Therapeutic effects of micronomicin on experimental infections in mice by intravenous administration

Protective effects of intravenous administration of micronomicin (MCR) on mouse experimental infections were investigated. Mice were better protected by intravenous administration in S. marcescens T-55 experimental infection than subcutaneous administration. No remarkable differences were found between the two administrations in cases of P. aeruginosa BMH No. 1 and E. coli GN 2411-5 infections. Intravenous administrations of MCR, gentamicin (GM), dibekacin (DKB), amikacin (AMK) and sisomicin (SISO) protected the infection of P. aeruginosa BMH No. 1 in a similar extent. MCR was more effective intravenously than AMK; DKB and AMK; DKB, AMK and SISO in experimental infections of E. coli GN 2411-5; S. marcescens T-55; P. aeruginosa KY-8510 harboring aminoglycoside inactivating enzyme AAC(6')-4, respectively.     

Pharmacokinetics of arbekacin in dogs. I. Serum concentration and urinary excretion

A new aminoglycoside antibiotic, arbekacin (HBK) was intramuscularly and intravenously administered to dogs in order to study its pharmacokinetics in comparison to amikacin (AMK). The results obtained are summarized as follows. Serum concentrations of HBK were well correlated with dose levels. The dose-serum concentration relationship with HBK was similar to other aminoglycoside antibiotics. Biological half-lives of HBK and AMK were both about 1 hour in dogs. This was also similar to other aminoglycoside antibiotics. There was no significant difference in peak serum concentrations between 1 hour intravenous infusion and intramuscular injection of HBK at 2 mg/kg in dogs. Repetitive administration of HBK to dogs at 2 mg/kg twice a day for 14 days did not affect its serum concentration and biological half-life. Urinary excretion of HBK in dogs in 24 hours after administration accounted for about 80-90%.     

Bacteriological evaluation of netilmicin

The following results were obtained from the bacteriological evaluations of netilmicin (NTL), a newly developed antibiotic agent, with gentamicin (GM), dibekacin (DKB) and amikacin (AMK) as the controls. (1) NTL demonstrated broad antibacterial spectra against both Gram-positive and Gram-negative bacteria, but its antibacterial potency against streptococci was not very strong among other Gram-positive bacteria. (2) In terms of distribution of sensitivity of clinically isolated bacterial strains, NTL proved to have antibacterial potency comparable to that of GM and higher potency than that of DKB of AMK against E. coli K. pneumonia, Enterobacter sp., or H. influenzae. However, its efficacy was inferior to GM against Proteus sp., S. marcescens and P. aeruginosa. (3) In conjunction with the influences of pH of culture media or of addition of horse sera upon the antibacterial efficacy, NTL showed an inclination similar to that of GM, DKB and AKM. Its antibacterial efficacy was fortified on the alkaline side or by addition of sera. In connection with the influences of the amounts of inoculated bacteria upon antibacterial efficacy, there were hardly any appreciable influences on it by any of the tested bacterial strains. (4) The interactions of NTL with carbenicillin were evaluated with the chequerboard titration method to find remarkable cooperative actions in any of E. coli, K. pneumoniae, S. marcescens, A. calcoaceticus and P. aeruginosa. (5) The results of evaluation on the patterns of its antibacterial effects revealed that it acted bactericidal in any tested bacterial strains. (6) As to the therapeutic effects against experimental infections in mice, it was found out that NTL = GM greater than DKB and AMK against E. coli, GM greater than NTL = DKB and AMK against K. pneumoniae and GM and DKB greater than NTL greater than or equal to AMK against A. calcoaceticus and P. aeruginosa in the decreasing order of efficacy.     

Antibacterial activities of arbekacin, a new aminoglycoside antibiotic, against methicillin-cephem-resistant Staphylococcus aureus

The in vitro and in vivo antibacterial activities of a new aminoglycoside antibiotic, arbekacin (HBK), against methicillin-cephem-resistant Staphylococcus aureus (MRSA) were compared with those of gentamicin (GM), netilmicin (NTL) and amikacin (AMK). The results obtained were summarized as follows: Compared to other aminoglycoside antibiotics, HBK had the highest antibacterial activities against clinically isolated MRSA (46 strains). Therapeutic effects of HBK against experimental systemic infections with MRSA in mice, were superior to those of GM, NTL and AMK. The ED50's of GM, NTL and AMK were more than 2 mg/mouse. Therapeutic effects of HBK against experimental subcutaneous infections with MRSA in mice were also superior to those of GM, NTL and AMK.     

