[Pharmacokinetic, bacteriological and clinical studies on cefozopran in neonates and premature infants. A study of cefozopran in the perinatal co-research group].
R FujiiAkihiro OkunoK FujitaFujio KakuyaS MaruyamaHiroshi SakataF InyakuTakanori AbeShintaro HashiraY NakazatoMutsumi SugiuraT. TajimaSyuugo NAGAIN. FunamotoSatoshi SugimoriS NishimuraKazuya YoshimuraYasuhiro KondohY KawaoiI TerashimaH MeguroYuto TakeuchiMasato KantakeKeisuke SunakawaMorimasa Yagisawa
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Abstract:
The following results were obtained in pharmacokinetic, bacteriological and clinical investigations of a cephem antibiotic for injection, cefozopran (SCE-2787, CZOP), administered to neonates and premature infants. 1. Pharmacokinetics (1) Half-lives (T 1/2's) of CZOP in 0-day-old (less than 24 hours after birth) neonates and premature infants were longer than those in 1-day-old or older infants. When half-lives were compared between 0-day-old neonates and 0-day-old premature infants, longer half-lives were observed in premature infants. (2) When CZOP was intravenously administered to 1-day-old or older neonates and premature infants at a dose of 20 mg/kg, no differences were noted in blood concentrations between neonates and premature infants from 30 minutes to 6 hours after administration as well as T 1/2's. (3) Blood concentration of CZOP administered at doses of 10, 20 and 40 mg/kg were dose-dependent. (4) Urine excretion rates of CZOP administered to 1-day-old or older neonates and premature infants were approximately 30 to 60% in the first 6 hours after administration. Urine excretion rates in 0-day-old neonates and premature infants were low. 2. Clinical results (1) Of a total of 136 cases to which CZOP was administered, clinical efficacy evaluation was possible in 96 cases, and safety evaluation in 132 cases. (2) The clinical efficacy rates were 78.6% (22/28) in 28 cases in which causative organisms were detected (Group A), and 97.1% (66/68) in 68 cases in which no such organisms were detected (Group B), with the total efficacy rate (Groups A and B) of as high as 91.7% (88/96). (3) Bacteriological evaluations were made with 33 strains isolated from the 28 cases of Group A. Elimination rates for Gram-positive and Gram-negative bacteria were 88.2% (15/17) and 92.3% (12/13), respectively, with the total elimination rate of 90.0% (27/30). No microbial substitution was noted. (4) As an adverse reaction, diarrhea was noted in one case (0.8%). Abnormal laboratory test values were noted in 15 cases (12.3%) including eosinophilia, elevated GPT, and elevated gamma-GTP. All of these abnormalities were transitory, and none of them critical. As a result of above pharmacokinetic and clinical investigations, CZOP is considered to be highly useful in the treatment of indicated infections in neonates and premature infants. It appears that 20 mg/kg of CZOP can be administered by intravenous injection or intravenous drip infusion to neonates and premature infants aged 0-day (less than 24 hours after birth) once or twice daily, to those aged 1 (24 or more hours after birth) to 7 days twice or three times daily, and to those aged 8 or more days three to four times daily, and that the dose can be increased up to 40 mg/kg in cases of critical or intractable infections.Keywords:
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A practical and efficient route leading to the synthesis of 4-(tert-butylcarbonyl)-7α-methoxy-3-methyl-Δ3-cephem 1,1-dioxide (2), a key-intermediate in the preparation of potent inhibitors of mammalian serine proteinases, is reported. The new synthetic pathway has allowed easy access to an array of 7-substituted cephem derivatives.
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Reaction of p-methoxybenzyl 7β-phenylacetamido-3-methyl-2-cephem-4α-carboxylate (1) with NaN3 and ICl were carried out. In CH3CN or AcOEt, two iodoazides (2a, 2b), in CH3NO2 or CCl4, the diazide (3) and in dioxane or CH2Cl2, the chloroazide (4) were obtained. Treatment of 2a, 2b and 4 with DABCO gave 2-azido-3-cephem. The same treatment of 3 gave 2-azido-2-cephem. By replacement of 7β-amido group or ester group, the same results were obtained. As a simple model of olefins, reaction of benzo [b] thiophene with NaN3 and ICl gave diazide, from which HN3 was eliminated by tert-BuOK. Configuration of 2-azidocephams and cephems were discussed.
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Abstract Das aus Penicillin‐G‐benzhydrylester über das Thiazolin‐azetidinon (I) hergestellte Silbersalz (II) wird mit dem aus einem Bromtetrazol (III) in einer Folge von Reaktionen synthetisierten Brommethylester (IV) kondensiert und durch Ozonisierung, Reduktion, Ylid‐Bildung und Erhitzen des Ylids in siedendem Benzol zum 3‐Cephem (V) cyclisiert.
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The instability of Δ2 cephem prodrug-type ester (5a) under acidic conditions prompted us to investigate the comparative stability of Δ3 and Δ2 cephems at various pHs. The Δ2 cephem ester 5a was found to show marked instability under neutral (pH 7) and acidic conditions (1M HCl) compared with the Δ3 cephem ester (4a). A comparative study between Δ3 (4c) and Δ2 cephem acid (5c) at pH 7 and in 1M HCl solution showed that the Δ2 acid 5c was as stable as the Δ3 acid 4c pH 7, while 5c was less stable than 4c in 1M HCl. Isolation of the degraded compounds demonstrated that the C-4 ester moiety was hydrolyzed in the initial stage to afford 5c, which was further degraded to more polar substances. This instability was observed in other types of Δ2 cephem esters (5d-f). Here we report comparative stability studies and elucidation of the degradation products.
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The esterification of Δ3-cephem-4-carboxylic acid sodium salt (1) with 1-iodoethyl isopropyl carbonate always afforded the Δ2 cephem ester (3) as an inseparable minor component. However, in the course of formamido cleavage reaction, the 7-amino-Δ2-cephem ester (5) was observed to be less stable than the Δ3 cephem ester (4), which led us to develop a practical synthetic process for Δ3 cephem esters, including a key intermediate of E1101, a new oral cephalosporin.
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1,1-Dioxo-7α-methoxy-3-methyl-Δ3-cephem-4-yl phenyl ketone, a valuable precursor of potent HLE inhibitors, was obtained in an efficient way starting from 7α-methoxy-3-methyl-Δ3-cephem-4-carboxylic acid. By employing the same methodology a variety of 1,1-dioxocephem-4-yl aryl ketones were prepared.
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