Piromidic acid is a new synthetic antibacterial agent which is considered to be applicable to urinary tract infections.
In order to check nephrotoxicity of piromidic acid, the drug was orally administered to rats and rabbits at doses of 200, 400 and 800 mg/kg/day for 21 days, and then urine protein, urinary osmolality, blood urea nitrogen and serum creatinine were determined concomitantly with histological observation of kidney.
No abnormality was detected except for slight change in the groups of 800 mg/kg/day.
The results suggest that piromidic acid is applicable at usual therapeutic doses without fear of nephrotoxicity.

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Fundamental studies on a new synthetic chemotherapeutic agent, piromidic acid were performed with the results which may be summarized as follows :
1) In a study by the agar plate dilution method on a total of 67 strains of 13 species, E. coli, Shigella, Salmonella and Proteus-Providence were found to be fairly sensitive to the agent with the MICs of 25μg/ml or less. Klebsiella was slightly sensitive to it with the MICs of 100μg/ml or less. Pseudomonas was found to be resistant with the MICs of more than 400μg/ml. Staphylococci were fairly sensitive to it with the MICs of 25μg/ml or less.
2) The antimicrobial activities of β-hydroxypiromidic acid and substance N (5, 8-Dihydro-8-ethyl-5-oxo-2-aminopyrido [2, 3-d] pyrimidine-6-carboxylic acid) which had been known to be its metabolites were campared with those of piromidic acid. β-Hydroxypiromidic acid showed 1 to 4 times higher activities against Gram-negative rods but 2 times or more lower activities against Staphylococcus than piromidic acid. Substance N showed considerably lower activities with the MICs of more than 100μg/ml.
3) An antagonistic effect was observed between piromidic acid or β-hydroxypiromidic acid and certain nitrofuran derivate (e. g. nitrofurantoin) in the antimicrobial activity against the group of ProtesProvidence.
4) By the thin-layer cylinder-plate method using Sh. flexneri 3a 5184 as the test organism, active concentrations in the body fluids were assayable to the lower limit of 0.1μg/ml. Following a single oral administration of 1, 000mg piromidic acid, the blood peak levels of 5.2-7.4μg/ml were observed at 3-4 hours with the persistence of more than 1.2μg/ml over ensuing 8 hours. Urinary levels were 68-300 μg/ml and urinary recovery was 5-15% during 12 hours. It was also excreted in the bile at its maximum concentration of 160μg/ml.
5) The metabolites of the agent in the body fluids were separated and identified by means of a thinlayer-chromatographic method combined with fluorescent and bioautographic technique using piromidic acid, β-hydroxypiromidic acid and substance N as the standard compounds.
In the experiment, there existed a linear relationship between the logarithmic concentration of the drug and the square root of dimension of inhibition zones in the bioautogram. Consequently, its each active metabolite seemed to be assayable quantitatively by this method.
The approximate ratio of piromidic acid (including some of Substance B) and β-hydroxypiromidic acid thus obtained were 2 to 5 : 1 in the blood, 1 : 3 to 25 in the urine and 2 to 7 : 1 in the bile, respectively.

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Results of bacterial studies for ophthalmic use of piromidic acid were summerized as follows.
1) The minimum (growth) inhibitory concentration of piromidic acid was 12.5 mcg/ml for K-W bacillus, 1.56 mcg/ml for M-A bacillus, >100 mcg/ml against Diplo. pneumoniae and Cory. diphtheriae, 1.56 mcg/ml for Neisseria gonorrhoeae, . 100-> mcg/ml for Strept. hemolyticus and Strept. viridans, 12.5-25 mcg/ml for Staphylococcus and >100 mcg/ml for Ps. aeruginosa.
2) The sensitivity distribution of 20 strains of Staph. aureus was in the range of 12.5-25 mcg/ml, and was mostly (16 strains, 80%) in 12.5 mcg/ml.
3) The blood level in adult by single oral administration of 500mg piromidic acid reached the highest after 2 hours and was maintained measurably until 6 hours.
4) By oral application of 500mg in rabbit, the peak levels of blood and aqueous were obtained after 2 hours, aqueous/serum ratio was 51.3%.
5) The concentration of the ocular tissues after 2 hours by oral administration of 500mg in rabbit was high in the anterior parts of the eye, such as lid, conjunctiva, extraocular muscle and corea; relatively low in the posterior parts of the eye, in iris and ciliary body, retina and choroid, and vitreous body; no in crystaline lens.

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The fundamental studies on piromidic acid, a new chemotherapeutic agent, were performed prior to its clinical use and following results were obtained.
1. Antibacterial activity of piromidic acid against gram-negative bacteria was slightly inferior to that of nalidixic acid in general, but the former drug was active against Staphylococci which was insensitive to the latter. β-Hydroxypiromidic acid, a main metabolites of piromidic acid, showed lower activity against Staphylococci, but instead, higher activity against gram-negative bacteria, especially Proteus mirabilis, than piromidic acid.
2. Piromidic acid showed maximum urine level 6 hours postadministration and long duration in urine compared to nalidixic acid. After singl oral administration of piromidic acid at a dose of 1, 000 mg/person, the recovery from urine for 12 hours was 3. 5-6. 8% calculated as β-hydroxypiromidic acid, although the recovery fluctuated depending on an indicator strain or pH of samples and the medium used.
3. After single oral administration of piromidic acid at doses of 1-1.5 g/person, the levels in kidney were high (i. e. 11.7-96.0 meg/ml) when assayed using Bacillus subtilis PCI-219, although the levels fluctuated depending on assay conditions.
4. In analysis using thin-layer chromatography, β-hydroxypiromidic acid was mainly detected in kidney 6 hours postadministration concurrently with a small amount of piromidic acid. β-Hydroxypiromidic acid, substance N (5, 8-dihydro-8-ethyl-5-oxo-2-aminopyrido [2, 3-d] pyrimidine-6-carboxylic acid) and 2 unknown metabolites were detected in urine without a detectable amount of piromidic acid.