Fundamental study of amikacin in the newborn

Amikacin (AMK) is one of the aminoglycoside antibiotics, derived from kanamycin A. It has a broad spectrum against Gram-negative rods but its usefulness is mainly in the efficacy against Gram-negative rods which do not respond to commonly used kanamycin and gentamicin. The efficacy and the safety of AMK have been confirmed in children and mature babies. In the trial reported here, we evaluated AMK in newborn. 1. AMK was administered to 13 mature and 8 premature babies via intramuscular injection or intravenous drip infusion for 30 minutes or 1 hour and its blood concentrations were determined. These administrations resulted in blood concentrations 4.47-9.67 mcg/ml with dosage levels 2.3 mg/kg (mean 6.92 +/- 1.66 mcg/ml), 5.86-26.1 mcg/ml with 5-6 mg/kg (mean 15.4 +/- 4.63 mcg/ml) and 27.5-37.7 mcg/ml with 7.5 mg/kg (mean 31.0 +/- 4.76 mcg/ml). Blood half-lives were 1.88 to 9.66 hours, showing longer half-lives in younger subjects. 2. Exchange transfusion (150-180 ml/kg) was performed in 5 mature babies and the variation of blood concentrations of AMK was studied. The study showed that blood concentrations of AMK after the exchange transfusion were 25.6-41.5% (mean 32.3 +/- 5.4%) of the levels detected before the transfusion.     

Isepamicin与六种氨基糖苷类体外抗菌活性研究

本文比较fsepamicin(ISP)、庆大霉素(GM)、地贝卡星(DKB)、乙基西索米星(NTL)、妥布霉素(TOB)、西索米星(SISO)与阿米卡星(AMK)的体外抗菌活性。金葡菌产酶株对上述抗生素的敏感性显较不产酶株为差,以ISP、NTL对金葡菌产酶株的作用最强。其平均MIC值分别为1.85和2.12mg/L;对革兰氏阴性杆菌的作用则以ISP和AMK为强。以ISP对各种细菌的MIC值最低0.32～3.39mg/L。TOB、GM、SISO、NTL与DKB对多数革兰氏阴性杆菌的作用相似,五者之间有很大程度交叉耐药。所测611株革兰氏阴性杆菌中对一种以上药物耐药者312株,占51％;其中对ISP和AMK仍敏感者分别为90.4％和91.7％,而对NTl、GM、TOB、DKB敏感者仅15～18％,本文讨论了细菌对氨基糖苷类的耐药机理及其临床意义。     

Double stage activity in aminoglycoside antibiotics

Fourteen different aminoglycoside antibiotics (AGs) were challenged with aminoglycoside acetyltransferases (AACs) of actinomycete origin in order to examine their 'double stage activity' that is arbitrarily defined as antibiotic activity retainable after enzymatic modification. In kanamycin (KM)-group AGs tested [KM, dibekacin (DKB), amikacin and arbekacin (ABK)], ABK retained activity after acetylations by AAC(3), AAC(2') and AAC(6'). DKB also retained a weak activity after acetylation by AAC(2'). In gentamicin (GM)-group AGs tested [GM, micronomicin, sisomicin (SISO), netilmicin (NTL) and isepamicin], GM, SISO and NTL retained activites after acetylation by AAC(2'). In neomycin (NM)-group AGs tested [ribostamycin, NM, paromomycin], NM retained activity after acetylation by AAC(6') and AAC(2'). None of astromicin (ASTM)-group AGs tested (ASTM and istamycin B) retained activity after acetylation by AAC(2') and AAC(6'). The activities of acetylated ABK derivatives by AAC(3) and AAC(2') were distinctively high, compared to the others. Streptomyces lividans TK21 containing the cloned aac genes were markedly sensitive to AGs that retained activities after acetylation, indicating the substantial effect of 'double stage activity'.     

