Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1- fluoromethyl-4-oxo-4H-[1,3thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives.

A series of 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H- [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives (2a-1) was prepared and evaluated for antibacterial activity. These compounds were obtained by deacylation of 4-benzoyloxy-2-(1-chloro-2-fluoroethyl)thio-6,7- difluoroquinoline-3-carboxylate (10) and subsequent intramolecular cyclization followed by substitution with cyclic amines and then hydrolysis. The intramolecular cyclization reaction of 18, one of the diastereomers (17, 18) revealed that the cyclization reaction proceeded through an inversion to afford (-)-11a in good chemical and optical yield. The enantiomers of 2a were prepared from the enantiomers of 11a, which were obtained by the optical resolution of the racemate using high-performance liquid chromatography (HPLC). Compounds 2a,b showed excellent in vitro and in vivo antibacterial activity against both gram-negative and gram-positive bacteria including quinolone and Methicillin-resistant Staphylococcus aureus.

In vivo antibacterial activity of a prodrug of NM394, a thiazetoquinoline carboxylic acid derivative.

NM394 (6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]-thiazeto [3,2-a]quinoline-3-carboxylic acid) has potent, broad-spectrum antibacterial activity in vitro, but not in vivo. To increase the bioavailability of NM394, various prodrugs were synthesized and tested. One of them, NM441, an N-(5-methyl-2-oxo-1,3-dioxol-4-yl) derivative, showed potent in vivo antibacterial activity. Using thin-layer chromatography-bioautography, we confirmed that after oral administration, NM441 was readily absorbed and hydrolyzed to NM394. Other prodrugs of NM394 were only partially metabolized to NM394. In pharmacokinetic studies in mice and monkeys, we found that the blood levels of NM394 were 7.8 and 5.9 times greater, respectively, when NM441 rather than NM394 was administered. These findings suggest that NM441 is an effective prodrug of NM394.

Structure-antibacterial activity and cytotoxicity relationships of thiazolo and thiazetoquinolone derivatives.

In the course of our search for derivatives with potent antibacterial activity and low cytotoxicity, we have studied the relationships among the structure, antibacterial activity and cytotoxicity of thiazoloquinolone and thiazetoquinolone derivatives (the term quinolone as used in this paper includes the quinolone, 1,8-naphthyridine and pyridopyrimidine nuclei). The antibacterial activities and cytotoxicity of these derivatives were compared with those of norfloxacin, ofloxacin, enoxacin and ciprofloxacin. The antibacterial activities of the thiazoloquinolone derivatives were more potent than those of the dihyrothiazoloquinolone derivatives, and comparable to that of ciprofloxacin. All of the thiazoloquinolone derivatives were highly cytotoxic against mammalian cells, but some of the dihyrothiazoloquinolone derivatives were less cytotoxic, being comparable in cytotoxicity to the reference drugs. The thiazetoquinolone derivatives were less cytotoxic than the thiazoloquinolone derivatives, and one of them, 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a] quinoline-3-carboxylic acid, showed the most potent antibacterial activity of all compounds tested in this study, as well as a very low cytotoxicity. The antibacterial activity and cytotoxicity of this compound were similar to that of ciprofloxacin.

Studies on pyridonecarboxylic acids. IV. Synthesis and antibacterial activity evaluation of S-(-)- and R-(+)-6-fluoro-1-methyl-4-oxo-7- (1-piperazinyl)-4H-[1,3] thiazeto[3,2-a]quinoline-3-carboxylic acids.

Optically active isomers of 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H- [1,3] thiazeto [3,2-alpha] quinoline-3- carboxylic acid (NM394, 3) were prepared through optical resolution of their racemic intermediate ( +/- )-1 by high-performance liquid chromatography (HPLC). The absolute configuration at the C-1 position in the thiazeto-quinolone ring of ( - )-3 was confirmed by X-ray analysis ( - )-4 to be S. The in vitro antibacterial activity of ( - )-3 was 2--8 times that of (+)-3.

Studies on pyridonecarboxylic acids. III. Synthesis and antibacterial activity evaluation of 1,8-disubstituted 6-fluoro-4-oxo-7-piperazinyl-4H-[1,3]thiazeto[3,2- a]quinoline-3-carboxylic acid derivatives.

A series of 1,8-disubstituted 6-fluoro-4-oxo-7-piperazinyl-4H-[1,3]thiazeto[3,2-a]quinoline-3- carboxylic acid derivatives was prepared and evaluated for antibacterial activity. In the 7-piperazinyl series, addition of a fluorine at C-8, which increased the in vitro activity for the 1-hydrogen and 1-methyl analogues and decreased it for the 1-phenyl analogue, improved the in vivo activity of all the analogues. Introduction of a methoxy group at C-8 of the 1-methyl-7-piperazinyl analogue also improved its in vivo antibacterial activity. The effect of 8-substituents on the in vitro and in vivo antibacterial activity of the 1-methyl-7-(4-methyl-1-piperazinyl) series is also discussed.

