Uptake, decreased, mechanism resistance

Decreased uptake as a mechanism of resistance was also observed in houseflies resistant to organochlorine, organophosphate, and carbamate insecticides. Resistant strains had higher total lipids, monoglycerides, diglycerides, fatty acids, sterols, and phospholipids in the cuticle than did the susceptible strain (Patil and Guthrie, 1979). 

Fluoroquinolones must penetrate bacteria to reach their target, DNA gyrase. The second mechanism of fluoroquinolone resistance is decreased cell wall permeability. The fluoroquinolones diffuse through porin channels in the outer membrane of Gram-negative bacteria. Mutation results in a decrease in porin channel proteins, resulting in decreased uptake of the fluoroquinolones into bacterial cells. Alterations in a wide range of outer membrane proteins in Pseudomonas spp. result in resistance. From these mutations, the increase in MIC of the fluoroquinolones is relatively low (2-to 32-fold). Flowever, there is cross-resistance with unrelated antibiotics, most frequently cefoxitin, chloramphenicol, trimethoprim and tetracycline. 

Resistance to pesticides arises primarily through changes in the sensitivity of the site of action or in the metabolism of the pesticide (25,27.28). Many pesticides are activated metabolically. While it is theoretically possible to generate resistance through reduced activation, it seems much more common to observe increased detoxification in resistant strains. In some cases decreased uptake or enhanced excretion also contribute. It is an obvious prerequisite for any type of scientifically-based attempt to combat resistance that the resistance mechanism and its genetic basis must be defined. 

Minoxidil is a direct-acting peripheral vasodilator. The exact mechanism of action on the vascular smooth muscle is unknown. It does not interfere with vasomotor reflexes therefore, it does not prodnce orthostatic hypotension. The drug does not affect CNS fnnction. It appears to block calcium uptake through the cell membrane. Minoxidil reduces elevated systolic and diastolic blood pressnre by decreasing peripheral vascnlar resistance. The blood pressure response to minoxidil is dose-related and proportional to the extent of hypertension. In humans, forearm and renal vascular resistance decline forearm blood flow increases, whereas renal blood flow and GFR are preserved. 

Mechanisms of action and resistance Cytarabine (cytosine arabinoside) is a pyrimidine antimetabolite. The drug is activated by kinases to AraCTP, an inhibitor of DNA polymerases. Of all the antimetabolites, cytarabine is the most specific for the S phase of the tumor cell cycle. Resistance to cytarabine can occur as a result of its decreased uptake or its decreased conversion to AraCTP. 

The biocidal spectrum of these compounds is generally broader compared to compounds with a specific mechanism. The unspecific action leads in general to a significant decrease in possible resistance (except resistance caused by reduced uptake and detoxification). The selectivity toward different organisms of these intrinsically unspecific compounds results from different transport-mechanisms and differences in the metabolism. The disadvantage is sometimes a higher toxicity toward warm-blooded animals and an increase in the possibility of other toxic effects like sensitization. 

The most common mechanism of intrinsic resistance is a decreased uptake of flucytosine by the fungus by a reduction in cytosine permease activity, which results in reduced concentrations of dmg entering into the cell. The development of resistance to flucytosine during therapy may be a result of reduced expression of, or a deficiency in, an enzyme at any step in the intracellular metabolism of flucytosine. However, the most common resistance mechanisms observed in clinical isolates are due to either reduced cytosine deaminase or URPTase activity. 

A second mechanism of acquired resistance to fosfomycin involves chromosomal mutations in sugar phosphate uptake pathways which are responsible for transporting fosfomycin into the cell. The alterations decrease accumulation of the antibiotic to levels below those required for inhibition. 

While the inhibition of noradrenaline re-uptake exerts predominantly an a-adrenergic effect, a selective jS-adrenergic effect can not be obtained by such an indirect mechanism. All selective /3-sympathomi-metics activate the receptors, P -, P2- or both sub-types, directly. The first pure jS-sympathomimetic in clinical use was isoproterenol which is structurally identical to adrenaline except the methyl-moiety at the N-position in the side-chain is replaced by an isopropyl-group. All effects produced by isoproterenol are due to either P -or 62-adrenoceptor stimulation tachycardia, increased stroke volume, decreased vascular resistance, broncho dilatation and, in pregnancy, uterus relaxation. The metabolic effects of isoproterenol are less pronounced than those of adrenaline. 

We have observed that suppression of elevated FFA levels is a very rapid (less than 12 hour) response to treatment of insulin-resistant rats with PPARy agonists (T. Doebber, unpublished data). Since PPARy agonists are known to promote adipose tissue uptake and storage of fatty acids, it is plausible that this effect constitutes a major mechanism of insulin sensitization, whereby elevated FFAs—a known cause of hepatic and muscle insulin resistance—can be alleviated. An additional effect of in vivo PPARy activation, shown to occur in rats, was an increase in the number of small white adipocytes, along with a relative shift in the size of visceral (decreased) versus subcutaneous (increased) adipose depots (73). This has important implications because visceral adiposity and larger fat cells are both associated with insulin resistance. 

A number of mechanisms allow a cell to become resistant to cisplatin. The most commonly acknowledged ones include decreased drug uptake [16], increased levels of sulfur-containing macromolecules reacting with cisplatin [17], and increased DNA repair [18]. Increased tolerance to cisplatin adducts may also play a role in the appearance of a resistant phenotype. This is as suggested by data obtained in some ovarian carcinoma cells in which resistance is accompanied by a reduced rate of adduct removal when compared to the sensitive parental cell-line [19]. The molecular mechanism of this phenomenon is unknown but has been correlated with an increased replicative bypass of platinum-DNA adducts. 

Chromosomal mutants of Ps. aeruginosa produced by stepwise exposure to the antibiotic polymyxin are resistant to this drug and to EDTA [175]. The mechanism of this resistance is related to a defective self-promoted uptake pathway in which the cells contain increased amounts of a major outer membrane protein (HI) with a corresponding decrease in envelope Mg2+ [175, 176]. Protein HI may replace Mg2+ at cross-bridging sites with LPS these sites are normally those at which interaction occurs with Mg2+, such as EDTA, or at which displacement of Mg2+ takes place, for example, polymyxin [177, 178],... 

The mechanism of L-1210 resistance to cisplatin and other platinum antitumour agents remains to be clearly defined. Both Waud [77] and others [78] suggest that reduced cisplatin uptake may be responsible in part for the resistance of the cell line. It has also been found that glutathione levels are high in human ovarian carcinoma cells made resistant to cisplatin in vitro [79]. However, reduction in the level did not alter the resistance to the drug [80]. Decreases in amino-acid transport and changes in amino-acid substrate specificities have also been suggested as the basis for the resistance [81], but definitive evidence has been difficult to obtain. 

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