decreased after 4 hr. These results show that under acute alcohol intoxication clotting and fibrinolytic factors (prothrombin, factor X and plasminogen) in golden hamsters were converted temporarily to their active forms (thrombin, factor Xa and plasmin). No influence of only ether anaesthesia on clotting and fibrinolytic activities was observed. At 1 hr after administration of alcohol some effects of ether anaesthesia on prothrombin, prekallikrein and kallikrein were observed and then were not observed after 4 hr. But it seems that the influence of ether anaesthesia on clotting and fibrinolytic activities was negligible in the process after alcohol consumption.

Usefulness of hysteroscopy for detection of cancer in the endocervical canal.

Preoperative hysteroscopic and histologic findings of endocervical cancerous lesions were compared with postoperative histologic findings of cervices. A total of 132 patients consisting of 72 carcinoma in situ, 16 microinvasive carcinoma and 44 invasive squamous cell carcinoma were examined during the 5 years beginning in 1977. The rates of cancerous lesions observed in the endocervix were 33.3% carcinoma in situ, 56.2% microinvasive carcinoma and 72.8% invasive squamous cell carcinoma. The preoperative diagnoses of endocervical lesions were histologically identical with the postoperative ones in 24 (88.9%) of 27 cases of carcinoma in situ, 7 (87.5%) of 8 cases of microinvasive carcinoma and all of 30 cases of invasive squamous cell carcinoma. Mosaics and punctations were noticed in the endocervix near the external os in the early stage of cancer, whereas white epithelia were observed more frequently and, over a wide range in the endocervix. Abnormal gland openings were noticed predominantly in carcinoma in situ. Atypical vessels were recognized mainly in microinvasive carcinoma. Gross irregular and dilated atypical vessels were recognized mainly in microinvasive carcinoma. Gross irregular and dilated atypical vessels, opacity, irregular surface and necrosis were observed predominantly in invasive carcinoma. In conclusion, hysteroscopy is useful in detecting cancerous lesions located in the endocervical canal.

[Contact hysteroscopic exploration of the uterine cavity].

The contact hysteroscope gives a clear view only upon contact with the observed surface. There are 6mm and 8mm diameter models. A total of 172 contact hysteroscopic examinations were performed to view the uterine cavity. The following results were obtained: After the previous observation with the panoramic hysteroscope, the rate of correct diagnosis with the 6mm model was 83.3% and that with the 8mm one was 98.5%. The rate of correct diagnosis with the 8mm model was 85.3% and that with the 6mm one was 92.7%, when used initially. The main disadvantages of the contact hysteroscope were a lack of perspective view and occasional existence of a dead angle just above the internal os. Among the contact hysteroscopic diagnosis, that of endometrial polyp was the most difficult, followed by those of slightly bulging submucous myoma and endometrial hyperplasia, while diagnosis of IUD, hydatidiform mole and endometrial carcinoma were easier. After acquiring the necessary experience, the 6mm model also gave very accurate results, requiring no cervical dilatation in multiparous cases. The 6mm model should therefore be a useful instrument to use in outpatient diagnosis.

[Diagnostic endoscopy for malignant uterine tumors].

A hysteroscope is a useful tool for detecting uterine tumors developed in the cervical canal and uterine cavity which are invisible areas. The hysteroscopy discloses easily the findings, location, size and extent of the lesions. Consequently more correct biopsies may be obtained than the conventional curettages which are blind procedures. This paper comprises the instrumentation, technique and hysteroscopic findings of the malignant uterine tumors. Observation of the cervical canal, namely cervicoscopy reveals mainly the appearance of normal cervical wall, preinvasive and invasive squamous cell carcinoma, adenocarcinoma and sarcoma. Hysteroscopy reveals the appearance of normal uterine cavity, endometrial carcinoma, sarcoma, metastatic uterine carcinoma, invasive carcinoma infiltrated from the adjacent organs and trophoblastic tumors. As a result, endoscopic features of each uterine malignant tumor are summarized as useful criteria for differential diagnosis.

Maternal serum CA125 levels in early intrauterine and tubal pregnancies.

Using an immunoradiometric assay, serum CA125 levels were measured in 13 women with a normal pregnancy, 9 with a spontaneous abortion, 3 with a hydatidiform mole, and 15 with a tubal pregnancy. Serum CA125 levels were high in patients with a normal pregnancy (154 +/- 169 U/ml; mean +/- S.D.), a spontaneous abortion (244 +/- 258 U/ml), or a hydatidiform mole (54 +/- 16 U/ml). In contrast, CA125 levels in patients with a tubal pregnancy (33 +/- 25 U/ml) were low, and almost all of those without uterine bleeding (25 +/- 9 U/ml) were within the normal range for non-pregnant women (< 35 U/ml). The difference between serum CA125 levels with intrauterine pregnancy and with tubal pregnancy may be ascribed to the difference of the amount of decidual tissues at the site of trophoblastic invasion.

Sensitive determination of phenothiazines in body fluids by gas chromatography with surface ionization detection.

Fourteen phenothiazine derivatives were tested for their detection by gas chromatography (GC) with surface ionization detection (SID). The sensitivity of GC-SID was highest with trimeprazine and levomepromazine, which contain aliphatic tertiary amino side chains, and lowest with thiethylperazine and thioproperazine, which contain sulphur residues. Chlorpromazine, trimeprazine and promazine showed excellent linearity between the SID response and the drug amount in the range 0.25-3.0 pmol on-column. Their detection limits were as low as ca. 5-10 pg (15-30 fmol) on-column (250-500 pg per ml of body fluid). A detailed procedure for isolation of phenothiazines from human whole blood and urine using Sep-Pak C18 cartridges, before the GC with SID, is also presented. The recoveries of the drugs (100 pmol), which were added to 1 ml of whole blood or urine, were more than 79%. The baselines remained steady as the column temperature was increased.

Determination of diphenylmethane antihistaminic drugs and their analogues in body fluids by gas chromatography with surface ionization detection.

Eleven diphenylmethane antihistaminic drugs and their analogues were tested for their detection by capillary gas chromatography (GC) with surface ionization detection (SID). The GC-SID response was highest for doxylamine, diphenhydramine and orphenadrine and lowest for terodiline, clemastine and pipethanate. The detection limits for drugs with the highest response were 2-5 pg (ca. 6-20 fmol) on-column (100-250 pg/ml of body fluid). The detection limits with GC-SID were 10-100 times higher than those with GC with nitrogen-phosphorus detection. A detailed procedure for the isolation of the antihistaminics from human whole blood and urine by the use of Sep-Pak C18 cartridges, prior to GC-SID, is also presented. The recoveries of the drugs (50 or 500 pmol), which had been added to 1 ml of body fluids, were > 60%. The baselines remained steady as the column temperature was increased and the background was clean, especially for whole blood extracts.