Block of single cardiac Na+ channels by antiarrhythmic drugs: The effect of amiodarone,propafenone and diprafenone

Summary Cell-attached patch-clamp experiments were performed in cultured cardicyytes of neonatal rats at 19°C to analyze elementary currents through single Na⁺ channels under control conditions and in the presence of the class 1 antiarrhythmic drugs amiodarone, propafenone, and diprafenone. As observed in a cell-attached patch with only one functioning Na⁺ channel, repetitive stepping of the membrane at 0.4 Hz triggered periodically channel openings except during a silent period of about 1.5 min. The latter began and ceased abruptly and did not fit the monoexponential distribution of the run length of sweeps without activity (blank sweeps). Treating the cardiocytes with amiodarone, propafenone or diprafenone (10 to 20 mol/liter) led rapidly to a blockage and reduced the likelihood that membrane depolarization triggers the opening of Na⁺ channels. The number of blank sweeps increased at the expense of the number of sweeps with activity. The fraction of activity sweeps with superpositions, indicating the simultaneous activation of two or more Na⁺ channels, also declined. As tested with amiodarone, the run length of blank sweeps is voltage- and time-dependent, analogous to the intensity of the block of macroscopic Na⁺ currents. Open time, open-time distribution, unitary current size and the tendency to reopen did not differ in unblocked cardiac Na⁺ channels (i.e. that channel fraction capable of opening in the presence of amiodarone or propafenone) from the respective control values obtained before superfusing the cardiocytes with these drugs. Apart from its blocking action, the propafenone derivative diprafenone exerted additionally a modifying effect and reduced mean open time by up to 45%. In contrast to the block, this reduction in conducting state proved insensitive to changes in holding potential, at least between –130 and –150 mV, the range tested. This means that block was attenuated on hyperpolarization whereas the reduction in open time persisted. It is concluded that, in the presence of these drugs, unblocked cardiac Na⁺ channels share a number of properties with normal Na⁺ channels in the absence of these drugs. Shortening of channel lifetime by diprafenone may be indicative of a channel modification brought about possibli by a receptor-mediated facilitation of the transition from the open to the inactivated state.     

In vitro multitarget activity of sulfadiazine substituted triazenes as antimicrobial,cytotoxic, and larvicidal agents

Multidrug resistance (MDR) causes difficulties in the treatment of infections and cancer. Research and development studies have become increasingly important for the strategy of preventing MDR. There is a need for new multitarget drug research and advancement to reduce the development of drug resistance in drug-drug interactions and reduce cost and toxic effects. This study aimed to determine the effects of multi-target triazene compounds on antibacterial, antifungal, antiviral, cytotoxic, and larvicidal activities were investigated in vitro. A series of 12 novel of 1,3-diaryltriazene-substituted sulfadiazine (SDZ) derivatives were synthesized, and the obtained pure products characterized in detail by spectroscopic and analytic methods (FT-IR, ¹H-NMR, ¹³C-NMR, and melting points). The antibacterial and antifungal activities of these derivatives (AH1-12) were determined by broth microdilution method. All derivatives have been evaluated in cell-based assays for cytotoxic and antiviral activities against Modified Vaccinia Virus Ankara. The larvicidal efficacy of these chemical compounds was also investigated by using Lucilia sericata (L. sericata) larvae. Twelve 1,3-diaryltriazene-substituted SDZ derivatives (AH1-12) were designed and developed as potent multitargeted compounds. Among them, the AH1 derivative showed the most antibacterial and antifungal activity. Besides, synthesized derivatives AH2, AH3, AH5, and AH7 showed higher antiviral activity than SDZ. All synthesized derivatives showed higher cytotoxic activity than SDZ. Also, they showed larvicidal activity at 72 h of the experiment. As a result, these compounds might be great leads for the development of next-generation multitargeted agents.     

