Cases analysis of rational use of medicine (27)

1.Patient's conditionsPatient,male,45 years old.Pulmonary infection and septicemia.2.Drug administrationCefotaxime 2 gsod chloride Inj 100 ml/iv drop bid×7Amikacin 800 mgSod chloride Inj 100 ml/iv drop qd×73.AnalysisSingle daily dosing of aminoglycoside…     

Cases analysis of rational use of medicine(18)

1.Patient’s conditions :A 17-year-old young boy,two days before he came tothe emergency room,began to have upper respiratory infec-tion,sore throat,nasal discharge,feeling of malaise and chillthen shivering,high fever,(39oC)and then more serioussymptoms,such as,terrible headache,frequent vomiting,nuchal rigidity,skin ecchymosis developed.Neurological(Reflex)examinations:Brudzinskis+Kernigs+Babinskis+Lab.examinations:WBC 25×109/LN 89%Blood smear of ecchymosis showed Neisseriameningitidis…     

Syntheses of (±)-homoepibatidine analogues

Syntheses of (+/-)-homoepibatidine analogues (2), which contain the 8-azabicyclo [3.2.1]octane ring system, were achieved by using palladium-catalyzed reductive-coupling reaction from 3 and the analgesic activity was tested by Mouse writhing antinociceptive assay.     

Cases analysis of rational use of medicine (20)

Case 11.Patient’s conditionsA56-Year-Old male has had recurrent chronic pro-statitis for about one year.A week ago,he had acute attackwith chills,fever,back and perineal pain,and frequent mic-turition.dysuria were also present.Onrectal examination,theprostate was tender,swollen and indurated.Urinary retentionresultingfrombladder outlet obstruction could be recognizedby bladder percussion.The prostatic secretion and midstreamurine sample had a lot of WBC.Diagnosis:acute attack of chronic p…     

Resolution of a1-Adrenoceptor Antagonist (±)-DDPH and Pharmacological Activity of (-)-DDPH

本文将ａ１受体拮抗剂（±）－ＤＤＰＨ用（＋）－酒石酸和（－）－二苯甲酰酒石酸为拆分剂拆分为（＋）－ＤＤＰＨ体和（－）－ＤＤＰＨ。（－）－ＤＤＰＨ和（±）－ＤＤＰＨ拮抗ａ１受体激动剂苯肾上腺素作用强度相近，ＰＡ２值分别为７．６９和７．５５。     

Stereoselective syntheses of (±)-epibatidine analogues

Stereoselective syntheses of (+/-)-epibatidine analogues 2, which contain the 8-azabicyclo [3.2.1]octane ring system, were achieved by using palladium-catalyzed cross-coupling reaction from 4 and the analgesic activity was tested by Mouse writhing antinociceptive assay.     

Characteristics of felodipine-located poly(ε-caprolactone) microspheres

Felodipine-loaded poly (ε-caprolactone) (PCL) microspheres were prepared by two methods, the conventional emulsion solvent evapouration method and the quenching method. The aim of this work was to investigate the effects of process parameters such as emulsion type, drug loading, molecular-weight of the polymer, types of emulsion stabilizer and dispersed phase solvents, as well as preparation methods. The results show that, when conventional emulsion solvent evapouration method was used, the o/w-method produced smaller mean size and higher encapsulation efficiency compared with the o/o-method. The encapsulation efficiencies increased with an increase in the molecular weight and a decrease in crystallinity of PCL. The size of microspheres varied with the type of emulsion stabilizer used, smaller microspheres with PVA and narrow size distribution with Pol 237. The water solubility of the dispersed phase solvent was one of the critical factors in controlling the encapsulation efficiency and microsphere mean size. When water-soluble solvents such as acetonitrile and ethyl formate were used, the encapsulation efficiencies decreased due to higher evapouration rate. When quenching methods were used, in contrast to the conventional emulsion solvent evapouration method, very narrowly size-distributed but bigger microspheres were obtained.     

Isolation of a New Alkaloid (O-Acetylretuline) and a Triterpenoid (Friedelin) from Strychnos henningsii of Zaïre

A new alkaloid (O-acetylretuline) has been isolated from barks and leaves of two samples of Strychnos henningsii collected in Za?re. A triterpenoid (friedelin) is also present in this African species of Strychnos.     