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Piromidic acid is a new synthetic chemotherapeutics developed at Research Laboratories of Dainippon Pharmaceutical Co. in 1970. In vitro and in vivo studies on the anti-microbial action of piromidic acid have been carried out and the following resullts were obtained :
1) It was active primarily against gram-negative bacteria and Staphylococci.
2) Cross-resistance was not observed between piromidic acid and antibiotics but observed between piromidic acid and nalidixic acid.
3) The anti-microbial activity tended to increase when the pH of culture increased in relative acidity.
4) Piromidic acid was apparently bactericidal in vitro at or above the minimal inhibitory concentration.
5) In the studies with mice experimentally infected with Escherichia coli, piromidic acid and β-hydroxypiromidic acid showed the curative effects which were parallel with respective minimal inhibitory concentration values, their ED₅₀ being found no more or less than that of nalidixic acid.

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Research Laboratories, Dainippon Pharmaceutical Co., Ltd.Piromidic acid (PA) was administered orally at daily doses of 200mg, 400mg, and 800mg per kg of body weight for 2 weeks to rats with liver damage induced by CCl₄ inhalation.
No differences were found in body weight gain, food consumption, hematological analysis, liver function tests and histopathological findings between rats treated with and without PA. The results obtained proved that no detectable toxicity was found in rats with the liver damage by the administration of PA.

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In order to evaluate the clinical use of piromidic acid in the obstetrics, placental transfer of the agent and its effect on reserve albumin binding capacity (RABC) of the neonates were investigated. Results obtained were as follows.
1. Concentration of the agent in the serum of the parturients showed delayed elevation and lower values as compared with the nonpregnant cases.
2. Placental transfer of the agent was found so smooth as a large amount of the agent was detectable in cord blood, reaching 73.3±14.7 percent of the amount in maternal blood.
3. Concentration in the neonates serum decreased within the first four hours to the value which corresponded to 44.4±19.2 percent of that in the cord blood at birth.
4. Intraplacental concentration of the agent was found as 33.8±14.2 percent of that in the maternal blood.
5. The agent was hardly detected in amniotic fluid.
6. The agent was not found excreted in the urine of the early neonates.
7. The agent had almost no effect on RABC.

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Piromidic acid (5, 8-dihydro-8-ethyl-5-oxo-2-pyrrolidinopyrido [2, 3-d] pyrimidine-6-carboxylic acid) is a new synthetic antibacterial agent having a pyridopyrimidine ring. It was active primarily against gram-negative bacteria and Staphylococci. Cross-resistance was not observed between piromidic acid and antibiotics or sulfonamides, while it was observed between piromidic acid and nalidixic acid. The minimal inhibitory concentration of piromidic acid for most susceptible strains was less than 10 μg/ml as determined by the serial dilution method in broth ; its activity was influenced by the addition of serum and sodium cholate, the inoculum size, and the pH of the medium. It was not effective on the systemic infections due to Staphylococcus aureus and Diplococcus pneumoniae in mice but effective on those due to Escherichia coli and Salmonella typhimurium. It was also effective on the ascending kidney infection with Escherichia coli in rabbits and on prevention of the kidney abscess formation in mice infected with Staphylococcus aureus. β-Hydroxypiromidic acid, the main metabolite of piromidic acid, was more active against most gram-negative bacteria than piromidic acid in vitro and showed outstanding effect in vivo. Synergism of piromidic acid and β-hydroxypiromidic acid was observed in vitro against various bacteria.

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Piromidic acid, a new synthetic antibacterial agent, was absorbed well from intestinal tracts and bacteriologically active substances mainly distributed to liver, kidney and intestinal tracts and excreted into urine and bile in high concentrations. At a dose of 100 mg/kg to rats, mean peak levels were 12 μg/ml in plasma 2-3 hours postadministration, 270 μg/ml in bile from 2 to 3 hours and 570 μg/ml in urine from 3 to 6 hours. The average recovery from bile for 6 hours was 3. 5% and that from urine for 24 hours was 6.0%. The active substances were found in stomach, small intestine, large intestine, liver and kidney at the peak concentrations of 174, 125, 68, 4. 5 and 4.9 μg/g respectively but were undetectable in other organs and tissues tested. The presence of the active substances in liver, kidney and intestinal tracts was also shown by bioautography. In whole body autoradiograms of mice receiving ¹⁴C-piromidic acid, radioactive substances were distributed to almost whole body at O. 5 or 1 hour after administration, decreased significantly at 6 hours and disappeared almost completely at 24 hours. The concentrations of radioactivity were high in urinary bladder and gastro-intestinal tracts, moderate in liver and kidney, and quite low in brain and spinal cord. In a crossover experiment on the plasma levels and urinary excretion of piromidic acid and nalidixic acid in human volunteers, it was found that piromidic acid showed low plasma level and equal urinary excretion as compared with nalidixic acid. Piromidic acid is changed by metabolism in living body into several metabolites. The main metabolite was substance A (β-hydroxypiromidic acid), in vitro antibacterial activity of which was lower against gram-positive bacteria than piromidic acid but higher against gram-negative ones. The active principles of piromidic acid in vivo seems to be substance A and unchanged piromidic acid.