Combined action of cephamycin and aminoglycoside antibiotics

The combined actions of cefoxitin (CFX) with amikacin (AMK), gentamicin (GM) and dibekacin (DKB) were studied against Gram-positive and Gram-negative bacteria. The following results were obtained. The synergistic actions of CFX with AMK, GM and DKB were observed on S. aureus, S. epidermidis, E. coli, S. marcescens, K. pneumoniae, Proteus spp. and Acinetobacter by checker board titration method. The combination of CFX with AMK was most effective. In case of the combination of CFX with AMK, the simultaneous administration showed the highest bactericidal effect, followed by the case of addition of AMK after adding CFX. The phase-contrast microscopic observation on S. marcescens revealed that the bacterial cell prolonged with CFX showed a filament-like form and with AMK almost a normal form. In the combination, lysed cells were observed. The therapeutic experiment of S. marcescens infection in mice demonstrated that the combination of CFX with AMK showed superior effect than that of each drug alone.     

Pharmacokinetics of amikacin in children and neonates

To evaluate pharmacokinetics of amikacin (AMK), one of the aminoglycoside antibiotics, children with ages from 2 days to 11 years were treated with various doses by various administration routes, and both plasma and urinary levels of AMK were determined. The following is a summary of the results obtained: 1. Of 6 children, three were treated with 2.0 mg/kg of AMK by a 30-minute intravenous drip infusion, and the other 3 with 4.0 mg/kg by a 60-minute. Peaks of average plasma levels were observed at the ends of the infusions in both cases, and their levels were 9.23 and 13.67 micrograms/ml, respectively, showing a dose-dependency. Both half-lives and areas under plasma concentration-time curves (AUCs) were similar to those of adults. However, the volume of distribution (Vd) showed a lower value than that of adults. Peaks of average urine levels were 149.3 micrograms/ml with 2.0 mg/kg in 0-2 hours after the start of the infusion and 223.3 micrograms/ml with 4.0 mg/kg in 2-4 hours. Average urinary recovery rates within 6 hours after the start of the infusion were 95.4% with 2.0 mg/kg and 85.7% with 4.0 mg/kg. These recoveries were equal to or higher than that of adults. 2. When 3.0, 4.0 and 6.0 mg/kg of AMK were administered to 3 groups of mature or premature babies by intramuscular injection, average peak levels of AMK in plasma were 6.26, 8.61 and 12.60 micrograms/ml, respectively, at 30 minutes after the injection, showing dose-dependency. In these groups, the younger the day age after birth was, the longer the half-life became. The AUCs were larger as the half-life became longer. The Vd was larger than that in the intravenous drip infusion group, but, any particular was not observed. Average peak levels of AMK in urine were 78.83 micrograms/ml at 4-6 hours with a dose level of 3.0 mg/kg, 99.17 micrograms/ml at 2-4 hours with 4.0 mg/kg and 139.20 micrograms/ml at 0-2 hours with 6.0 mg/kg. Average urinary recovery rates within 6 hours were 36.57% with 3.0 mg/kg, 34.67% with 4.0 mg/kg and 43.77% with 6.0 mg/kg. These recovery rates were markedly lower than those observed in adults and children. One of the causes of this low recovery is that mature and premature babies have immature renal functions. 3. When 3.0 mg/kg of AMK was administered to three premature babies by a 30-minute intravenous drip infusion, the average peak plasma levels was 7.61 micrograms/ml at the end of the drip infusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative activity of ceftizoxime against aminoglycoside-resistant aerobic gram-negative bacilli

The in vitro activity of ceftizoxime was compared with that of other beta-lactam antibiotics against 331 aminoglycoside (AG)-resistant clinical isolates. Two hundred and six AG-resistant, beta-lactamase producing, R-plasmid harbouring Enterobacteriaceae strains had MICs ranging from 0.0125 to 0.063 mg/l. AG-resistant Escherichia coli (36 strains) and Klebsiella pneumoniae (19) had MIC 90 values of 8 mg/l. Proteus rettgeri and P. vulgaris as well as Morganella morganii, resistant to several AGs, had MICs ranging from 0.5 to 4 mg/ml. Against all six isolates of AG-resistant Salmonella enteritidis the MIC90 was 0.5 mg/l. Twenty-seven strains of Serratia marcescens, most of which were resistant to beta-lactam and AG antibiotics, had MICs ranging from 0.5 to 8 mg/l. The AG-resistant strains of Enterobacteriaceae producing several AG-modifying enzymes (AAC(3); AAC(2'); AAC(6'); APH(3')) showed MICs ranging from 0.6 to 4 mg/l. Against 10 AG-resistant strains of Pseudomonas aeruginosa producing AAC(3), AAC(6') and APH(3') enzymes, the MICs ranged from 16 to 64 mg/l. In conclusion, ceftizoxime was equally or more active than cefotaxime, cefoperazone, ceftazidime and moxalactam against AG-resistant E. coli, Klebsiella, Morganella, Proteus, Serratia, Salmonella and R-plasmid harbouring Enterobacteriaceae. Ceftizoxime was less active than cefotaxime, moxalactam and ceftazidime against P. aeruginosa.     

