BRL 25000, consisting of 250 mg amoxicillin (AMPC) and 125 mg clavulanic acid (CVA), was studied in the field of obstetrics and gynecology.
1. Tissue concentrations
The concentrat ions in venous serum and arterial serum of uterus, different sites of uterus, oviduct and ovarium were determined. Tissue concentrations of AMPC and CVA corresponded to 45-75% and 20-50%, respectively, of serum concentrations.
2. The good responses were obtained in cases with intrapelvic infection and the overall clinical effective responses were obtained in 100% of patients. Effectiveness was found microbiologically and clinically in infections due to AMPC resistant organisms.
No side effects were found.

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BRL 25000 was administered to 37 cases with infections in the fields of obstetrics and gynecology, and the following results were obtained.
1. The drug was administered to 17 cases with adnexitis, 13 cases with intrauterine infection and 7 cases with parametritis and/or inflammation of pelvic dead space, etc. The percentage of efficacy (excellent and good) was 74.3%.
Of 7 cases where no therapeutic effect was obtained with other drugs, the percentage of efficacy was 57.1%.
2. Antibacterial effect of BRL 25000 was studied in terms of percentage of eradication (including re placement) of clinical isolates. A high percentage of eradication (94.4% or 17/18) was obtained.
Among all clinical isolates, 37.9% or 11/29 were β-lactamase producing organisms. Eradication or replacement by BRL 25000 was noted in all these 9 strains, and BRL 25000 was proved to have a high efficacy also against penicillin or cephalosporin resistant organisms.
3. No abnormality was noted in any pat ient in hematological, hepatic and renal function before and after administration of BRL 25000.
4. As adverse reacti on, diarrhea was found in 1 of 37 cases (2.7%), but it reduced after off-dose.

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We studied BRL 25000,(amoxicillin trihydrate and potassium clavulanate a β-lactamase inhibitor in ratio of 2: 1), in the otorhinolaryngological field in terms of its basic and clinical utility.
1. Pharmacokinetics
The distribution of BRL 25000 in mucous membrane of maxillary sinus and retaining liquid of maxillary sinus after administration of 1 tablet (375 mg) was favorable and the good transitional properties were obtained. It was similar to chepherns.
2. Clinical results
BRL 25000 was administered to 26 patients (6 cases with otitis media, 9 cases with tonsillitis, 2 cases with sinusitis, 1 case with laryngitis, 5 cases with pharyngitis, 1 case with epipharyngitis and 2 cases with pharyngolaryngitis). The overall clinical effective response was obtained in 88.5% of patients.
3. Bacteriological effects
BRL 25000 was effe ctive against amoxicillin-resistant S. aureus and K. rhinoscleromatis.
4. Side effects
No adverse reactions were seen.

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A total of 39 patients was admitted to the obstetric and gynecological wards of Nagoya University Hospital and the University's 5 related hospitals during the period from July 1981 to March 1982. The efficacy of cefoxitin sodium was evaluated in the 39 pateints with a wide variety of obstetric and gynecological infections.
The findings are the follows:
1. Of the 39 patients, the responses in 7 were judged “excellent”, 28 “good” and 4 “poor” with the clinical efficacy rate of 89.7%.
2. The causative pathogens in 23 of the cases were isolated from clinical materials submitted to the Institute of Anaerobic Bacteriology, School of Medicine, Gifu University. In these 23 cases, it was found that 8 were due to aerobic bacteria only (34.8%), 8 mixed aerobic-anaerobic bacteria (34.8%) and the remaining 6 anaerobic bacteria only (26.1%), i.e. a substantial percentage (60.9%)was due to anaerobic bacteria or mixed aerobicanaerobic bacteria.
3. Cefoxitin was active against most strains of Bacteroides spp.and was not affected by the inoculum size.
On the other hand, most strains of Bacteroides spp. were resistant to cefazolin when the inoculum size was increased from 10⁶/ml to 10⁸/ml.
Lincomycin was also found to be active against many of the strains of Bacteroides spp.
Cefoxitin and cefazolin were fairly active against anaerobic bacteria other than Bacteroides spp., while these same bacteria were resistant to sulbenicillin and many of them showed resistance to lincomycin.
4. Cefoxitin was well tolerated and no untoward side effects were observed.
5. The clinical and bacteriological results indicate that cefoxitin is a very effective antibiotic in the treatment of a wide variety of obstetric and gynecological infections and is a suitable choice as initial antibiotic therapy in these conditions.