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General pharmacological studies on piromidic acid, a new antibacterial agent, were performed in comparison with nalidixic acid.
By intravenous administration, piromidic acid showed equal or slightly weak effects compared to nalidixic acid with regard to respiration, systemic blood pressure and electrocardiogram in rabbits, cats and dogs, and neuromuscular junction in rats.
By oral administration in mice, piromidic acid showed fairly weaker effects than nalidixic acid with regard to spontaneous and methamphetamine-stimulated locomotion, antagonism against convulsion induced by pentetrazol and strychnine the time of sleeping induced by hexobarbital, and increase of urine volume. By oral administration to dogs, piromidic acid did not show vomiting which was observed in nalidixic acid.
In the experiments with isolated organs, piromidic acid showed weak effects as well as nalidixic acid in relatively high concentrations.
These results suggest that piromidic acid can be used as an oral chemotherapeutic agent with less possibility of undesirable pharmacological side effects than nalidixic acid.

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Toxicological studies on piromidic acid were performed in comparison with nalidixic acid.
In acute toxicity tests in mice and rats, piromidic acid showed low toxicity in both sexes by intravenous, subcutaneous and oral routes. No appreciable toxicities were observed in mice and rats at an oral dose of 5 g/kg, and in dogs and monkeys at an oral dose of 2 g/kg.
In oral subacute toxicity tests in male and female rats, piromidic acid showed no abnormalities except a slight weight increase of liver and kidney at a dose of 3, 200 mg/kg/day, while nalidixic acid showed significant abnormalities at doses more than 800 mg/kg/day.
In oral chronic toxicity tests in male and female rats, piromidic acid showed some toxicities at doses more than 800 mg/kg/day, while nalidixic acid showed significant toxicities even at a dose of 200 mg/kg/ day. β-Hydroxypiromidic acid, a main metabolite of piromidic acid, also showed low toxicity in an acute toxicity test in mice and in a subacute toxicity test in rats. These results suggest that piromidic acid is an oral chemotherapeutic agent with lower toxicities than nalidixic acid.

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Teratological studies on piromidic acid compared to nalidixic acid were carried out with the following results.
Piromidic acid showed no teratogenicity in mice at oral doses of 100 and 5, 400 mg/kg/day, and in rats at oral doses of 100 and 1, 600 mg/kg/day. Nalidixic acid also showed no teratogenicity in mice at oral doses of 73, 220 and 660 mg/kg/day, and in rats at oral doses of 73 and 220 mg/kg/day. However, piromidic acid had less influences on pregnant animals and fetuses than nalidixic acid did.

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Bacteriological and clinical studies on piromidic acid were performed with the following results.
1) Piromidic acid showed fairly broad antibacterial spectrum when sensitivity of clinical isolates was measured by a disc method and an agar dilution method.
2) Piromidic acid was applied to 20 cases in the field of internal medicine at doses of 1.5-3 g/day. The results were good in 18 cases and fairly good in 1 case. No side effects were observed at all.

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Laboratory and clinical studies were performed with piromidic acid, a new synthetic antibacterial agent, with the following results.
1. Piromidic acid showed MIC values of 6.25->100mcg/ml against 23 gram-negative bacilli (Klebsiella, 10; Cloaca, 6; E. coli, 6; Morganella, 1) isolated from respiratory tracts in 1971.β-Hydroxypiromidic acid, a main active metabolite of piromidic acid, was more active than piromidic acid but less active than nalidixic acid. Cross-resistance was observed between piromidic acid, β-hydroxypiromidic acid and nalidixic acid but was not observed between these agents and antibiotics such as chloramphenicol, streptomycin and tetracycline. Piromidic acid showed 2 peaks in sensitivity distribution of 19 strains of Haemophilus influenzae at the concentrations of 12.5 and 50mcg/ml.
2. Piromidic acid was administered at a dose of 2g/day for 5 to 7 days in 9 cases of urinary tract infections, 1 case of acute cholecystitis 1 case of chronic colitis and 2 cases of chronic respiratory infections. The results were excellent or good in all cases except for 1 slightly effective case.

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Piromidic acid (capsule) was used for the treatment of 25 cases of infantile dysentery mainly caused by Shigella sonnei at a dose of about 50 mg/kg/day for about 5 days. Dysentery bacilli disappeared rather slowly in feces and in some cases reappeared following cessation of drug administration.
If the latter cases were regarded as ineffective, the rate of effectiveness was 28%.
No side effects were detected at all.

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Piromidic acid was given at a dose of 500 mg, 3 times a day, to 15 patients mainly suffering from enteritis, cholecystitis and urinary tract infections. Effectiveness was observed in 14 patients (93.3%) without side effects.

