Renal specific delivery of sulfamethoxazole in the rat by coupling to the low molecular weight protein lysozyme via an acid-sensitive linker

Sulfamethaxazole (SM) was converted to a renal specific drug targeting preparation by coupling the drug to egg-white lysozyme via an acid-sensitive cis-aconityl linker (1:1). Due to this chemical manipulation SM was rapidly distributed to the kidney. Both in vitro and in vivo data indicate that SM was uncoupled from the carrier by chemical hydrolysis in the lysosomes of proximal tubular cells, resulting in parent active drug at the target site. This concept is applicable to other drug-polypeptide conjugates which rapidly distribute to the kidney and might enable selective manipulation of renal (patho)physiology.     

A phase II study of chloroquinoxaline sulfonamide (CQS) in patients with metastatic colorectal carcinoma (MCRC)

Summary Purpose: Phase II multicenter study investigated the efficacy and toxicity of the novel halogenated derivative of sulfaquixonaline Chloroquinoxaline Sulfonamide (CQS) in metastatic colorectal cancer. Experimental design: Eligible patients with metastatic or recurrent colorectal cancer received CQS at a dose schedule of 2000 mg/m² over an hour weekly for 4 weeks every 42 days. Treatment was continued until unexpected toxicity or disease progression. Results: A total of seventeen patients were enrolled on this study. 94% of all patients enrolled had prior treatment. Sixteen patients were evaluable for response with fifteen patients showing evidence of disease progression and one patient with prolonged stable disease. One patient had non-evaluable disease. Following this interim analysis, the drug was considered ineffective and the study was terminated early. The most frequent adverse event was anemia. No patients discontinued the treatment because of toxicity. Conclusion: CQS, when given at a dose of 2000 mg/m² weekly for 4 weeks every 42 days to patients with metastatic colorectal cancer, does not result in significant tumor regression.     

Synthesis and cytotoxicity of new aromatic ceramide analogs with alkylsulfonamido chains

A series of D-erythro ceramide analogues, N-(2S, 3R, 4E)-1, 3-dihydroxy-5-phenyl pent-4-en-2-yl alkyl sulfonamides, were synthesized and evaluated for their in vitro cytotoxic activities against five human tumor cell lines. The aromatic sulfon amido ceramide analogue (10f) showed more potent cytotoxic activity than that of the B13, indicating that a sulfonamide group appears to serve as a bioisostere of an amide in drug design. Variations in the alkyl sulfonyl chain length significantly influenced the cytotoxic activity of the sulfonamido ceramide analogues, but the introduction of a para halogen on the phenyl ring of aromatic ceramide analogues had no affect on the activity.     

Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation

Background and purpose

Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. The aim of this study was to evaluate the antitumor activity of a high CAIX-affinity indanesulfonamide (11c) combined with irradiation, compared with the general CA inhibitor acetazolamide (AZA).

Material and methods

HT-29 carcinoma cells with or without (genetic knockdown, KD) CAIX expression were incubated with 11c/AZA under different oxygen levels and proliferation, apoptosis and radiosensitivity were evaluated. 11c/AZA was administered intravenously (1×/day; 5 days) to tumor-bearing mice and tumor irradiation (10 Gy) was performed at day 3 of the injection period. Tumor growth and potential treatment toxicity were monitored (3×/week).

Results

Treatment with 11c/AZA alone resulted in tumor regression, which was further increased in CAIX expressing cells by combining 11c with irradiation. AZA demonstrated also an additional effect in the KD tumors when combined with irradiation. CAIX inhibition in vitro significantly reduced proliferation and increased apoptosis upon hypoxia exposure without affecting intrinsic radiosensitivity.

Conclusions

Specific inhibition of CAIX activity enhanced the effect of tumor irradiation and might, therefore, be an attractive strategy to improve overall cancer treatment.     

Determination of sulfamonomethoxine in tilapia (Oreochromis niloticus × Oreochromis mossambicus) by liquid chromatography-tandem mass spectrometry and its application pharmacokinetics study

A precise and reliable analytical method to measure trace levels of sulfamonomethoxine (SMM) and N⁴-acetyl metabolite in tilapia samples using liquid chromatography-tandem mass spectrometry was developed. Optimized chromatographic separation was performed on C18 reversed-phase columns using gradient elution with methanol and 5 mmol/L of an ammonium acetate aqueous solution (adjusted to pH 3.5 using formic acid). This study investigated the pharmacokinetic properties and tissue distribution of SMM and its major metabolite N⁴-acetyl sulfamonomethoxine (AC-SMM) in tilapia after a single dose of 100 mg kg^?1 body weight of orally administered SMM. Blood and tissues were collected between 0.5 and 192 h with 14 total sampling time points. SMM was rapidly absorbed, and extensively distributed in the bile and liver through systemic circulation. Enterohepatic circulation of SMM was observed in the tilapia body. Acetylation percentages were 45% (blood), 90% (liver), 62% (kidney), 98% (bile), and 52% (muscle). High concentrations of AC-SMM accumulated in the tilapia bile. At 192 h, AC-SMM concentration in the bile remained at 4710 μg kg^?1. The k_e value of AC-SMM (0.015 h^?1) in the blood was lower than that of SMM (0.032 h^?1). This study demonstrated effective residue monitoring and determined the pharmacokinetic properties of SMM and AC-SMM in tilapia.     