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The intrathecal administration of amikacin (AMK)(56-100 mg/day) was effective for 3 cases of postoperative refractory meningitis caused by gentamicin (GM) resistant organisms.
The infecting pathogen of case 1 was K. pneumoniae and that of case 2 was S. epidermidis, while no pathogen was cultured in case 3. The causative pathogens in the former were eradicated only with AMK. No therapeutic response was gained with GM, but with AMK in the latter.
High tone hearing impairment was observed in case 1 and transient vomiting was observed in case 3. However, these side effects were trivial for the severity of disease.
It is suggested in these 3 cases that the high dose intrathe cal administration of AMK may be extremely useful in the treatment of postoperative refractory meningitis which has shown no response to GM.

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From clinical study on micronomicin (MCR) Sagamicin® KW-10621, the following results were obtained.
1. MCR was administered clinically at the daily dose of 120-240 mg for 1-45 days to 23 patients.
2. The clinical effectiveness rate of MCR was 72.7% in all cases.
3. As side effects, exanthema, drop of blood pressure and shortness of breath were observed in 1 patient (malignant lymphoma). Elevations of S-GOT, S-GPT and BUN were encountered in some patients. However, these results might not be due to the administration of MCR, because antitumor agents on the blood transfusion had been applied to the patients suffering from underlying diseases such as leukemia or malignant tumor. Side effects, such as impairement of the 8th nerve, renal and liver function were not noted.
4. MCR is considered to be a useful antibiotic in the treatment of various infectious diseases combined with underlying diseases, such as progressive cancer and leukemia, and the infectious diseases of the aged.

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The pharmacokinetics of intravenously administered cefotiam (CTM), using a two-compartment or threecompartment open model, have been investigated in patients undergoing thoracic surgery.
Patients (Group 1) given 1 hour drip infusion of 1 g of CTM, had the peak serum level (32.8 μg/ml) at 1 hour, and the peak pleural effusion level (8.3 μg/ml) was achieved at 2.08 hours.
Patients (Group 2) given an one-shot intravenous injection of 1 g of CTM, had the maximum pleural effusion concentration (8.35 μg/ml) at 2.67 hours.
Patients (Group 3) given 1 hour drip infusion of 1 g of CTM, had the mean concentration (2.3-2.5 μg/g)in the pleural tissue for 2 to 3.5 hours.
Clinical study comprizing 20 patients was performed to evaluate the effects of CTM as a prophylactic antimicrobial agent in the thoracic surgery. Patients received intravenous administration of 4 g/day of CTM for 7 10 days.
Each patients was evaluated daily for fever, signs of allergic reaction, and wound infection and so on.
No infections occurred in these thoracic surgery except 1, and no serious side effects was observed in this study.

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We compared the efficacy of intravenously, intramuscularly administered or intravenously infused over 45 minutes gentamicin (GM) by the experimental system in rabbits using diffusion chambers.
1. Serum concentrations of GM obtained with 3 administration methods w ere different, while the peak values after intramuscular injection and intravenous drip infusion were similar. Similar concentration time curves of GM in the chambers were revealed after intramuscular injection and intravenous infusion. No marked difference in 3 administration methods was showed in the effects on the growth of P. aeruginosa in the chamber.
2. Viable bacterial number in the chambers decreased when the GM concentration in the chamber was 4-5times of MIC, and thereafter regrowth was observed after the decrease of GM concentration in the chambers to 2-3 times of MIC. About 8 hours were required for growth to the base line value.
3. In the leucocyte containing chambers, viable bacterial number similary decreased, but the rate of regrowth was slow. About 12 hours were required for growth to the base line value.
4. The regrowth rate in the GM containing chamber was similar to that in the antibiotic free chamber.
From this result, it is suggested that, when the antibiotic concentration in the chamber is 1-2 times of MIC, antibiotic does not show the growth suppressive effect and the activating effect on phagocytosis of leucocytes in the environment closed to the practical pathological condition such as this model.
5. For the patients with qualitative or quantitative abnormal changes of phagocyte, short interval of drug administration might be needed. For this purpose, intravenous drip infusion under monitoring of serum concentration is more suitable than intramuscular injection, which might be accompanied with severe pain and contracture of injected muscle.