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In clinical observations of eight cases treated with piromidic acid satisfactory results were obtained in five cases of urinary tract infections, and one of Salmonella enteric infection. Bacteriological recurrence was occured in one patient of chronic pyelonephritis during the use of piromidic acid, and no response was obtained in the other patient of chronic pyelonephritis. No side effect except anorexia in one case was observed.

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Clinical effect of piromidic acid, a new synthetic antibacterial agent, on dysentery and dysentery-like diseases was studied concomitantly with some in vitro examinations.
The treated cases were totally 31 which consisted of bacillary dysentery (1), carrier state of Shigella strains (6), Salmonella infections (2), dysentery-like diseases where no infecting bacterium was detected (19) and enteritis induced by Vibrio parahaemolyticus (3). Piromidic acid was effective in 27 cases (87.1%) by the oral administration at doses of 40-80mg/kg/day for 5 days. No adverse reactions were observed except for mild nausea (4 cases).
Antibacterial activity of piromidic acid depended on medium pH. The minimum inhibitory concentrations (MIC) of piromidic acid against Shigella and Salmonella strains were mostly 3.13-12.5 mcg/ml at pH 7.5 whereas 0. 78-3.13 mcg/ml at pH 6.0. The MIC values were 2-4 times higher than those of nalidixic acid. β-Hydroxypiromidic acid, a main metabolite of piromidic acid, was more active against these gram-negative bacilli than piromidic acid and almost as active as nalidixic acid.

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Fifteen patients (seven patients were enteritis acuta, two patients were appendicitis acuta and six patients were cholecystitis) were treated with piromidic acid. Piromidic acid was effective in the treatment of seven patients with enteritis acuta, one patient with appendicitis acuta and four patients with cholecystitis, and showed no side effect.

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Piromidic acid is a new antibacterial agent which was synthesized and developed in Japan. It is primarily active against gram-negative bacteria and shows no cross-resistance to antibiotics and synthetic chemotherapeutics other than nalidixic acid. Its clinical usefulness for the treatment of dysentery and dysentery-like diseases was investigated with some fundamental examinations. The results obtained were as follows.
1. The minimum inhibitory concentrations of piromidic acid against most Shigella strains were 6.25-25 mcg/ml, which were 4-8 times higher than those of nalidixic acid. Piromidic acid was less active against the other gram-negative bacteria than nalidixic acid.
2. In comparison with antibacterial activities between β-hydroxypiromidic acid, a main metabolite of piromidic acid, and piromidic acid, the former was 2-4 times more active against Shigella, Salmonella and Pseudomonas strains and pathogenic Escherichia coli, 2 times less active against Vibrio parahaemolyticus and equally active against Plesiomonas shigelloides.
3. After single oral administration of 500 mg of piromidic acid to 5 healthy adult volunteers, an average serum level was 2.7 mcg/ml at 1 hour, 3.2 mcg/ml at 2 hours, 3.1 mcg/ml at 3 hours, 2.9 mcg/ml at 4 hours and 2.6 mcg/ml at 6 hours.
4. Piromidic acid was orally administered to patients of dysentery, carriers of dysentery bacilli and patients of dysentery-like diseases at doses of 30, 40 and 60 mg/kg/day with favorable clinical effects. Efficacy was better at 60 mg/kg/day than at 40 mg/kg/day.
5. No abnormalities were observed in hematological and biochemical examinations after serial administration of piromidic acid to patients for 5 days. Among 40 patients receiving piromidic acid, 1 complained of thirst and 2 nausea and headache. No other adverse reactions were observed.

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Piromidic acid is a new synthetic chemotherapeutics which is active against gram-negative bacteria and Staphylococci. It was used for the treatment of infectious diarrhea with the following results.
1. Piromidic acid improved the symptoms of infectious diarrhea when it was applied to 29 cases at doses of 1-3g/day. Reappearance of the causative bacteria was observed in one case of dysentery and 2 cases of salmonellosis. No side effects were observed at all.
2. Minimal inhibitory concentration (MIC) of piromidic acid against gram-negative bacteria was higher than that of nalidixic acid. However, MIC of β-hydroxypiromidic acid, a main metabolite of piromidic acid, was lower than that of piromidic acid and nearly equal to that of nalidixic acid.

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Piromidic acid was applied to 6 cases of infantile urinary tract infections at a dose of 50 mg/kg/day for 10 to 21 days with favorable clinical effect in all cases. No side effect was observed at all. Piromidic acid was active against Staphylococci differing from nalidixic acid in this respect.

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Piromidic acid is a new synthetic chemotherapeutics developed in Japan on which a series of fundamental and clinical studies in pediatric field were performed with the following results.
1. The minimal inhibitory concentrations of piromidic acid were less than 3. 13 mcg/ml against most strains of Staphylococcus aureus and were less than 12.5 mcg/ml against most susceptible gram-negative bacilli such as pathogenic Escherichia coli and members of the genera Shigella and Salmonella. The drug was active against the bacteria resistant to various antibiotics and synthetic chemotherapeutics but cross-resistance between piromidic acid and nalidixic acid has been observed.
2. Piromidic acid was absorbed well by an oral route. Blood level attained the peak from 3 to 5 hours postadministration and was significantly high even at 8 hours.
3. Piromidic acid was excreted into urine in active form from 1 hour postadministration and recovery for 10 hours ranged from about 1 to 4. 3%.
4. Rather large quantity of piromidic acid was excreted into feces in active form.
5. Oral administration of piromidic acid usually succeeded in therapy of various infantile diarrhea and infantile acute cystitis. The rate of effectiveness was about 70-90% at doses of 50-70 mg/kg/day.
6. No abnormalities were observed in blood analysis, urinalysis, and tests on liver or kidney function, and in digestive system after serial administration of piromidic acid at usual therapeutic doses.