国产利妥昔单抗治疗弥漫大B细胞淋巴瘤的疗效及安全性

摘要 目的：探讨弥漫大B细胞淋巴瘤患者采用国产利妥昔单抗为基础的化疗方案的疗效及安全性。方法：回顾性分析2020年3月至2022年5月份在安徽省第二人民医院血液内科诊治的弥漫大B淋巴瘤患者31例,均接受国产利妥昔单抗为基础的联合方案化疗,其中非生发中心来源的弥漫大B细胞淋巴瘤患者25例,生发中心来源的弥漫大B细胞淋巴瘤患者6例。21~28 d为一个疗程,这些患者至少接受2~8个疗程的联合化疗,并且2个疗程以后进行疗效评估及不良反应监测。结果：①本研究31例弥漫大B细胞淋巴瘤患者接受利妥昔单抗为基础的联合化疗方案治疗后,疗效评估为完全缓解CR 16例（51.6%）,部分缓解PR 10例（32.3%）,疾病稳定SD 2例（6.5%）,疾病进展PD 3例（9.7%）,总体反应率ORR 83.9%。②31例弥漫大B细胞淋巴瘤患者接受国产利妥昔单抗治疗后,常见的不良反应发生率依次为：血液学毒性29.0%（9/31）,包括中性粒细胞减少、血小板减少等等。其次为感染19.4%（6/31）、消化道症状16.1%（5/31）,包括腹痛、腹泻、便秘等等。所有常见不良反应经过对症处理后均可好转。仅有1例患者发生过敏反应3.2%（1/31）,1例患者因病情严重而死亡。结论：国产利妥昔单抗在弥漫大B细胞淋巴瘤患者的治疗中具有良好的临床疗效及安全性,不良反应较少,值得进一步探讨和应用。     

Marked enantioselective protein binding in humans of ketorolac in vitro: Elucidation of enantiomer unbound fractions following facile synthesis and direct chiral hplc resolution of tritium-labelled ketorolac

The protein binding of the enantiomers of the nonopiate analgesic, ketorolac, was investigated in vitro using human plasma and solutions of human serum albumin (HSA) at physiological pH and temperature. In order to detect the very low levels of unbound enantiomers in protein solutions, tritium-labelled rac-ketorolac was synthesised by regiospecific isotopic exchange of the parent drug with tritiated water as the isotope donor. Radio-chemical purification of this compound by reversed-phase HPLC followed by direct resolution using a chiral α₁-acid glycoprotein (Chiral-AGP) HPLC column afforded labelled enantiomers of high specific activity. The in vitro use of (R)- and (S)-[³H₄]ketorolac enabled reproducible radiometric detection of enantiomers in protein solution ultrafiltrate. The unbound fractions of (R)- and (S)-ketorolac [fu(R) and fu(S), respectively] were determined when drug was added to various plasma or albumin solutions as either the separate enantiomers or as the racemate. Over an enantiomeric plasma concentration range of 2.0—15.0 μg/ml, fu(S) (mean range: 1.572—1.795%) was more than 2-fold greater (P < 0.001) than fu(R) (mean range: 0.565—0.674%). Both fu(R) and fu(S) were constant over this concentration range, and each was unaffected by the presence of the corresponding antipode (P > 0.05). At a concentration of 2.0 μg/ml in 40.0 g/liter fatty acid-free HSA, fu(R) and fu(S) were approximately 0.5 and 1.1%, respectively, and both values declined with increasing concentrations of the long chain fatty acid, oleic acid. We have previously shown that the pharmacokinetics of ketorolac in humans are markedly enantioselective and suggest in this report that these differences are largely the result of substantial differences in the protein binding of ketorolac enantiomers. These findings stress the importance of monitoring the unbound concentrations of the enantiomers of chiral drugs if correct interpretations are to be made of enantioselective pharmacokinetic data. © 1994 Wiley-Liss, Inc.     

A Randomized Double-Blind Crossover Study of the Antiobesity Effects of Etiocholanedione

Etiocholanedione (ED), a natural metabolite of dehy-droepiandrosterone, has antiobesity effects in animals when given orally and is nontoxic. We carried out a trial of oral ED in obese humans. In a 20-week randomized double-blind crossover study, 14 subjects lost significantly more weight and body fat during treatment with oral ED, 4 gm daily, than during placebo administration. Mean weight loss during ED administration was 2.8 ± 5.5 kilograms, which was equivalent to 0.53 k 0.91 kilograms per week per 100 kilograms of body fat; mean weight change during placebo administration was essentially zero: M.21 ± 4.2 kg, or 4.04 ± 0.74 kg/wk/100 kg body fat. The difference between the weight changes in the two periods was significant: for A kg, P<0.05; for Δ kg/wk/100 kg body fat, P<0.03. Densitometric measurement of body fat content showed that the mean weight loss coincided almost exactly with the mean decrease in fat content; thus, over the 10-week period of ED administration, the mean fat loss was about 5% of the initial body fat content. Three of the obese subjects had strikingly greater fat loss, about 18%, 19%, and 25% of the initial body fat content. There were no significant subjective or objective side effects of ED administration .     