Comparative studies of poly(ε-caprolactone) and poly(D,L-lactide) as core materials of polymeric micelles

Polymeric micelles have been successfully used to deliver a variety of therapeutic agents. Nonetheless, several limitations and considerations must be clarified and well-studied to achieve the highest therapeutic effect. In this study, a series of methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) and methoxy poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-b-PLA) with varying molecular weight (MW) of hydrophobic core segment were synthesized. These block copolymers can form micelle with PCL or PLA as core-forming blocks and PEG as a coronal material. The effect of MW on micelle size and critical micelle concentration (CMC) was studied. DOX (DOX) was encapsulated inside the micelle core. Drug-loading content and size of micelles were studied. Drug release studies inside cells were evaluated by confocal laser scanning microscopy. In summary, the PLA core which is less hydrophobic than PCL showed higher CMC, smaller micelle size and faster DOX release inside nucleus.     

Human pharmacokinetics of esorubicin (4′ -deoxydoxorubicin)

Summary The pharmacokinetics of esorubicin, a new anthracycline antibiotic, was investigated in conjunction with a phase I clinical trial. The drug was administered to 12 patients as an intravenous bolus at a dose of 20 to 40mg/m². All patients had normal renal and hepatic functions and no third space fluid accumulation. Plasma and urine samples were assayed by HPLC. The peak plasma concentration of esorubicin was 0.74 ± 0.57 M (mean ± SE). Esorubicin disappeared from plasma according to a tri-exponential pattern with a terminal half-life of 20.4 ± 7.3 hr. The area under the plasma concentration versus time curve was 0.64 ± 0.31 Mxhr. Total body plasma clearance was 45.5 ± 26.8 liter/min/m² and the apparent volume of the central compartment, 41.0 ± 24.8 L. A single metabolite, 4-deoxydoxorubicinol, was detected in plasma. This metabolite was observed in 5 patients only and its mean peak concentration was 0.029 ± 0.017 M. The area under the plasma versus concentration time curve for 4-deoxydoxorubicinol was 0.02 ± 0.014 Mxhr. The urinary excretion of total fluorescence within 5 days of therapy was 7.3 ± 1.3% of the administered dose. Esorubicin represented more than 80% of the excreted anthracyclines. As in plasma, 4 -deoxydoxorubicinol was the only metabolite detectable in urine. No correlation between the various pharmacokinetic parameters and drug-induced toxicity was observed in this small group of patients.This work was presented in part at the 4th NCI EORTC Symposium on New Drugs in Cancer Therapy (Brussels, Belgium, December 14–17, 1983) and at the 20th Annual Meeting of the American Society of Clinical Oncology (Toronto, Canada, May 6–8, 1984).     

Comparison of dynamics of extracellular accesses to the β(1) and β(2) adrenoceptors binding sites uncovers the potential of kinetic basis of antagonist selectivity

From the molecular mechanism of antagonist unbinding in the β(1) and β(2) adrenoceptors investigated by steered molecular dynamics, we attempt to provide further possibilities of ligand subtype and subspecies selectivity. We have simulated unbinding of β(1)-selective Esmolol and β(2)-selective ICI-118551 from both receptors to the extracellular environment and found distinct molecular features of unbinding. By calculating work profiles, we show different preference in antagonist unbinding pathways between the receptors, in particular, perpendicular to the membrane pathway is favourable in the β(1) adrenoceptor, whereas the lateral pathway involving helices 5, 6 and 7 is preferable in the β(2) adrenoceptor. The estimated free energy change of unbinding based on the preferable pathway correlates with the experimental ligand selectivity. We then show that the non-conserved K347 (6.58) appears to facilitate in guiding Esmolol to the extracellular surface via hydrogen bonds in the β(1) adrenoceptor. In contrast, hydrophobic and aromatic interactions dominate in driving ICI-118551 through the easiest pathway in the β(2) adrenoceptor. We show how our study can stimulate design of selective antagonists and discuss other possible molecular reasons of ligand selectivity, involving sequential binding of agonists and glycosylation of the receptor extracellular surface.     

Effect of 2,4-D herbicide (2,4-dichlorophenoxyacetic acid) on oxygen consumption and ammonium excretion of juveniles of Geophagus brasiliensis (Quoy & Gaimard, 1824) (Osteichthyes, Cichlidae)

Fish form important fisheries and aquaculture resources worldwide. In Brazil, pearl eartheater (Geophagus brasiliensis) is an important commercially exploited species and is an ideal animal for studying the impairment caused by the effects of herbicides that are often detected in the aquatic environment. The main purpose of the present study was to detect the acute toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) to G. brasiliensis and investigate its effects on oxygen consumption, ammonium excretion, and the neutral red retention time assay to estimate effects at the cellular level. Such investigations have not been carried out before with this species. First, the acute toxicity of 2,4-D to G. brasiliensis in terms of the 24-, 48-, 72-, and 96-h medium lethal concentration (LC₅₀) was calculated to be 45.95, 32.49, 28.28, and 15.16 mg/l, respectively. Furthermore, it was found that exposure of fish to 40 mg/l 2,4-D caused reduction in oxygen consumption and ammonium excretion of 59% and 85%, respectively, in relation to the controls. Mean neutral red retention time assay was significantly lower in comparison with control for organisms exposed to 1, 5, 10, and 40 mg/l 2,4-D. However, the effects at the cellular level were progressive, suggesting that the fish are not able to recover from such increasing effects.     