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Piromidic acid (dry syrup) was used for the treatment of 21 cases of acute indigestion in infants. By administration of 61-99 mg/kg/day for 1. 5-4 days, clinical symptoms disappeared in 13 cases and did not in 8 cases. Reduction of the number of bacteria in feces correlated with clinical effectiveness. No significant side effects were seen at all.

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Piromidic acid is a new synthetic antibacterial agent having a pyridopyrimidine ring. Its antibacterial property is similar to that of nalidixic acid but differs from it in activity against Staphylococci. The growth of most clinically isolated Staphylococci was inhibited at the concentrations less than 25 mcg/ml of piromidic acid but not inhibited at the same concentrations of nalidixic acid. Piromidic acid, however, was about 4 times less active against members of Escherichia coli and the genus Proteus than nalidixic acid. Antibacterial activity of piromidic acid especially against Staphylococci was intensified when the culture medium acidified. β-Hydroxypiromidic acid, one of active principles in vivo, showed 2 to 4 times higher activity against Escherichia coli but lower activity against Staphylococci. The average serum level in children receiving 25 mg/kg of piromidic acid attained a maximum of 5. 3 mcg/ml at 4 hours later and was 3. 1 mcg/ml even at 8 hours later. The recovery of piromidic acid from urine for first 8 hours was 12. 1% in average.
Piromidic acid clinically showed effectiveness in 15 of 20 cases of intestinal and urinary tract infections (the rate of effectiveness ; 75%).
The drug was easy to administer and side effects such as nausea and vomiting were not observed. No abnormality was detected by urinalysis, blood analysis and tests on liver function. Proper therapeutic doses of piromidic acid seemed to be 50-100 mg/kg/day in children.

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Piromidic acid, a new antibacterial agent, was used for the treatment of infantile diarrhea at doses of 50-100 mg/kg/day.
The results obtained were as follows.
1. The rate of effectiveness was 76. 4 % in 34 cases consisting of 18 cases of acute indigestion, 13 cases of acute enteritis and 3 cases of acute colitis.
2. Piromidic acid was effective in 87. 5 % on the diseases caused by Escherichia coli and in 66. 6% on those caused by Staphylococcus aureus.
3. By the sensitivity disc method, piromidic acid was active against 90. 9 % of the strains of Escherichia coli and 58.4 % of those of Klebsiella which were freshly isolated from infants suffering from diarrhea.
4. Vomiting was observed in 1 of 34 cases but no other side effects were observed.

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Piromidic acid is a new synthetic antibacterial agent having a pyridopyrimidine ring and primary active against gram-negative bacteria and Staphylococci. A piromidic acid syrup was used for the treatment of 28 cases of infant diarrhea and urinary tract infection at a dose of 50 mg/kg/day (divided into 3-4 doses a day). The effect of piromidic acid was excellent in 21 cases (75%), good in 5 cases (17. 9%) and poor in 2 cases (7. 1%). No side effect was observed in all cases. The syrup preparation of piromidic acid was easy to administer to infants.

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Thirty-five patients of bacillary dysentery and 30 patients of acute diarrheal disease due to pathogenic Escherichia coli were treated with piromidic acid (PA) at the daily dose of 30-50 mg/kg/day orally to children every 6 hours for 7 days.
The following data were obtained.
1. Clinical examination :
a) Out of 12 cases of this bacillary dysentery, 2 cases showed remarkably effective result, while 3 cases showed fairly effective and the other 7 cases had no effective result.
b) Out of 11 cases of this acute diarrheal disease due to pathogenic Escherichia coli, 1 case showed remarkably effective result, while 5 cases showed fairly effective and the other 5 cases had no effective result.
2. In vitro antibiotic activity :
The sensitivity to PA of 35 strains of Shigella sonnei and 30 strains of pathogenic Escherichia coli were studied with plate dilution method. MIC of Shigella sonnei was 3. 12 mcg/ml against 1, 6. 25 mcg/ml against 19, 12. 5 mcg/ml against 11 and 100 ≤ mcg/ml against 4 strains. This 4 strains resistant to MIC 100 ≤ mcg/ml of PA showed 50 ≤ mcg/ml of nalidixic acid (NA).
MIC of pathogenic Escherichia coli was 6. 25 mcg/ml against 5 strains, 12. 5 mcg/ml against 13, 25 mcg/ml against 10 and 100 ≤ mcg/ml against 2. These 2 strains resistant to PA showed MIC ranging from 12. 5 to 50 mcg/ml to NA.
It was also found that PA have cross resistance with NA.
3. Side effect :
Side effects were not recognized in all cases.