Pharmacokinetic and clinical studies on amikacin in neonates

Pharmacokinetic and clinical studies on amikacin (AMK) were performed in neonates and the results obtained are summarized as follows. 1. After intramuscular injection of single doses of AMK at 3 mg/kg, peak serum levels were 6.8 micrograms/ml in a 2-day-old neonate and 7.0 micrograms/ml in a 20-day-old neonate. Serum levels of AMK in the above 2 neonates at 8 hours after injection were 1.5 micrograms/ml and 1.4 micrograms/ml, respectively, and the half-life of AMK was 3.3 hours. After intramuscular injection of single doses of 4 mg/kg of AMK, the mean peak serum level was 8.1 +/- 1.1 micrograms/ml, and half-lives of AMK were 6.1 hours in a 1-day-old neonate and 4.0 hours in a 3-day-old neonate. The mean peak serum level of AMK reached at 1 hour after intramuscular administrations at single dose of 6 mg/kg was 10.5 +/- 0.5 micrograms/ml in a 3-day and a 4-day-old neonates. Serum levels at 8 hours after administrations were 3.1 micrograms/ml and 2.8 micrograms/ml, in the 3-day and the 4-day-old neonates, respectively. Half-lives of AMK in sera were 3.9 hours in the 3-day-old neonate and 3.5 hours in the 4-day-old neonate. 2. In three 2-day-old neonates, the mean peak serum level of AMK after an intravenous drip infusion for 30 minutes at single dose of 3 mg/kg was 10.0 +/- 1.1 micrograms/ml at the end of infusion and serum levels decreased to 2.3 +/- 0.6 micrograms/ml at 6.5 hours after infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antibacterial activities of various aminoglycosides against clinically isolated methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) were isolated from samples collected from various patients during 1986, and antibacterial activities of 6 aminoglycosides (AGs) (netilmicin (NTL), gentamicin (GM), sisomicin (SISO), dibekacin (DKB), tobramycin (TOB) and amikacin (AMK] and 4 beta-lactam antibiotics (cefazolin (CEZ), cefmetazole (CMZ), cloxacillin (MCIPC) and methicillin (DMPPC) against these MRSA were evaluated. Among these 6 AGs, NTL was the most potent, and its MIC50 and MIC80 were 1.56 and 3.13 micrograms/ml, respectively. Antibacterial activities of GM, SISO, DKB and TOB were weak, and MIC50's of GM and DKB were both 100 micrograms/ml, while those of SISO and TOB were 50 and greater than 100 micrograms/ml, respectively. Frequency of highly resistant specimens to AMK was rather low and its MIC50 and MIC80 were 12.5 and 25 micrograms/ml, respectively. As for antibacterial activities of the above 4 beta-lactam antibiotics, the MIC50 and MIC80 of CMZ were 6.25 and 12.5 micrograms/ml, respectively, and therefore, its antibacterial activity to MRSA is relatively good. However, MIC50's of CEZ, MCIPC and DMPPC were all greater than 100 micrograms/ml, showing poor antibacterial activities. Recently, MRSA became a problem in various fields of clinical practice, and a number of literatures reporting refractory infections caused by MRSA have been published. Since MRSA is featured as multiply resistant bacteria, it is known that MRSA is resistant to the majority of existing antibiotics (penicillins, cephems, macrolides, AGs, etc.). In 1985, we reported results of our study concerning the antibacterial activities of a number of CEPs and some of AGs against multiply resistant S. aureus including MRSA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fundamental studies of combination of antibiotics, especially on pharmacokinetics. III. Combination of ampicillin and dibekacin (author's transl)]