[The efficacy of external high frequency oscillation: experience in a quadriplegic patient with alveolar hypoventilation].

External high frequency oscillation (EHFO) around a negative pressure using a thoracoabdominal chamber without an artificial airway has been shown to be an effective form of ventilation in a quadriplegic patient. The patient was an 18 year old male, suffering from high-level cervical cord tumor (lipoma). His respiratory distress was severe, respiration was diaphragmatic only. Because of acute respiratory insufficiency, he was intubated and put on IPPV. Attempts at weaning were not thought to be feasible. Then the Hayek Oscillator was applied with a frequency of 120. After 5 days on the Hayek Oscillator, he was extubated. EHFO was associated with a significant increase in PaO2 and VA, and a significant decrease in PaCO2. It is remarkable that the patient expelled sputum whenever he was connected to the Hayek Oscillator, far beyond that achievable by physiotherapy. EHFO avoids the need for endotracheal intubation, thus reducing the hazards of mechanical ventilation attributable to intubation. We conclude that EHFO produces gas exchange significantly and that this technique may have potential clinical application.

Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3- carboxylic acids.

A series of [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids and their esters were prepared and evaluated for antibacterial activity. The derivatives with a hydrogen or methyl group at C-1, fluorine at C-6, and piperazinyl or 4-methyl-1-piperazinyl group at C-7 showed superior in vitro antibacterial activity, and the derivatives with 4-methyl-1-piperazinyl group at C-7 had potent in vivo activity. Compound 29a (NM394) showed excellent in vitro antibacterial activity and low toxicity but poor absorption from the gastrointestinal tract. Compound 29ee (NM441), an N-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] derivative of 29a, was found to possess a favorable pharmacokinetic profile and oral activity superior to that of ciprofloxacin in experimental animals.

[A case of heterozygous familial hypercholesterolemia showing the regression of coronary atherosclerosis by LDL-apheresis].

A case showing the regression of coronary atherosclerosis by the treatment with LDL-apheresis, was reported. The patient was a 67-year old female with heterozygous familial hypercholesterolemia. She had noticed the xanthelasma or left cubital xanthoma at the age of 50 years old. She was informed about her high serum cholesterol level (greater than 350 mg/dl), and the abnormal thickness of her bilateral achilles tendon at the age of 61 years. As her serum cholesterol level did not decrease sufficiently with several lipid-lowering drugs, she was referred to our hospital in order to obtain treatment for it by LDL-apheresis at the age of 66 years. LDL-apheresis was performed once every two weeks with drugs such as probucol, cholestyramine and pravastatin. Her coronary angiogram after two and half years of LDL-apheresis showed a decrease of the coronary narrowing in segment 1 and segment 13 (from 96.8% to 74.6% in segment 1, and from 81.5% to 61.7% in segment 13, respectively). The thickness of her bilateral achilles tendons had also decreased from 18 mm in the right and 19 mm in the left to 14 mm in both, after receiving LDL-apheresis for two and half years. It is suggested from the result of this case that the regression of coronary atherosclerosis could be expected after treatment with LDL-apheresis in hypercholesterolemic patients.

Proteoglycan obtained from bovine aorta suppress thrombin-induced platelet aggregation.

Proteoglycan (PG), isolated and purified from bovine aorta (intima-media), consisted of 68.6% chondroitin 4/6-sulfate (CS 4/6-S), 30% dermatan sulfate (DS), 1.4% heparan sulfate (HS), and a trace of hyaluronic acid (HA). PG did not affect platelet aggregation induced by ADP, collagen, and epinephrine, but inhibited that induced by thrombin. Of the standard GAGs investigated, hyaluronic acid (HA) and CS-4/6-S slightly inhibited only thrombin-induced platelet aggregation. However, PG and standard GAGs did not affect the thrombin induced aggregation of washed platelets. The effect of PG after papain digestion on thrombin-induced platelet aggregation was less potent than that before. It is suggested by the results of this study that PG in the aorta inactivates plasma thrombin, probably by inhibiting thrombin activators or potentiating substances which inactivate thrombin and that these effect of PG would be mainly due to PG-DS and partly due to PG-HS.

In vivo evaluation of NM441, a new thiazeto-quinoline derivative.

