Development of amino- and dimethylcarbamate-substituted resorcinol as programmed cell death-1 (PD-1) inhibitor.

Blockading the interaction of programmed death-1 (PD-1) protein with its ligands (PD-Ls, such as PD-L1) was proved to be a pathway for suppressing the development of tumors and other degradations of biological species. Thus, finding PD-1 inhibitors situated at the convergence point of drug discovery. In addition to some monoclonal antibodies applied to treat cancers clinically, the screening of organic molecules for hindering the interaction of PD-1 with PD-L1 became an efficient strategy in the development of PD-1 inhibitors. We herein applied resorcinol and 3-hydroxythiophenol as the core to link with N,N-dimethylcarbamate and other alkyl-substituted amines to afford 13 amine-appended phenyl dimethylcarbamates (AAPDs). The test for blockading the combination of PD-1 with PD-L1 revealed that abilities of 13 AAPDs were higher than that of sulfamethizole, a successful PD-1 inhibitor. In particular, large hydrophobic substituents at amine moiety or a nitro at resorcinol skeleton enhanced the inhibitory effect of AAPD even higher than that of sulfamethoxypyridazine, another successful PD-1 inhibitor. The present results may provide valuable information for further investigation on synthetic PD-1 inhibitors.

In vitro susceptibility of Mycobacterium avium to a new macrolide (RU-28965).

The in vitro susceptibility of Mycobacterium avium to RU-28965 alone and in combination with rifampin, isoniazid, and sulfametoxipiridazine was studied by the agar dilution method. The synergistic effect of the RU-28965 with rifampin has been demonstrated. At a concentration of 16 micrograms/ml or lower of RU-28965, 100% of M. avium strains were inhibited. If 2 micrograms/ml of rifampin is added the MIC of RU-28965 is lowered to 0.25 microgram/ml.

Postnatal development and inducibility of renal tubular transport processes in rats.

The reason for the immaturity and for the time course of postnatal development of renal tubular transport of organic anions was studied, measuring age differences in renal tubular transport of p-aminohippurate (PAH) under various experimental conditions. In principle, PAH transport can be stimulated by repeated administration of weak organic anions, which were eliminated by the carrier system for weak organic anions. However, there is nearly no effect in neonatal rats. Pretreatment with thyroid hormones can enhance the low tubular transport capacity of young rats, too. Pretreatment with dexamethasone is preferentially effective in 5- to 15-day-old rats. The data indicate the involvement of hormonal regulation in postnatal development of renal tubular transport of PAH.

Enhancement of p-aminohippurate accumulation in renal cortical slices after repeated administrations of various organic anionic drugs to rats of different ages.

After repeated administrations of various organic anionic drugs to rats of different ages, an enhancement of paminohippurate accumulation was observed in renal cortical slices from adult but not from newborn and infant rats. The effect can be interpreted as specific substrate-induced stimulation of the organic anion transport.

The effect of sulphamethoxypyridazine on liver and plasma levels of vitamin A in rats.

1 Long-acting sulphonamides are highly bound to plasma proteins; the present study deals with the effects of this binding property upon a vitamin A compound also transported by plasma proteins. 2 Sulphamethoxypyridazine was administered in rats either orally or by intraperitoneal injection. 3 A significant fall in plasma vitamin A level and an increase in hepatic vitamin A concentration were observed. 4 These results suggest an interference by sulphamethoxypyridazine with the transport of vitamin A, either through competition between the drug and vitamin A for binding sites of plasma proteins, or through altered secretion of the vitamin from the liver.

Sensitivity of Neisseria meningitidis to sulfonamides and antibiotics. In vitro trials on 302 strains isolated during the Brazilian epidemic of 1974.

During the recent epidemic of meningitis in Brazil, 1974, bacteriological and antibiotic sensitivity investigations were performed on 302 strains of Neisseria meningitidis, isolated from meningitis patients from the São Paulo and Rio de Janeiro districts in the first half of 1974. The experiments have shown that 58% of the strains belong to the serological type A, 25% belong to type C and the remaining 17% to a group designated 'untypable' in that they did not react with the diagnostic antisera A, B, C, and D. Antibiotic sensitivity tests in vitro have made evident that, independently of the serological type, 89.8% of the 302 strains were inhibited by 10 mug/ml of a long-acting sulfonamide (sulfamethoxypyrazine, SMP), that is, by levels easily reached in the CSF during a normal prophylactic or therapeutic treatment.