Zur Pharmakodynamik von zwei neuen Sulfonylharnstoffderivaten

Zusammenfassung Das Verhalten zweier neuer im Milligrammbereich wirksamer Sulfonylharnstoffderivate — Gliquidon und Gliflumid — wurde an stoffwechselgesunden Normalpersonen geprüft und der Reaktion von Tolbutamid und Glibenclamid gegenübergestellt. Äquipotenzdosen auf der Basis der ED 30 wurden sowohl für die intravenöse als auch für die orale Applikation erstellt.Es zeigte sich, daß Gliquidon gemessen an seiner Insulinsekretionsdynamik eine tolbutamidähnliche Wirkungscharakteristik besitzt, während Gliflumin glibenclamidähnlich reagiert. Die Verzögerung der Insulinsekretion ist nach Gliflumid noch ausgeprägter als nach Glibenclamid. Unterschiede der Insulinsekretion ergeben sich allerdings nur für die intravenöse Applikation. Bei oraler Gabe finden sich kaum nennenswerte Insulinanstiege im peripheren Blut.     

Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a]pyrimidines

New series of sulfonamide derivatives of [1,3,4]thiadiazolo[3,2-a]pyrimidine were synthesized and investigated as antitumor agents. Some of the newly prepared compounds were tested for their in vitro and in vivo antitumor activities. Preliminary biological studies revealed that compounds 4c, 4f, and 4j exhibited the highest affinity to DNA, while compounds 4h,i, 6a-c, 8 and 12-14 exhibited moderate activity. Also, compounds 4j, 4f and 4c showed the highest percentage increase in lifespan of mice inoculated with Ehrlich ascites cells over 5-flurouracil (positive control). The detailed synthesis, spectroscopic and biological data are reported.     

Abhängigkeit der Speichelkonzentration körperfremder Stoffe von der Blutwasserkonzentration an dem Modell von fünf Sulfonamiden

Zusammenfassung Es wurde die Ausscheidung von fünf Sulfonamiden in den menschlichen Speichel untersucht. Die Speichelkonzentration weicht erheblich ab von der Konzentration im Blutwasser. Die Art der Ausscheidung im Vergleich zu anderen Körperräumen wurde betrachtet und die für die Speichelausscheidung der Sulfonamide verantwortlichen Faktoren wurden diskutiert. Als bestimmend wurde wegen des Speichelflusses (offenes System) in erster Linie der Dissoziationsgrad der Sulfonamide herausgestellt. Für Sulfacetamid konnte ein Abbau im Organismus nachgewiesen werden. Es besteht eine feste Relation zwischen Blutwasser- und Speichelkonzentration, die nach Festlegung des jeweiligen Quotienten von der Speichelmessung verbindliche Rückschlüsse auf die Blutwasserkonzentration erlaubt.     

克林霉素磷酸酯阴道凝胶与磺胺乳膏治疗细菌性阴道炎疗效比较

目的：比较克林霉素磷酸酯阴道凝胶与磺胺乳膏治疗细菌性阴道炎的疗效。方法：使用随机双盲试验,纳入无妊娠、无哺乳、16岁以上有细菌性阴道炎的患者,使用7 d克林霉素磷酸酯阴道凝胶与磺胺乳膏,治疗完成后5-10d及25-39d随访。结果：在25-39d随访时,80名接受克林霉素磷酸酯阴道凝胶患者中的70名,78名接受磺胺乳膏患者中的38名治愈或缓解（ P＜0．05）。大部分的差异出现在有病史组。副作用发生率在两组间无差异。结论：克林霉素磷酸酯阴道凝胶治疗细菌性阴道炎的疗效优于磺胺乳膏。     

Synthesis and antimalarial activity of sulfonamide chalcone derivatives

A series of sulfonamide chalcone derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation in vitro and their activity against cultured Plasmodium falciparum parasites. Inhibition of beta-hematin formation was minimal in the aromatic ring of the chalcone moiety as it appeared for compounds 4b, 4d-f, and greatest with compounds 4g (IC50 0.48 microM) and 4k (IC50 0.50 microM) with a substitution of 3,4,5-trimethoxyl and 3-pyridinyl, respectively. In this study, the most active compound resulted 1[4'-N(2',5'-dichlorophenyl) sulfonyl-amidephenyl]-3-(4-methylphenyl)-2-propen-1-one 4i, effective as antimalarial by the inhibition of cultured P. falciparum parasites (1 microM). These studies open up the novel possibility of development of sulfonamide derivatives as antimalarials that target beta-hematin formation and the inhibition of the development of cultured P. falciparum parasites, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that chalcones exert their antimalarial activity via multiple mechanisms.