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Paromomycin sulfate were administered to 118 cases of diphyllobothriasis lata at a dosage of 50 mg/kg single or divided into 2 at an interval of 30 minutes, followed by purgation after 1.5 hours. Except for 6 cases in which the follow-up examination of 1 month later were not available 112 cases were confirmed completely cured. Nausea was observed in 2 cases, anorexia in 1 and slight transient loss in hearing and in articulation were claimed in 1 case, All side effects were subsided after a shortwhile without treatment. Eleven cases of taeniasis saginata were similarly treated. Ten of them were completely cured and the remaining 1 case was cured after the second treatment. Each 1 case of Diplogonoporus grandis and Mesocestoides lineatus respectively was also successfully cured by paromomycin sulfate. However, in 1 case of Hymenolepis diminuta of 6 years girl the administration of drug at above mentioned dosage failed to cure. Diphyllobothrium erinacei infection in dogs and cats required a higher dosage, however, 200 mg/kg gave a result of around 60% of cure rate. In the trials with experimentally infected Golden hamsters with D. ditremum the treatment even at the highest dosage of 530 mg/kg did not give any success.
Morphological investigations by either light or electron microscope (scanning and transmission) with successfully expelled D. latum from human cases or isolated from experimentally infected Golden hamsters showed serious damages of tegument at the anterior-most part of the worm. Destruction and excoriation of microtriches, epidermis and basal lamina were observed. The features decreased in intensity according to going to posterior part of the worm. Expelled Taenia saginata showed the same results.
The bioassays using Bacillus subtilis to determine the concen tration of paromomycin sulfate in the expelled D. latum resulted a higher concentration of 1, 760 mcg/g in the anterior half than 700 mcg/g in the posterior half of the worm. This seems in accordance with the location where the worms suffered the most serious damages. The findings may explain the observation that 75% of expelled D. latum and 90% of T. saginata were found without scolex and nevertheless the complete cure was achieved in all treated cases.
In the in vitro test the intact worms of D. latum obtained from human cas es by DAMASO DE RIVAS method were placed in saline containing 1% solution of paromomycin sulfate. The worms were almost instantly immobilized. This implied that paromomycin sulfate exerted a neurotoxic effect on the worms. It was suggested that the mechanism of action of paromomycin sulfate against tapeworms is the combination of paralysing effect and the destruction of tegument in the anterior-most part of the worms and leading to the loss of their abililty to fix on the wall of host intestine. The digestive enzymes might aggravate the destructive damages and the peristaltic movement of the intestine expells the entire worm out of the host.

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The most characteristic difference of Japanese Diphyllobothrium latum from those of European and Canadian species is it's second intermediate host. The Japanese Diphyllobothrium latum take genus Oncorhynchus as it's most important 2nd intermediate host and plerocercoids are always found in their fillet not in their viscera which phenomena can not be observed in the cases of the latter Diphyllobothrium.
From 1977 to 1982, we examined 723 Cherry salmon, Oncorhynchus masou which were caught in the northern Japan Sea from March to May every year. Out of 723 Cherry salmon, 218 (30.2%) were showed the infection of plerocercoids of D. latum (Table 1 & 2). The yearly data of the infection rate of fish varied from 15.9 to 48.4%. The plerocercoids were found most likely in the back hind part of the fish (Figure 1).
The sex ratios (Table 4) of Cherry salmon caught in the Japan Sea indicated that thesr sal mon was mainly derivled not from Japanese rivers, but from Kamchatka, Sakhalin or the coastal part of Siverian continent (Table 3.)
It remains totally unknown where these Cherry salmon got infection of D. latum.