Biomarkers of environmental contaminants in field population of green mussel (Perna viridis) from Karnataka–Kerala coast (South West coast of India)

The green mussel Perna viridis was sampled from relatively clean and contaminated sites along the Kartanata–Kerala coast (south west coast of India) to study the tissue concentration of trace metals and biological responses to stress (biomarkers) such as sister chromatid exchange (SCE), chromosomal aberration, micronucleus (MN) test, hemic neoplasia (HN), Chromotest (Ames test) and comet assay. In general, mean tissue concentrations of toxic trace metals collected from 25 sampling sites were found to be below the World Health Organisation (WHO) permissible concentration given for seafood. The digestive gland extract of mussels from all 25 sampling sites showed negative reaction for mutagenic activity (Ames test) in the absence of metabolic activation. Very low levels of chromosomal aberration, SCE, MN, HN and comet cells were observed in mussels collected from both the urban associated and relatively clean sites. This study seems to indicate that that the coastal waters of Karnataka and Kerala are minimally contaminated with genotoxic and carcinogenic chemicals.Special Issue on Biomarkers of Marine Pollution and Bioremediation     

Synthesis and antibacterial evaluation of Cu(II) and Zn(II) complexes of the β-lactum antibiotic, cefdinir

In this study, the coordination chemistry of the antibiotic, cefdinir, and its metal complexes with Cu (II) and Zn (II) was described and characterized on the basis of analytical and spectral studies. The synthesized complexes were evaluated in vitro for their antibacterial activity against Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. The metal complexes possessed the better antibacterial activity against the selected species of bacteria than the free antibiotic (cefdinir). The results were supported by the increase in log P values of metal complexes in comparison to the free ligand cefdinir. The importance of these findings lies in the fact that these complexes could be applied in the treatment of common bacterial infections.     

Synthesis and evaluation of antitumor activity of a homologous series of 1-(ω-cyanoalkyl)-and 1,3-bis (ω-cyanoalkyl)uracil nucleoside analogues

Acyclonucleoside homologues of 1-(ω-cyanoalkyl)-and 1,3-bis (ω-cyanoalkyl) uracils were synthesized by the series of alkylation reactions of uracil with the ω-chloroalkyl nitrile (Cl-(CH₂)_n-CN; n=1, 2, 3, 4) in DMSO under 50～75°C temperature. The 1-(ω-cyanoalkyl)-and 1,3-bis(ω-cyanoalkyl) uracils were separated either by the fractional crystallization or column chromatography. The antitumor activities for these synthesized compounds were determined against four cell lines (J-82 cell, P388 cell, FM-3A cell and U-937 cell lines). These compounds failed to exhibit any significant antitumor activity.     

Structure-guided design of β-secretase (BACE-1) inhibitors

β-secretase (BACE-1) is a membrane-tethered aspartyl protease that serves as the rate-limiting enzyme in processing the amyloid precursor protein (APP) and, thus, is believed to play a central role in the neurodegenerative disorder, Alzheimer's disease. Due to the availability of X-ray crystal structures for the soluble domain of BACE-1, structure-based methods have been widely employed in the design of BACE-1 inhibitors. A variety of computational methods have been used, ranging from quantum mechanical studies to molecular dynamics calculations and scoring methods, all aimed at understanding the unique chemical features of the BACE-1 active site. However, BACE-1 has proven to be a difficult target due to its extended active site, its intrinsic flexibility and the requirement for brain penetration.     

Thermodynamic Study of Sulfanilamide Polymorphism: (I) Monotropy of the α-Variety

Purpose. Sulfanilamide was chosen as a model compound in order to gain insights on the stability hierarchy of drug polymorphs from structural and thermodynamic criteria. Despite numerous studies, disagreements remained on the reported enthalpies associated with the mutual interconvertions of the -, -, and -forms of sulfanilamide. Therefore, the unambiguous determination of these enthalpies was the purpose of this work. Methods. Samples, free of solvent inclusions and made of only one form, were prepared, and analyzed combining X-ray powder diffraction and Differential Scanning Calorimetry (DSC). Results. The enthalpy values associated with the - to - and - to -transitions were found to be + 10.2 and + 10.9 J g^–1, respectively. The calculated enthalpy of the - to -transition is consistent with the experimental one ( + 1 J g^–1). Conclusions. The monotropy of the -form was ascertained over the explored temperature range at ordinary pressure.