1. Pharmacokinetics was investigated when ampicillin (ABPC) (50 mg/kg) and dibekacin (DKB) (5 mg/kg), in combination with pre- or post-treatment, were intravenously injected to the rat or rabbit. 2. The antibiotics in the samples were separated by the paper-electrophoretic technique and then concentrations were determined by the cup thin-layer plate method using Bacillus subtilis ATCC 6633 as the test organism. 3. The biological half-life of DKB was prolonged in pretreatment with ABPC and that of ABPC was shortened in pretreatment with DKB. An initial level of ABPC was elevated. Similar tendency was observed in both of the rat and rabbit. 4. Urinary excretion rates of both antibiotics in the combining group tended to decrease compared with the single administration group. 5. Binding of ABPC to serum proteins was competitively inhibited by DKB. Binding of DKB to serum proteins increased.     

Toxicological studies on isepamicin (HAPA-B). IV. Intramuscular subacute toxicity test in the dog

The subacute toxicity in the dog of isepamicin (HAPA-B), a new aminoglycoside antibiotic, was studied in comparison with amikacin (AMK). HAPA-B at dose levels of 6.25, 25 and 100 mg/kg/day and AMK at dose levels of 25 and 100 mg/kg/day were given intramuscularly for 30 days. Only one female dog in the AMK 100 mg/kg dose group died on day 29. The activities of urinary NAG and gamma-GTP increased dose-relatedly in dogs in the 25 and 100 mg/kg dose groups of either drug. Discoloration and/or enlargement of the kidneys were observed in dogs at 100 mg/kg of either drug. Hemorrhage and/or edema at the injection sites were observed in dogs in the 25 and 100 mg/kg dose groups of either drug. Increases of absolute and relative kidney weights were observed in the AMK 100 mg/kg group. An increase of relative kidney weights was also observed in the HAPA-B 100 mg/kg group. In microscopic observations, various histopathological changes of renal tubules and tubular epithelium were observed dose-relatedly in the 25 and 100 mg/kg groups of both drugs. At a dose of 25 mg/kg, there was no significant difference of the incidence and severity of these renal changes between HAPA-B and AMK groups. Desquamation and necrosis of the renal tubular epithelium were observed only in the AMK 100 mg/kg group. The necrosis in these changes was considered to be one of the severest possible changes in renal tubules, hence the renal toxicity of HAPA-B was judged to be milder than that of AMK at the dose level of 100 mg/kg. The non-toxic dose of HAPA-B in this study was estimated to be 6.25 mg/kg.     

Studies on sub-MIC activities of beta-lactam antibiotics and aminoglycoside antibiotics against clinically isolated strain

Sub-MIC range of 8 kinds of beta-lactam antibiotics and 3 kinds of aminoglycoside antibiotics against strain of Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa isolated from clinical source were determined by nephlometic method, and following results were obtained. When 10 strains of S. aureus tested to ampicillin (ABPC), hetacillin (IPABPC), mecillinam (MPC), cephalexin (CEX), cefotaxime (CTX), latamoxef (LMOX), cefatrizine (CFT), cephapirin (CEPR), gentamicin (GM), dibekacin (DKB) and amikacin (AMK), ratio of MIC to MAC were 36.8, 53.6, 156.8, 29.6, 61.6, 34.4, 50.0, 111.2, 9.2, 20.0 and 13.6, respectively. When 10 strains of K. pneumoniae tested to MPC, CEX, CTX, LMOX, CFT, CEPR, GM, DKB and AMK, ratio of MIC to MAC were 409.6, 10.4, 34.4, 123.2, 39.2, 167.2, 5.2, 5.6 and 13.2, respectively. When 10 strains of P. aeruginosa tested against CTX, LMOX, GM, DKB and AMK, ratio of MIC to MAC were 16.8, 38.4, 6.8, 3.2 and 10.4, respectively.     