NM441 is a lipophilic prodrug of a new thiazeto-quinoline carboxylic acid derivative NM394, and when it is administered orally it is readily absorbed and hydrolyzed to its parent compound. After oral administration of NM441 at a dose of 20 mg/kg to dogs, the peak concentration of NM394 in plasma was 2.39 micrograms/ml, whereas it was 0.63 micrograms/ml for NM394 administered alone. The in vivo activity of NM441 was compared with those of ciprofloxacin, ofloxacin, and enoxacin in mouse protection studies. NM441 was as effective as ofloxacin and was twice as effective as ciprofloxacin against systemic infection with Staphylococcus aureus. Against infections with streptococci, NM441 was two to three times as effective as ofloxacin and five times as effective as ciprofloxacin. Against infection with Escherichia coli, NM441 was as effective as ciprofloxacin and ofloxacin, but against infections with Klebsiella pneumoniae, Serratia marcescens, and Pseudomonas aeruginosa, NM441 was two to four times as effective as ciprofloxacin and ofloxacin. NM441 was three to seven times as effective as enoxacin in systemic infections. Against urinary tract infections with E. coli, NM441 reduced the number of bacterial CFU per gram of kidney by 1 to 2 log10 more and, with P. aeruginosa, by 1 to 6 log10 more than did ciprofloxacin and ofloxacin. Against respiratory tract infections with K. pneumoniae, NM441 was as effective as ofloxacin and was twice as effective as ciprofloxacin.

A case in which coronary spasms were induced by ergonovine provocation at the sites of coronary artery ectasia.

We experienced a patient in whom coronary spasms were induced by an ergonovine provocation test during coronary angiography at the sites of coronary artery ectasia. The patient was a 45-year-old male with chest pain at rest, which promptly disappeared when given sublingual nitroglycerin. Similar attacks occurred frequently even with the administration of drugs after admission, but no significant changes were observed in electrocardiography (ECG) during the attacks or by repeated Holter ECG. The results of exercise ECG and provocation tests such as Valsalva maneuver, hyperventilation, and cold pressor test were negative. Coronary angiography showed ectatic changes in the left coronary artery, and the coronary spasms were induced by ergonovine administration at the ectatic portion of the left anterior descending artery and left circumflex artery, and right coronary artery with chest symptoms similar to those observed during spontaneous attacks. However, there were no significant changes in ECG. This rare case suggests an involvement of spasms in the pathogenic mechanism of myocardial ischemia in coronary artery ectasia.

Chronic arterial occlusion with PGE1-resistant skin lesions treated by glycosaminoglycan compound--case reports.

The authors report on 2 patients with chronic arterial occlusion in whom the intravenous administration of the glycosaminoglycan compound FPFD 101 was markedly effective. One patient suffered from thromboembolic episodes of the left hand, and the other had peripheral circulatory impairment related to collagen disease. In these patients, the oral administration of anticoagulants and antiplatelet agents in combination with intravenous infusion of prostaglandin E1 was not adequately effective. However, the addition of intravenous injection of FPFD 101 resulted in a marked improvement in their symptoms. FPFD 101, which has an anticoagulant effect and also inhibits platelet aggregation, seems to be useful for the treatment and prevention of chronic arterial occlusion when combined with drugs such as anticoagulants, antiplatelet agents, and vasodilators.

Factors predictive of marked decrease in HDL-C by probucol treatment.

Probucol markedly reduces the LDL-C level in hyperlipidemic patients. However, it also reduces HDL-C which is believed to result in an anti-atherosclerotic effect. Many hyperlipidemic patients treated with Probucol show a marked reduction in the HDL-C level, and administration of the agent to these patients requires proper caution. In this study, factors useful for predicting the reduction in HDL-C were examined in order to be able to predict the problem before actual administration. Probucol (250-750 mg/day) was administered to 30 patients with type II hypercholesterolemia. Among them, 23 patients showed a decrease greater than 20% in the HDL-C level after administration. To evaluate the factors which permit identification of this group, linear descriminant function analysis was performed using 12 pre-administration lipid levels. The analysis indicated that the Apo A-I/HDL-C ratio before Probucol has the greatest predictive value (F = 17.8, P less than 0.01) of all the parameters, and that the HDL-C level is reduced by 20% or more by Probucol administration when this ratio is 5.3 or less.

K-edge effect calibration of the Ge(Li)/Si(Li)-multichannel analyser system.

The positions of the steps produced in the spectral distribution of a bremsstrahlung beam by a mixture of powdered substances, give a single measurement calibration of the Ge(Li)/Si(Li)-multichannel analyser system as reported here. Through a set of linear equations, from the step heights one gets a chemical analysis of the mixture, or pointwise the spectral distribution of the primary X-ray beam.