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Piromidic acid (dry syrup) was orally used for the treatment of bacillary dysentery and diarrhea in-duced by pathogenic Escherichia coll. Administration was continued for 7 days at a dose of 50 or 100 mg/kg/day.
The results obtained were as follows.
1. Clinical effect
a) Out of 6 cases of bacillary dysentery, effectiveness was observed in 2 cases.
b) Out of 6 cases of acute diarrhea due to pathogenic Escherichia coli, effective results were obtained in 2 cases and was not in the others.
2. Side effect
Anorexia and vomiting observed in 1 case (1. 2%). Kidney and liver seemed to be unaffected according to the measurement of BUN, GOT and GPT.
3. In vitro antibacterial activity
a) Piromidic acid showed the MIC of 6.25 mcg/ml against all the strains (56) of dysentery bacilli. No resistant strains were found.
b) Piromidic acid showed the MIC of 6.25 mcg/ml against 1 strain of pathogenic Escherichia coli and that of 12.5-25 mcg/ml against 16 strains.
c) Cross-resistance was observed between piromidic acid and nalidixic acid.
d) The strains resistance to piromidic acid was observed in ineffective or recurrent cases.

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The biliary excretion and the clinical therapeutic effect of piromidic acid on biliary inflammatory disease were studied. The biliary excretion after a single oral dose of 1, 000-1, 500mg was measured. In a case with relatively normal hepatic function, biliary excretion of piromidic acid was good, biliary concentration reached the peak, as much as 30 times of serum level, at 4 hours after 1, 500mg oral administration. However, biliary excretion delayed in a case with impaired hepatic function, especially in jaundiced patient. Clinical applications were performed to. 10 cases with acute inflammatory disease, 7 cases with post-operative cholangitis, 3 cases with post-operative pancreatitis and 10 cases with gallbladder stone, 30 cases.in total.
The results were excellent in 2, good in 25, ineffective in 1 and undecided in 2. The total effective rate was about 90%. Three patients experienced side of on gastro-intestinal disorders as nausea, vomitting or diarrhoea.

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Piromidic acid, a new antibacterial agent, was applied to acute cystitis in obstetrical and gynecological fields with the following results.
1. Minimal inhibitory concentrations of piromidic acid against most strains of Escherichia coli isolated from urinary tracts were 3.13-6.25mcg/ml. Cross-resistance was not observed between piromidic acid and drugs other than nalidixic acid.
2. Piromidic acid was excreted into urine in 8-10 % and its urine level was high enough to use for urinary tract infections.
3. Good therapeutic results were obtained in the treatment of acute cystitis at doses of 1.5-2.0g/day without detectable side effects.

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Clinical studies on piromidic acid (PA) were carried out, and the results were as follows;
1) Serum concentration and urinary excretion;
Nine adult healthy volunteers took 1.0 g of PA orally. Maximal blood level was 5.6-13.2mcg/ml at 2-4 hours after administration. The urinary recovery for 24 hours was 7.1% on average.
2) Concentration of PA in umbilical cord blood;
No detectable amount of PA was found within the first 2 hours after administration. Thereafter, considerable amount of PA was found in the umbilical cord blood in several cases. Excretion of PA in amniotic fluid and milk was observed in small amount.
3) Clinical effect;
PA was administered to patients with urinary tract infection, and was found to be effective in 6 of 7 cases of Staphylococcal infection and effective in 21 of 31 cases of E. coli infection.
4) Side effect;
No significant side effect was detected but observed mild gastrointestinal disorders in 4 cases.

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The fundamental and clinical studies were performed on piromidic acid, a new synthetic chemotherapeutics, with the following results obtained.
1) Gram-negative bacteria and Staphylococci were sensitive to piromidic acid, but the sensitivity of gram-negative bacteria to piromidic acid was less than that to nalidixic acid.
2) After oral administration of piromidic acid, plasma levels usually attained to a peak at 2 hours and were detectable even at 8 hours. The peak levels were 1/3-1/4 those of nalidixic acid. Recovery of piromidic acid from urine was 4.6% for 6 hours, which was nearly equal to that of nalidixic acid.
3) Piromidic acid was orally administered to 32 female patients with mild urinary tract infections. At a dose of 2g/day (divided into 4 doses), piromidic acid was effective in 20 patients (71.4%) without no special side effect except for a few cases of mild gastro-intestinal disturbance.

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Piromidic acid was orally administered to seventeen outpatients who had acute cystitis, and two of acute pyelitis, with daily dose of 2, 000 mg for seven or more days. Check of the clinical symptoms and laboratory examination of the urine were performed repeatedly before, during and after the medication.
In three out of the total nineteen cases good effect was obtained, and the other fourteen cases showed moderately good effect, while in the remaining two cases no improvement was seen in symptoms and laboratory findings of the urine.
Sensitivity tests on cultured gram-negative bacilli revealed slight to moderate inhibition of the growth.

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Piromidic acid was used for the treatment of 22 cases of female acute cystitis and 10 cases of pyelonephritis at doses of mostly 1.5 g/day for about 10 days. Clinical response was excellent in 21 cases (65.6%), good in 7 cases (21.9%) and poor in 3 cases (9.4%). Vomiting was observed in 1 of the total 32 cases.

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Twenty-eight patients with various urinary tract infections were treated with piromidic acid at doses of 1.5 to 3 g/day for 2 to 28 days. In 8 cases of acute cystitis, the results were excellent in 5 cases and good in 3 cases (the rate of effectiveness : 100%). In 20 cases of chronic urinary tract infections, the results were excellent in 2 cases, good in 11 cases and ineffective in 7 cases (the rate of effectiveness : 65%). The therapeutic effect of piromidic acid was good especially against gram-negative bacilli such as E. coli and Klebsiella, and against Staphylococci.