[Observations on the sensibility of many chemical antibodies on the blocks of the Mimeae isolated during the acute respiratory affections (author's transl)]. / Osservazioni relative alla sensibilitá di alcuni chemio-antibiotici nei confronti di ceppi di Mimeae isolate nel corso di affezioni respiratorie acute

The AA. studied the sensibility of 7 stocks of Mimeae isolated from subjects with acute respiratory affections against numerous chemical antibodies. The observed that the examined stocks were sensibility resistent to usual antibiotic employed but with a great variability of antwort among the single stocks.

[Sensitivity to dapsone, sulfamethoxypyridazine and ethionamide of mycobacterium leprae taken from patients treated by the drugs]. / Sensibilité envers la dapsone, la sulfamethoxypyridazine et l'éthionamide, de Mycobacterium leprae provenant de malades traités par ces substances

Suspensions of M. leprae from skin biopsies of patients treated with dapsone (DDS) (four cases), sulfamethoxypyridazine (SMP) (six cases), and ethionamide (ETH) (seven cases), were inoculated into mouse foot pads and their sensitivity for the different drugs determined. Two strains were DDS resistant. Resistance appeared after 13 and 14 years respectively after the start of treatment. Five strains were isolated from patients treated with SMP. Relapses during sulfonamide treatment are considered to be due to the low effective serum concentrations reached by SMP, a situation which is aggravated by irregularities in drug intake. Fortunately all strains were sensitive to SMP and DDS as well. Four strains were ETH resistant. ETH resistance at the present moment reaches 4% and appeared in two cases six years after the start of treatment. It is concluded that SMP is not indicated for the treatment of multibacillary leprosy and that ETH can be used only in association with other drugs during the introductory phase of treatment of multibacillary forms of leprosy.

[Effect of corticosteroids on the enzymatic activity of hepatic tissue]. / Vliianie kortikosteroidov na aktivnost' fermentov pechenochnoi tkani

Tests conducted with rats demonstrated that hydrocortisone and desoxycorticosterone-acetate (DOCA) manifest an effect close by its orientation with regard to mitochondrial and extramitochondrial forms of aspartate- and alanine-aminotransferase (ACT and ALT), as well as cytoplasmatic malate-dehydrogenase (MDG) of the liver. It was only mitochondrial MDG that lent itself to be inhibited by hydrocortisone, but it was induced by DOCA. Adrenalectomy resulted in inhibition on ALT and MDG and in activation of ACT and of mitochondrial LDG. A course-wise introduction of sulphapyridazine with an excess of deficiency of corticosteroids changed the effects of hydrocortisone with respect to cytoplasmatic LDG, as well as the effects of DOCA or adrenalectomy in regard to LDG and MDG.

[Study of the sensitivity of Halprowia (microorganisms of the OLT group) isolated in joint pathology to antibiotics and sodium sulfapyridazine in in ovo experiments]. / Izuchenie chuvstvitel'nosti gal'provii (mikoorganizmov gruppy OLT), vydelennykh pri sustavnoi patologii, k antibiotikam i sul'fapiridazinu natriia v opyrakh in ovo

Sensitivity to antibiotics and sodium sulfapiridasin of the microorganisms of group OLT, i. e. Halprowia and Chlamidia isolated from the joint fluid and synovial of the affected joints in patients with rheumatoid or non-specific infectious arthritis and Raiter syndrome was studied in ovo. The data provided determination of the spectrum of their sensitivity to various drugs. The antibiotics of the tetracycline group, i. e. olemorphocycline, tetracycline and rondomycin were shown to have the highest inhibitory effect. Penicillin and ampicillin only delayed the death of the infected embryons. As for kanamycin and streptomycin used in the doses tested, the agents were not sensitive to them. The isolates were also resistant to sodium sulfapiridasin which once more confirmed the questionable value of this criterion for differentiation of Halprowia.

[Stimulation of renal excretion of p-aminohippuric acid by repeated administration of drugs in young and adult rats]. / Stimulierung der renalen Ausscheidung von-Aminohippursäure durch wiederholte Zufuhr von Pharmaka bei jungen und erwachsenen Ratten

The velocity of renal excretion of p-aminohippuric acid (PAH) could be raised by repeated administration of phenol red, probenecid and penicillin, which are actively transported by the acid carrier into the urine like PAH. These drugs produced an effect in fairly lower doses than PAH. The renal excretion of PAH can be accelerated by repeated pretreatment with the lipid-soluble drugs sulfaclomide, sulfamethoxypyridazine and cyclopenthiazide. It could be demonstrated that the stimulation of renal excretion of PAH by repeated administration of the investigated compounds is less pronounced in young rats than in adult animals.