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Control of the Large Bowel Microflora
Published in Michael J. Hill, Philip D. Marsh, Human Microbial Ecology, 2020
Bohumil S. Drasar, April K. Roberts
Although changes in the bacterial species and genera comprising the microflora are difficult to demonstrate, changes in the metabolic properties of the flora due to changes in dietary compounds can be shown to occur. During studies on the metabolism of cyclamate by man it was observed that administration of cyclamate was followed by the excretion of cyclohexylamine resulting from the breakdown of the cyclamate by the gut microflora. Before exposure to cyclamate the microflora was not able to perform this reaction.77 Studies of the metabolic activity of the microflora based on measurements of bacterial enzymes have revealed marked changes as a function of diet.57,78
General toxicology
Published in Timbrell John, Study Toxicology Through Questions, 2017
However, if the elimination of becomes saturated as the plasma concentration rises, then the rate of elimination will reach a maximum and will be constant. Consequently, increasing the infusion rate further will result in a decrease in plasma clearance (as reported here) and dramatic rises in the concentration of in the blood and tissues, possibly with toxicological consequences. This is referred to as dose-dependent or non-linear kinetics and is an important concept in toxicology as it often coincides with the dose-response of toxic compounds, e.g. saccharin, cyclohexylamine and 2,4,5-trichlorophenoxyacetic acid.
Ovotoxic Environmental Chemicals: Indirect Endocrine Disruptors
Published in Rajesh K. Naz, Endocrine Disruptors, 2004
Patrick J. Devine, Patricia B. Hoyer
Chemotherapy is one of the most toxic exposures to humans as regards germ cell destruction.[120] Cyclophosphamide has been studied more thoroughly than most due to its widespread use as a chemotherapeutic agent. CPA induces loss of primordial follicles and can cause sterility. Phosphoramide mustard has been determined to be the antineoplastic and ovotoxic form of this chemical.[42,121] Mice were dosed with chemicals capable of forming specific metabolites of cyclophosphamide (phosphoramide mustard, phosphoramide mustard cyclohexylamine salt or trans-4-phenylcyclophosphamide; or acrolein, didechlorocyclophosphamide and allyl alcohol). Only those chemicals that released phosphoramide mustard induced ovarian toxicity. The greater potency of phosphoramide mustard-producing chemicals compared to CPA in mice was attributed to a bypassing of detoxification steps, allowing more toxic metabolite to reach the ovary.[42] Metabolism of cyclophosphamide is thought to occur in the liver with uptake of the reactive metabolites from the blood to the ovary.[121] However, the possibility exists for detoxification of toxic metabolites in specific regions of the ovary, which might explain the follicle-stage-specific toxicity.
Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFRWT and EGFRT790M
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ahmed A. Gaber, Mohamed Sobhy, Abdallah Turky, Hanan Gaber Abdulwahab, Ahmed A. Al-Karmalawy, Mostafa. A. Elhendawy, Mohamed. M. Radwan, Eslam B. Elkaeed, Ibrahim M. Ibrahim, Heba S. A. Elzahabi, Ibrahim H. Eissa
The designed compounds were synthesised as outlined in Schemes 1–3. Ethoxymethylene malononitrile 141 was allowed to react with phenylhydrazine to produce 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile 244. Compound 2 underwent partial hydrolysis using alcoholic NaOH to produce carboxamide derivative 345. Fusion of compound 3 with urea afforded 1-phenyl-1,7-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4,6(5H)-dion 4. Chlorination of compound 4 using phosphorus oxychloride and phosphorus pentachloride produced 4,6-dichloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine 546. Stirring of compound 5 with aniline at room temperature afforded 4-chloro-N,1-diphenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-amine 647. The obtained compound 6 was heated with commercially available different amines, namely ethylamine, propylamine, aniline, and cyclohexylamine in the presence of triethylamine afforded the target compounds 7a,b, 8, and 9, respectively. The IR spectra of 7a,b, and 9 demonstrated stretching bands at a range of 2950 − 2980 cm−1 corresponding to CH aliphatic groups. The 1H NMR spectra were characterised with abroad singlet at approximately 7–8 ppm due to the additional NH group.
Novel uses of ketamine in the emergency department
Published in Expert Opinion on Drug Safety, 2022
Brian N. Corwell, Sergey M. Motov, Natalie L. Davis, Hong K. Kim
Ketamine, a cyclohexylamine compound, is a dissociative anesthetic agent that has been used in human and veterinary medicine for approximately 50 years [1]. Phencyclidine (PCP) and ketamine were favored as anesthetic agents as they lacked respiratory and cardiovascular depression frequently associated with other anesthetic agents [2]. PCP was associated with intense and prolonged emergence delirium and psychodysleptic effects that made it unfavorable for human use [2,3], thus ketamine was introduced as a safer alternative [4]. Ketamine primarily antagonizes the N-methyl-D-aspartate (NMDA) receptors to exert its dissociative anesthetic effect, though it also has pharmacologic activity at numerous receptor systems including opioid, nicotinic, muscarinic receptors, and ion channels [4,5]. Ketamine’s unique pharmacologic properties extend beyond the well-characterized dissociative anesthetic effects. Today, ketamine is undergoing a renaissance due to renewed interests and potential applicability in the management of pain, depression, and acute agitation [1,6–8].
Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders
Published in Expert Opinion on Drug Discovery, 2021
The first observations that a pharmacological effect of S1R activation resulted in a bi-phasic concentration-response curve were made during the early 1990s, on S1R-induced modulation of NMDA-evoked responses in vitro and in vivo. Release of [3H]norepinephrine from rat hippocampal slices can be evoked by administration of 100 µM NMDA. This NMDA response was potentiated by up to 20% of the basal value by low)3–50 nM(concentrations of S1R ligands including ditolylguanidine (DTG; Figure 1), (R)-(+)-N-cyclopropylmethyl-α-ethyl-N-methyl-α-[(2E)-3-phenyl-2-propenyl)benzenemethanamine hydrochloride (igmesine, JO-1784; Figure 1), and N-n-propyl-3-(3-hydroxyphenyl)piperidine ((+)-3-PPP; Figure 1) or the peptides neuropeptide Y or peptide YY [94,95] (Figure 2a). All drugs effects followed a bi-phasic curve and disappeared at higher concentrations in the µM range. Similarly, In vivo, the NMDA-induced firing activity of CA3 pyramidal neurons was increased by 2- to 10-fold with low doses of DTG (0.5–3 µg/kg i.v.), igmesine (1–100 µg/kg i.v.) (Figure 2b), and (+)-pentazocine (1–100 µg/kg i.v.), among others [96–100]. These effects were suppressed at higher doses (0.1 mg/kg i.v. for igmesine or 5 mg/kg i.v. for DTG) following a bi-phasic dose-response curve [97,100]. More generally, high doses of the S1R agonists, DTG, igmesine, (+)-cis-N-methyl-N-[2,(3,4-dichlorophenyl) ethyl]-2-(1-pyrrolidinyl) cyclohexylamine (BD737; Figure 1) and 1′-benzyl-3,4-dihydrospiro-[naphthalene-1-(2 H),4′-piperidine] (L-687,834; Figure 1) suppressed the potentiation induced by low doses of these drugs, demonstrating that at high doses, they acted in a similar way to the S1R antagonists haloperidol, 4-methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzeneethanamine (NE-100; Figure 1) or BD1047 [100,101]. The descending phase of the curve could be due to either a direct NMDA receptor antagonistic effect of the drugs at high doses, or to S2R activation. S1R activation may differently impact NMDA receptor activity, directly or indirectly through regulation of intracellular Ca2+ levels [102].