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Paromomycin sulfate (Aminosidine; Kyowa-Hakko Kogyo Co. Ltd., Tokyo) is a poorl y absorbed antibiotic produced by Streptomyces chrestomyceticus. It has been widely used in the treatment of bacterial and some protozoan diseases. The observation of ULIVELLI (1963) that patients treated for intestinal amoebiasis with paromomycin were cured of a concurrent Taenia infection, suggested its use in the treatment of intestinal cestodes.
The aim of the present study is to assess the efficacy and to investigate the mode of action of paromo mycin sulfate in the treatment of human and animal cestodiases.
1. Although the authors proved its efficacy against Diphyllobothrium latum in Golden hamster with a dosage schedule of over 60 mg/kg single, it was not effective against Hymenolepis nana in the mice with a dosage schedule of 2,000 mg/kg single or 100 mg/kg daily for 3 days.
2. A 100% cure rate was achieved in all patients of diphyllobothriasis latum (11 cases), diphyllobothriasis sp.(1 case), diplogonoporiasis grandis (1 case) and taeniasis saginata (5 cases) receiving paromomycin sulfate with a dosage of 35-50 mg/kg divided into 2 parts at an interval of 30 minutes. However, this drug was not effective in 1 case of hymenolepiasis diminuta.
3. In all expelled worms the scolex were not found. Histological observations revealed that the detachment of microtriches and destruction of tegument occurred on the body surface. The damages were most distinct in the neck and following immature proglottides.
4. The microbioassays for the amount of paromomycin sulfate remaining in the expelled worms indicated that the anterior part of worm body of D. latum contained the drug at the level of concentration range from 355 to 2,060 μg/g, but the amount decreased remarkably in the posterior part of the worm. Simillar results were obtained with Taenia saginata and Diplogonoporus grandis, however, with the less susceptible species as D. erinacei and Dipylidium caninum only a small amount of the drug would be detected. The drug was observed not effective against Hymenolepis nana. The worms isolated from animals treated even with the highest dosage of 2,000 mg/kg of the drug did not show any residue of the drug in the body.
5. It was confirmed that paromomycin sulfate was absorbed by suscepti ble species of cestodes and the absorption was mostly occurred in the anterior part of the body, particularly at neck and apparently at scolex. The higher degree of destruction of body surface observed by histological examinations in the anterior part than in the middle or posterior part of the worms coincided with the amount of drug absorbed.
6. It was strongly suggested that paromomycin sulfate causes the tegumental damage of susceptible cestodes mostly at the anterior most end of the worm body and leads to the detachment of whole body to expelling.

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The effects of paromomycin sulfate on Diphyllobothrium erinacei and Hymenolepis nana in vitro were examined morphologically with a scanning and a transmission electron microscope. D. erinacei was incubated for 3 and 6 hours at 37 & deg;C in a culture medium, 0.85% physiological saline solution, containing 0.5% paromomycin sulfate. H. nana was incubated in the same medium for 3 hours only. The concentration of paromomycin sulfate was set basing on the results which KITAMOTO(1968) reported as the concentration level in feces after administrations of this drug in a clinical survey.
The effect of the drug on the surface structure in both worms appeared markedly in the neck region. Mechanisms of breakdown on the tegument were supposed as follows. First, microtriches were disconnected from the tegumental surface and many vesicles were formed in the cytoplasm of the tegument. Finally, the tegument layer was excoriated to exposed the basal lamina. In 6 hours incubation, this surface of the worm suffered more damage than that in 3 hours.
The damage of the basal lamina as in the case of D. latum expelled from a man by paromomycin (Y. TONGU et al.), however, could not be observed in the present study in vitro. It suggests that the destruction of basal lamina usually observed with the expelled worms from clinically treated human might be due to the combined effect of digestive enzymes secreted from host and the mechanical impact of intestinal peristalsis. Some of the vesicles in the tegument may originate from mitochondria because the fine structure of cristae were occasionally observed remaining in the vesicles.