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Piromidic acid was administered to 30 patients suffering from urinary tract infections at doses of 1. 5 to 2.25 g/person/day for 3 to 9 days. Excellent result was obtained in 5 (4 cases of acute cystitis and 1 case of acute pyelitis) of 6 cases of simple acute urinary tract infections. Among 24 cases of chronic urinary tract infections, good result was obtained in 3 of 19 cases of complicated infections occurring after the operation of lower urinary tracts and during the use of urinary catheter, and in 4 of 5 cases of rather uncomplicated ones. Gastro-intestinal disturbance was observed in 30% as side effects. In a sensitivity disk method, 37 of 44 clinically isolated strains of Escherichia coli were sensitive to piromidic acid.

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Piromidic acid (PA) is a new synthetic chemotherapeutic drug, chiefly composed of pyridopyrimidine ring, the structural formula of which is closely similized to nalidixic acid (NA). In vitro and clinical studies were undertaken to determine its efficacy in simple acute cystitis. The method of clinical evaluations was employed by double blind technique.
1. In vitro studies : The tested strains were 43 gram negative rods, which had been isolated from infected urine specimens, in addition, 2 standard strains, E. coli O-111, E. coli NIHJ. The MIC of PA against those strains was generally higher than that of PA-OH (β-hydroxypiromidic acid, one of the metabolites of PA) or NA. Against E. coli group strains and about a half of indol negative Proteus and Klebsiella strains, the sensitivity to PA was mostly ranged to 6. 25-25 mcg/ml. However many strains-Rettgerella, Morganella and Pseudomonas-were resistant to PA, PA-OH and NA. It was interesting that PA-OH showed more antimicrobial effect than that of PA in vitro. The MIC of PA-OH against the tested strains was generally ranged in between that of PA and of NA.
2. Clinical studies : Fifty four cases of simple acute cystitis were chosen for clinical investigations of PA or NA. Of 54 cases, 32 were treated with PA, and the rest 22, with NA. The clinical results of 32 cases treated with PA were 17 (85%) excellent, 3 failure, and 12 indeterminate after 8 days administration of the drug.
In the 22 NA treated cases, the results were 11 (84. 6 %) excellent, 2 failure, 9 indeterminate. No difference in the clinical efficacy between PA and NA was experienced. No remarkable side effects were noted except temporary mild gastric discomforts in 5 of 32 PA treated group, and 2 of 22 NA treated group. The relapse occurred in 3 of 19 PA treated cases (15.8%), and in one of 15 NA cases (6.8%) within 3 weeks after the discontinuance of the drug.

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Piromidic acid is a chemotherapeutic agent which is active against gram-negative bacilli and staphylococci. In vitro antibacterial activity, plasma and urine levels and clinical effects were investigated with the following results.
1. The MIC of piromidic acid against Escherichia coli and Staphylococci isolated from urinary tracts mainly ranged 12.5-25mcg/ml and 6.25-12.5 mcg/ml respectively.
2. The peak levels were obtained in plasma 2-4 hours postadministration and in urine 4-6 hours.
3. Effectiveness was observed in 86.2% of 29 cases of acute uncomplicated urinary tract infections by administration of piromidic acid at daily doses of 2-2.25g for 3 days.
4. Gastro-intestinal disturbances were observed in 20.7% of these cases.

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Clinical studies on piromidic acid were carried out with the following results.
1. Piromidic acid was orally administered to 93 patients with simple acute cystitis at a dose of 1. 5 or 3 g/day for 3 days. The results were effective in 81 cases and ineffective in 4 cases, except for 8 cases in which the effectiveness was unable to evaluate (the rate of effectiveness : 87.1%). This clinical effect was almost equal to that reported in nalidixic acid. There was no marked difference in clinical effects between 2 dosage groups of 1. 5 and 3 g/day.
2. Minimal inhibitory concentrations (MIC) of piromidic acid and β-hydroxypiromidic acid, a main metabolite of piromidic acid, against clinical isolates were determined by an agar dilution method, and the correlation between MICs and clinical effects was investigated. The MIC of β-hydroxypiromidic acid seemed to correlate well with the clinical effects.
3. Antibacterial activity in urine was measured 2-3 hours postadministration and its relationship to clinical effects was investigated. Effectiveness was observed in all cases with high urinary antibacterial activity.
4. Recurrence was observed in 2 of 27 effective cases as checked at 1 week after discontinuation of drug administration.
5. Side effects were observed in 12 of total 93 cases which were mainly mild gastro-intestinal disturbances.

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Piromidic acid was orally administered to 13 patients with urinary tract infections at a dose of 2. 25 g/day for 7 days. The drug was effective in 11 patients and ineffective in 1 patient. One case was excluded due to the discontinuation of drug administration.

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Piromidic acid was given to the 25 patients with urinary tract infections. In 11 cases with acute urinary tract infections, piromidic acid was highly effective in all cases. In chronic urinary tract infections, consisted of 6 cases with chronic cystitis and 8 cases with chronic pyelonephritis, piromidic acid was effective in 6 cases. Subjective side effects were observed in 4 cases.