The TpG chelate of cis(diammineplatinum) forms two head-to-head rotamers in H2O solution

 d(TpG)^– reacts with cis-[Pt(NH₃)₂(H₂O)₂]²⁺ in two steps to yield the platinum chelate cis-[Pt(NH₃)₂{d(TpG)-N3(1),N7(2)}]. In the latter, hindered rotation of the bases leads to an equilibrium between two rotamers interconverting slowly on the NMR time scale. The structure of the two rotameric chelates was studied by means of ¹H NMR and molecular modeling techniques. The major and minor rotamers could be assigned unambiguously to the two head-to-head conformational domains which are characterized by syn/anti and anti/anti sugar-base orientations, respectively. Molecular models derived for both rotamers show that the orientations of the bases are mutually quasi-enantiomeric. The interconversion between the two rotamers (k ≈ 1 s^–1 at 293 K) is approximately 10⁴ times faster than the analogous rotamer interconversion observed in cis-[Pt(NH₃)₂{r(CpG)-N3(1),N7(2)}]⁺ [Girault J-P, Chottard G, Lallemand J-Y, Huguenin F, Chottard J-C (1984) J Am Chem Soc 106 : 7227–7232], suggesting that the steric clash of the exocyclic amino group of the platinum-bound cytosine with the ligands in cis position is more severe than that of the two thymine oxo groups. Received: 23 June 1997 / Accepted: 30 September 1997     

Secnidazole vs. paromomycin: Comparative antiprotozoan treatment in captive primates

The antiprotozoan activity of secnidazole was studied in Cercocebus t. torquatus, Cercopithecus campbelli, Erythrocebus patas (Cercopithecidae), and Gorilla gorilla (Pongidae) compared with that of paromomycin in Cercocebus t. lunulatus (Cercopithecidae), E. patas, and G. gorilla (Pongidae) by coprological analysis. The antiprotozoan activity of both drugs depended on the parasite species and the host species. The drugs acted in a similar way on Entamoeba coli parasitising C. t. torquatus, and E. patas. This activity was different from that observed on I. buestchlii from the same host species. Nevertheless, E. coli parasitising cercopithecids and pongids responded to drugs differently.     

阿胶,五味子,刺五加,枸杞对双歧杆菌生长的影响

本文选用１５种传统抗衰老中药对双歧杆菌进行了体外生长促进实验。结果发现刺五加、五味子、宁夏枸杞子及阿胶对婴儿双歧杆菌有明显的促进作用。     

Role of Intestinal Bacteria in Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug

The role of intestinal bacteria in induction and repression of ulcer formation in the ileum of rats treated with one of the nonsteroidal antiinflammatory drugs (NSAIDs), 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene (BFMeT), was examined in this study. BFMeT was administered by intragastric gavage once at doses of 500-1,500 mg/kg of body weight to Wistar rats treated with and without antibiotics (bacitracin, neomycin, streptomycin), germ-free rats and gnotobiotic rats, and 72 hr later their gastrointestinal tracts were examined for ulcer formation. A single oral administration of BFMeT induced ileal ulcers in specific pathogen-free rats. However, the rats given antibiotics to reduce the intestinal bacteria had no ulcers. BFMeT-treated germ-free rats and gnotobiotic rats mono-associated with Bifidobacterium adolescentis or Lactobacillus acidophilus also had no intestinal ulcers. However, the drug induced ileal ulcers in gnotobiotic rats mono-associated with Eubacterium limosum or Escherichia coli. An overnight culture of B. adolescentis or L. acidophilus or yogurt containing Bifidobacterium breve and Streptococcus thermophilus, when given as drinking water, inhibited ulcer formation in the ileum of rats treated with BFMeT. Gram staining of the ileal contents of normal rats revealed that 97.4% of the stained microorganisms were Gram-positive rods and only 1.2% were Gram-negative rods. In the group of rats with ulcers induced by BFMeT, the Gram-positive rods decreased by 56.4% and the Gram-negative rods including Escherichia coli, Klebsiella, Proteus and Bacteroides increased by 37.3%. However, in the group of rats administered the Bifidobacterium culture, the Lactobacillus culture or yogurt, the percentages of the Gram-negative rods were decreased. Although Lactobacillus was a major bacterium in the ileum of normal rats, the Gram-negative facultatively anaerobic rods E. coli, Klebsiella and Proteus were increased in the ulcerated ileum of rats treated with BFMeT, suggesting that these bacteria are associated with ulcer formation in rats treated with NSAIDs, and that Lactobacillus and Bifidobacterium inhibit it by repressing the growth of ulcer-inducing bacteria.