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Recently, it has been reported that paromomycin sulfate has marked anthelmintic efficacy against tapeworm infections in man. In the present study this drug was used in the treatment of 14 cases of diphyllobothriasis latum and 1 case of taeniasis saginata. Also, the actions of paromomycin sulfate on Diphyllobothrium ditremum and D. erinacei were examined pharmacologically using MAGNUS apparatus and biochemical methods. The results obtained were as follows.
1. For the treatment, a total of 50 mg/kg of paromomycin sulfate divided into 2 doses was given orally at intervals of 30 minutes. Two hours after medication, 20g of magnesium sulfate disolved in 200-300 ml of water was given as purgative. One or 2 worms were found in the stools of 11 cases with D. latum and 1 case with T. saginata within 24 hours after medication, but scolex was found in only 2 of them. All cases were negative for the eggs or segments in stool examinations at 1 and 3 months after treatment.
2. Except 1 case complained mild and transient vomitting no side effects w ere noticed. All cases showed no abnormality in blood examination, liver function test and urinalysis.
3. Both of the proglottids of D. ditremum and D. erinacei showed muscle relaxation in TYRODE solution containing 10^-4 g/ml of paromomycin sulfate. In D. ditremum the recovery of muscle tonus was observed within 10-15 minutes after affection of this drug, while the persistence of muscle relaxation was seen in D. erinacei.
4. The activity of phosphoglucose isomerase was slightly inhibited by 10^-8 M paromomycin sulfa te while those of hexokinase, phosphofructokinase and glucose-6-phosphate dehydrogenase were not inhibited.
5. In phosphoenolpyruvate-succinate pathway, the activity of fumarate reductase was slightly inhibited 10^-3m paromomycin sulfate while those of phosphoenolpyruvate carboxykinase and malate dehydrogenase were not inhibited.

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Plerocercoids of D. ditremum were obtained from the Japanese surfsmelt (Hypomesus pretiosus) and administered to Golden hamsters. The animals were treated with paromomycin sulfate on the 16th day of infection. Anthelmintic effect was imperfection after administration of 530 mg/kg in 4 divided doses.
Kamala and bithionol, however, successfully expelled the worm at the doses of 80 and 160 mg/kg and 12.5-70 mg/kg, respectively.
The balloon-like structures and the other morphological changes of the tegument such as exfoliation of microtriches were remarkably observed on the worms immersed in 2% solution of paromomycin sulfate.
Four human cases of diphyllobothriasis were treated with paromomycin sulfate at the doses of 46-56 mg/kg. No side effects were observed. Stool examination made 1 month after treatment were negative to the eggs.
From these results, an anthelmintic effect of paromomycin sulfate was shown in the concentration of 2% on D. ditremum in vitro and in the dosage of 46-56 mg/kg in diphyllobothriasis lata patients.

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Nine vital tapeworms were expelled from 7 patients with diphyllobothriasis latum by the modified DAMASO DE RIVAS' method. Seven worms of them placed in 1% and 5% paromomycin solution (37°C, pH 6.8-6.9) and 2 were in physiological saline at 37°C as controls.
In both 1% and 5% solution, the movement of worms stopped completely within 15 minutes. When they were taken out from the solution and washed thoroughly with physiological saline solution, they did not move any longer and died soon. As for the controls, they were moving with animation in physiological saline at 37°Ceven after 60 minutes. Pathohistologically (H. E. stain), the scolex was seriously affected down to the immature proglottid; degeneration and desquamation of the villi and cuticle with somatic cells exposed and edematous swelling of the whole body. Somatic cells had degenerative necrosis, plasmatomy and disorder in the disposition of the circular muscle and longitudinal muscle were marked.
Scanning electronmicroscopy revealed that the worms treated with paromomycin had the scolex remarkablyimpaired and destroyed the villous epithelial layer and cuticle of the immature proglottid adjacent to the scolex desquamated exposing somatic cells regardless of the duration of exposure to and the concentration of paromomycin, while in the controls, the scolex was normal and the worm surface was closely covered with normal villi.
Aminoglycoside antibiotics are known to have neurotoxic effect in general. It seems to be related to this neurotoxicity that paromomycin solution stopped the movement of worms. The changes occurring in the tapeworms were irreversible and the worms died soon. It is suggested that when patients with diphyllobothriasis latum are administered with paromomycin, the alterations of the worms induced by paromomycin are accelerated by potent human digestive juice.

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About 50 mg/kg of paromomycin sulfate was administered orally in a single or 2 divided doses to patients with Diphyllobothrium latum infections.
The following results were obtained.
1. After the treatment with paromomycin sulfate mature strobilae were expelled in all of 7 patients with Diphyllobothrium latum infections.
2. We couldn't find scolices in all cases.
3. Although these stools were examined for 2 months after the treatment, the eggs of Diphyllobothrium latum were not identified.
4. No side effects were observed in all cases.
It was concluded that paromomycin sulfate was effective on the treatment of Diphyllobothrium latum infections.