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A double-blind drug trial comparing piromidic acid and lactose in 30 patients with acute noncomplicated cystitis or urethrocystitis was done. Fourteen of sixteen patients benefited from piromidic acid treatment and 7/14 from placebo group. In only 1 case treated with piromidic acid slight diarrhea was observed.
Minimum inhibitory concentrations of piromidic acid against 52 organisms isolated from the clinical cases mostly ranged between 3.12 mcg/ml and 12.5 mcg/ml. Activity of β-hydroxypiromidic acid (metabolic substance of piromidic acid) against the organisms was slightly higher than that of former. Activity of piromidic acid against anaerobes was proved to be low.

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Piromidic acid was administered to the twenty-two patients with urinary tract infection and the following results were obtained.
1. Twelve cases with uncomplicated urinary tract infections and ten cases with complicated ones were treated mostly with oral administration of 1. 5 grams of PA for one week. Effectiveness was recognized in eightythree per cents in the former group and sixty per cents the latter.
2. Twenty one strains of microorganism were isolated from urine specimens of twenty cases. Two thirds of them showed disappearance from urine after treatment.
3. When 1 gram of PA was orally administered to the two persons with normal renal function, the blood level reached the peak in two to four hours and the urine level in four to six hours. No concentration of PA was recognized after twelve hours in blood and after twenty-four hours in urine.
In contrast, when the person of renal insufficiency was tested in the same manner, PA still remained at the concentration of a half of the maximum. The blood level, however, decreased in normal fashion when he was treated with hemodialysis.
4. As to side effect, only one case of slight gastrointestinal disorder was noted. And no ill effects on routine laboratory findings were noted.
5. PA was thought to be recommended as the therapeutics to urinary tract infection.

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Piromidic acid, a new synthetic antibacterial agent, was applied orally to simple and complex urinary tract infections. The results were excellent in 21 and good in 1 among 22 cases of simple urinary tract infections (the rate of effectiveness : 100%), and excellent in 2, good in 3 and ineffective in 2 among 7 cases of complex ones (the rate of effectiveness : 71. 4%). The in vitro antibacterial activity against the pathogenes isolated in these cases was measured by an agar dilution method. The activity of piromidic acid was superior against Staphylococcus aureus, almost equal against Escherichia coli and inferior against the strains of the genera Proteus and Klebsiella to that of nalidixic acid. Side effects were not observed in all cases at all.

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The clinical effect of piromidic acid was compared to nalidixic acid by a double-blind controlled trial. Among the 114 cases of acute uncomplicated cystitis which fitted in predetermined conditions, 53 cases happened to be assigned to piromidic acid and 61 cases to nalidixic acid. The data were analysed by a chi-square test or FISHER exact probability test with the following results.
There were no significant differences (P>0.05) between piromidic acid and nalidixic acid in whole clinical effect, the rate of excellent effect, the effect against gram-negative bacteria, disappearance of bacteria and leucocytes in urine, normalization of pollakiuria, disappearance of a miction pain and side effects.

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Piromidic acid (dry syrup) was administered at a dose of 50mg/kg/day for the treatment of infantile urinary tract infections. The rate of effectiveness was 100% in 5 cases of uncomplicated urinary tract infections and 67% in 15 cases of complicated ones. No untoward effects were noticed at all.

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Piromidic acid (abbreviated as PA) was applied to treatment of urinary tract infections.
1) Disc-sensitivity of PA and nalidixic acid (abbreviated as NA) was tested on clinical isolates from urinary tract. Gram positive cocci (68 particles) were more sensitive to PA than NA, but gram-negative bacilli (102 particles) were more sensitive to NA. But, Enterococci (17 particles) and Pseudomonas (17 particles) were little sensitive to PA and NA.
2) Twenty-nine cases of urinary tract infections (6 pyelonephritis, 23 cystitis) were treated with PA (0. 75-2. 25 g/day). Of 29 cases, 13 showed excellent, 7 showed fair and 9 showed no response. Acute and simple infected cases showed excellent response, but chronic and complicated cases (combined infection with urinary stone, neurogenic bladder et al.) showed little response.
3) Little relation was found between sensitivity of clinical isolates to PA disc and clinical effects, but clinical effects were shown some relation with sensitivity of pathogenic organisms which were decided by bacterial count and clinical course.
4) Side effect : seven patients complained gastrointestinal disorders and headache.

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Piromidic acid, a new synthetic antibacterial agent, was applied to 26 in-and out-patients suffering from simple or complicated genito-urinary infections. The drug was orally administered at doses of 1, 500-2, 250 mg/person/day for 7 days. Effectiveness was confirmed in 9 of 13 cases of the simple infections and in 6 of 13 cases of the complicated ones. Escherichia coli, a main causative bacterium, responded well to the drug. Gastric disturbance was observed in 2 cases, in one of which administration was discontinued.

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A double blind comparative study was made on piromidic acid (PA) and nalidixic acid (NA) for adults of 153 nonspecific acute cystitis in the Department of Urology, Kyusyu University, and other 11 hospitals. PA and NA were administered orally 2 g/day for 5 days respectively.
Fifty-eight cases were treated with PA and 56 (96. 5%) responded, whereas 61 were treated with NA and 60 (98. 3%) responded.
Side effect was observed in 11. 8% (PA) and 15. 1% (NA). Concerning the effect and side effect, there was no statisically significant difference between these two drugs.
It was evaluated that PA had excellent effect on the nonspecific acute cystitis.

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