Antibacterial activities and PK/PD parameters of aminoglycosides against recent clinical isolates of gram-negative rods

We examined antibacterial activities and PK/PD parameters of six kinds of aminoglycosides against seven bacterial species of clinical isolates in 2001. Aminoglycoseides examined were gentamicin (GM), dibekacin (DKB), tobramycin (TOB), amikacin (AMK), netilmicin (NTL), and isepamicin (ISP), and bacterial isolates used were each 50 strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii, Proteus spp., Serratia marcescens and Pseudomonas aeruginosa. All aminoglycosides showed good activities with low MICs against 6 species of Enterobacteriacea except S. marcescens. Eight strains (3.2%) among them were resistant to one or more aminoglycosides. Resistance to multiple aminoglycosides were detected in 16 strains (32%) of S. marcescens, among which 13 strains were resistant to AMK but susceptible to ISP. Three (6%) strains of P. aeruginosa were resistant to multiple drugs, one of which was resistant to all six aminoglycosides, and others were moderately susceptible to AMK and ISP, and susceptible to GM, AMK and ISP. Using a ratio of peak serum concentration to MIC90 (Cmax/MIC90) or a ratio of area under the curve to MIC90 (AUC/MIC90) as a pharmacokinetic and pharmacodynamic (PK/PD) parameter, we estimated the efficacy of the drug. An excellent effect of ISP, which was injected intramuscularly or intravenously at a dose of 400 mg, was expected for strains of Enterobacteriacea except S. marcescens. The Cmax/MIC90 ratios for S. marcescens were comparably higher in GM and ISP and that for P. aeruginosa were rather high in TOB when compared to other aminoglycosides. Another PK/PD parameter, AUC/MIC90 ratio, was high enough in NTL and ISP for Enterobacteriacea, suggesting good efficacy of these drugs. The (AUC/MIC90) ratios for S. marcescens were comparably high in GM and ISP, and that for P. aeruginosa were high in TOB, DKB, and ISP.     

Susceptibility of methicillin-resistant Staphylococcus aureus to various antibiotics. Classification by aminoglycoside-modifying enzymes and antibiotics active against MRSA]

MICs of 14 aminoglycoside antibiotics including 10 of those used clinically were determined against 50 strains of methicillin-resistant Staphylococcus aureus (MRSA) which had been isolated at a hospital in Osaka between 1986 and 1990. Arbekacin (ABK) inhibited the growth of all strains at less than or equal to 0.20-6.25 micrograms/ml, showing the most potent activities. Streptomycin showed good activities (1.56-6.25 micrograms/ml) against all strains except one resistant strain (greater than 100 micrograms/ml). Based on susceptibilities to kanamycin (98% resistant), tobramycin (84%), gentamicin (62%), amikacin (36%) and ABK (0%), MRSA strains were classified into 5 types; type 0 producing no aminoglycoside-modifying enzyme, type 1a producing APH(3'), type 1b producing AAD(4', 4'), type 2a producing APH (2')/AAC(6') and APH(3'), and type 2b producing APH(2')/AAC(6') and AAD(4', 4'). In addition to the aminoglycoside antibiotics, 13 known antibiotics including vancomycin (VCM) were found active against MRSA upon random screening. Taitomycin (0.013-0.050 micrograms/ml) was the most potent, and griseoluteins A and B (each 0.10-0.39 micrograms/ml), and macarbomycin (0.05-0.20 micrograms/ml) were more active than VCM (0.39-1.56 micrograms/ml). Novobiocin (less than or equal to 0.20-0.78 micrograms/ml) also showed good activities.     

Clinical evaluation of aztreonam for infections accompanying febrile neutropenic children with hematologic disorders and solid tumors. A cooperative study

One hundred four children with infection accompanying hematologic disorders and solid tumors were treated with aztreonam (AZT) (120-150 mg/kg), either alone or in combination with one of the following drugs; cefmetazole (CMZ) (120-150 mg/kg), piperacillin (PIPC) (120-150 mg/kg), or amikacin (AMK) (5-10 mg/kg). The overall efficacy rate was 69.2%. Efficacy rates by regimen were as follows: AZT alone was 63.2%, AZT plus CMZ was 73.6%, AZT plus PIPC was 74.1% and AZT plus AMK was 20.0%. Efficacy rates in different types of infections were 53.2% for sepsis and suspected sepsis, 78.9% for pneumonia and respiratory tract infection, 93.1% for fever of undetermined origin and 55.6% for other infections. The efficacy rate was 71.3% in 94 patients in whom causative organisms were not identified and 50.0% in 10 patients in whom causative organisms were identified. Most of infections in which causative organisms were identified were caused by Gram-negative pathogens. The response rate among infections caused by Gram-negative bacilli was 50.0%. A combination of AZT and CMZ or PIPC was effective in 3 (100.0%) out of 3 patients in whom Escherichia coli was the causative organism. Efficacies classified according to different neutrophil counts were 59.3% for less than or equal to 100/microliters, 78.6% for 101-500/microliters and 82.4% for greater than or equal to 501/microliters. No significant adverse reactions were observed. These results indicated that combination of AZT and 2nd generation cephalosporins or penicillins were well tolerated and effective for infections complicated with accompanying hematologic disorders and solid tumors.     