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Forty-one patients, aged 2 to 68 years old, infected with Diphyllobothrium latum in Akita prefecture were treated using paromomycin sulfate from 1974 to 1981.
Paromomycin sulfate was administered orally in a single dose of 20, 30 mg/kg or 50 mg/kg. Twenty-three cases expelled tapeworms. However, only 9 (28.1%) out of 32 tapeworms expelled had their scolex. It can be said that all cases were successfully treated with paromomycin sulfate, since they showed the egg-negative on 3 weeks or 1 month after the treatment. The drug was well tolerated and no side effects were encountered in any patients.
It was suggested that paromomycin sulfate was effective and also safe therapeutic agent for the treatment ofD. latum infection.

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Paromomycin sulfate (aminosidine) at a single dose of 32 to 53 mg/kg was orally given to 24 cases with proven diphyllobothriasis. Evaluation of efficacy of the drug was based on stool examination for the eggs after 3-4 weeks of treatment. The cure rate was obtained as 96% (23/24), and 30 worms were expelled from 24 patients. Only 1 unsuccessfully treated case of 34-year-old man was retreated at the same dose of the drug 3 weeks later to obtain the cure. Thirty worms were composed of a single worm each from 21 patients, 2 worms from a patient, 3 from 1, and 4 from 1. Scolices of 7 (23.3%) out 30 worms were found.
Vomiting as side effect of the drug was observed in only a case of 4-year-old girl at 40 minutes after administration of the drug but it was mild and transient.
Clinical symptoms or complaints before treatment were as follows; abdominal discomfort in 12 cases, abdominal pain in 7, diarrhea in 4, fatigue in 2, tinnitus, vomiting and frequent stool in 1 each. Seven cases were almost asymptomatic.
Morphological changes of the worms immersed in paromomycin solution (aminosidine)(1.66 mg/ml) for 1, 2 and 3 hours were observed in comparison with worms kept in physiological saline solution. The destructive effects were fragmentation, dissolution and desquamation of the outer cuticle and basement membrane with PAS stain at 3 hours of the experiment. The damages were also demonstrated in subcuticular tissues composing of muscle layer and parenchymal cells.

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Mesocestoides tapeworm is a common cestode in carnivorous mammals, but human infection with the tapeworm of this genus have been infrequent. We have recently observed the 13th case of human infection with Mesocestoides lineatus in Japan. A 35-year-old man living in Gifu prefecture was admitted to our University Hospital with chief complaints of general fatigue and discharge of cestode segments in his stool. The patient gave a history of drinking blood and eating the raw liver of a snake Agkistrodon halys for medicinal purposes as same as the previous cases of all reported in Japan. The segments were identified as those of M. lineatus.
He was treated orally 3 g of paromomycin sulfate. Stool examination after treatment with paromomycin sulfate revealed no evidence of parasitism. The present case may be the 2nd to have been successfully treated with paramomycin sulfate and the 21st case of Mesocestoides tapeworm infection in man described in the literature.

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Recently it has been known that paromomycin sulfate had marked anthelmintic activity against some species of tapeworms. In this investigation, paromomycin sulfate was used for treating 6 cases of diphyllobothriasis and 1 case of Taenia saginata infection. Paromomycin sulfate was administered orally in a single dose or 2 divided doses of 40-60 mg/kg, being followed by a purge about 1.5 hours later. Strobila or fragments of proglottids were expelled from 5 cases, of which only 1 scolex was found in a case of infection with marine species of Diphyllobothrium. In 1 case of diphyllobothriasis no worm or worm-fragment was found in the stool even after the second challenge of treatment. Nevertheless follow-up examination for more than 1 month showed no evidence of remaining infection in all cases.
Transient dizziness was observed in only 1 case, disappearing within about 30 minutes. Serum-and urineexaminations detected no abnormal signs in all cases excepting 1 case of diphyllobothriasis with suspected hepatitis. It was concluded that paromomycin sulfate is effective therapeutic agent for the treatment of taeniasis and diphyllobothriasis including marine species.

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