Effects of Aminoglycoside Antibiotics on the Auditory Brainstem Response and Post Rotatory Nystagmus in Rats

Effects of three aminoglycoside antibiotics, amikacin (AMIK),tobramycin (TOB), and gentamicin (GM), on the auditory and vestibularfunctions were assessed in rats, the most frequently used speciesin toxicity studies. Chronic electrodes for auditory brainstemresponse (ABR) recording were implanted on the epidural surface,and those for post rotatory nystagmus (PRN) were implanted atthe nictitating membrane and the outer canthus. AMK, TOB, andGM were given intramuscularly twice daily for 3–4 weeksat a daily dose of 350, 150, and 100 mg/kg, respectively. Theamplitude of each wave of the ABR was decreased or disappearedin the groups treated with AMK, TOB, and GM. In the PRN, theduration of the nystagmus was decreased in the TOB group andcompletely lost in the GM group. No abnormality was observedin the PRN in the AMK group. These results were similar to thosereported in the ototoxicity studies of these drugs in guineapigs and indicate that ototoxicity can be evaluated in ratsas successfully as in guinea pigs by this procedure.     

Anticonvulsive properties of cinnarizine and flunarizine in rats and mice.

The anticonvulsive properties of orally administered cinnarizine [(E)-1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazine], its difluoro derivative flunarizine [(E)-1-(bis-(4-fluorophenyl)methyl)-4-(3-phenyl-2-propenyl)-piperazine], diphenylhydantoin and phenobarbital, were studied against maximal metrazol seizures (MMS) in rats and maximal electroshock seizures (MES) in mice. In rats (MMS), the lowest ED50 for protection against tonic extension of hindpaws was 4.10 mg/kg (1 h 35 min after treatment) with sodium phenobarbital, 6.04 mg/kg (5 h 45 min) with flunarizine dihydrochloride, 9.84 mg/kg (2 h 34 min) with cinnarizine and 19.30 mg/kg (3 h 38 min) with diphenylhydantoin. In mice (MES), protection against tonic extension of hindpaws was (2 h after treatment) 7.0 mg/kg with diphenylhydantoin, 13.2 mg/kg with sodium phenobarbital, 20.9 mg/kg with flunarizine kihydrochloride and 49.0 mg/kg with cinnarizine. Except at subtoxic doses no side effects were observed in rats and mice given cinnarizine, flunarizine kihydrochloride or kiphenylhydantoin. Phenobarbital induced ataxia in rats and mice at 22 mg/kg and 42.7 mg/kg, respectively, and loss of righting reflex at 112.8 mg/kg and 160 mg/kg, respectively. Flunarizine is the longest-acting drug and has the slowest onset. At a dose of twice the minimal ED50 flunarizine affords protection against tonic extension of hindpaws in rats (MMS) for 23 h 30 min dephenylhydantoin for 11 h 38 min, phenobarbital for 8 h 22 min and cinnarizine for 8 h 16 min. Peak effect was reached with flunarizine at 5 h 45 min, with diphenylhydantoin at 3 h 38 min, with cinnarizine at 2 h 34 min and with phenobarbital at 1 h 35 min. The anti-MMS profiles of cinnarizine and flunarizine resemble that of dephenylhydantoin as all three compounds are selective blockers of tonic extension of hindpaws. Phenobarbital antagonized the whole MMS-pattern, i.e., tremors, clonic convulsions and tonic extension of fore- and hindpaws. However, the effects of phenobarbital against tremors, clonic convulsions and tonic extension of forepaws may reflect more a general CNS-depressant effect than a specific anticonvulsive activity since neurotoxic effects (ataxia and loss of righting reflex) appear at the same doses.