Sequential inhibition

Trimethoprim-sulfamethoxazole (TMP-SMX) was introduced as a fixed dose combination in 1968. Trimethoprim was added to sulfamethoxazole to synergisti-cally and sequentially inhibit bacterial synthesis of tetrahydrofolic acid. The combination was also designed to delay development of bacterial resistance. Sulfamethoxazole was selected in part because it is a congener of the frequently used sulhsoxazole but exhibits slower enteric absorption and urinary excretion. Sulfamethoxazole has a half-life similar to that of trimethoprim. 

Venlafaxine, a phenylethylamine, sequentially inhibits first the neuronal uptake pump for serotonin and then NE ( 137). In contrast to tertiary amine TCAs, which can also inhibit serotonin and NE uptake pumps, venlafaxine has low binding for most other neuroreceptors and does not inhibit Na ion fast channels, making it relatively safe in overdoses compared with TCAs. 

Combination of a sulfonamide with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) provides synergistic activity because of sequential inhibition of folate synthesis (Figure 46-2). 

A widely available fixed combination is co-trimoxazole (Bactrim, Eusaprim, Septrin), which contains trimethoprim and sulfamethoxazole in a ratio of 1 5. Both trimethoprim and sulfamethoxazole have favorable and comparable pharmacokinetics and the combination is bactericidal (4). Synergy between trimethoprim and sulfonamides has conventionally been ascribed to sequential inhibition of dihydropteroate synthetase by sulfonamides (in competition with pora-aminobenzoic acid) and of dihydrofolate reductase by trimethoprim (in competition with dihydrofolate). However, sulfonamides in high concentrations also inhibit dihydrofolate reductase. Thus, an initial partial sequential blockade by trimethoprim (inhibition of dihydrofolate reductase) and sulfonamides (inhibition of dihydropteroate synthetase) leads to defective protein synthesis and cytoplasmic damage, which in turn results in marked increases in the uptake of both agents and double strength inhibition of dihydrofolate reductase (5). 

TMP inhibits dihydrofolic acid reduction to tetrahydrofolate, resulting in sequential inhibition of enzymes of the folic acid pathway. 

Venlafaxine and its active metabolite, 0-desmethylvenlafaxine (ODV), have dual mechanisms of action, with preferential affinity for 5-HT reuptake and weak inhibition of NE and dopamine reuptake. Venlafaxine is approximately 30 times more potent as an inhibitor of SERT than of NET (68). Because of the 30 times difference in transporter affinities, increasing the dose of venlafaxine from 75 to 375 mg/day can sequentially inhibit SERT and NERT. Thus, venlafaxine displays an ascending dose-dependent antidepressant response in contrast to the flat dose-antidepressant response curve observed with the SSRIs. This sequential action for venlafaxine also is consistent with its dose-dependent adverse-effect profile. Its mechanism of action is similar to imipramine. 

Calorimetry measures the total metabolic activity. In order to quantify the contributions of different metabolic fluxes, sequential inhibition of respective metabolism by inhibitors may be used. If an organism, for example, has the ability to perform both respiration and fermentation as part of their catabolism, inhibitors of respiration and fermentation may be used in order to quantify... 

In addition, several progestins have been used in the absence of estrogens for purposes of contraception. It is clear that they owe their efficacy, which is not as high as that of the combination or sequential treatments, to some mechanism other than inhibition of ovulation. These are not yet represented by marketed entities for that indication. 

A short and efficient synthetic approach to hydroxy-substituted ( )-stil-benoids, as exemplified by the natural compound resveratrol (371b) via solid-phase CM, was reported by a Korean group (Scheme 71) [154]. When two different stilbenes were allowed to couple by catalyst C, all three kinds of possible stilbenes were obtained as an inseparable mixture. Anchoring 4-vinylphenol to Merrifield resin, followed by exposing the supported styrenyl ether 368 and diacetoxy styrene 369 (10 equiv) to the catalyst, inhibited self-metathesis of the supported substrate. Sequential separation of the homodimer formed from 369 by washing and subsequent cleavage of the resin 370 with acid provided (E)-stilbene 371a with complete stereocontrol in 61% yield. 

Enantioconvergent hydrolysis of para-chlorostyrene oxide (Figure 6.67) using a one-pot sequential bienzymatic strategy provided the corresponding (R)-diol in high yield (96% ee, yield = 93%) [186]. The second enzyme was added after about 50% conversion because the first one was sensitive to inhibition by the (R)-diol. 

Abstract The entry of viruses into target cells involves a complex series of sequential steps, with opportunities for inhibition at every stage. Entry inhibitors exert their biological properties by inhibiting protein-protein interactions either within the viral envelope (Env) glycoproteins or between viral Env and host-cell receptors. The nature of resistance to entry inhibitors also differs from compounds inhibiting enzymatic targets due to their different modes of action and the relative variability in... 

Product inhibition studies are used to complement kinetic analyses and to distinguish between ordered and random Bi-Bi reactions. For example, in a random-order Bi-Bi reaction, each product will be a competitive inhibitor regardless of which substrate is designated the variable substrate. However, for a sequential mechanism (Figure 8-11, bottom), only product Q will give the pattern indicative of competitive inhibition when A is the variable substrate, while only product P will produce this pattern with B as the variable substrate. The... 

Denitrification involves the sequential formation of nitrite, nitric oxide, and nitrous oxide. Two aspects of nitric oxide have attracted attention (a) chemical oxidation of biogenic nitric oxide to Nq, in the context of increased ozone formation (Stohl et al. 1996) and (b) the physiological role in mammalian systems (Feldman et al. 1993 Stuehr et al. 2004), in parasitic infections (James 1995), and in the inhibition of bacterial respiration (Nagata et al. 1998). Nitric oxide may be produced microbiologically in widely different reactions such as... 

Fig. 7.10 (Continued) (b) VN-x inhibits response to female urine by male guinea-pig X-2 sequential trials (duration, sec. x s.e.) (from Beauchamp et al., 1982). (c) Inter-strain (domestic vs. wild) discrimination by male domestic guinea pig of female urines [sequential testing sec/4 min, s.e., Ss above each bar intact/sham-VN-x. above]. WF= wild female, F = domestic female (from Beauchamp et al., 1982). (d) Effects of VN-x on maternal chemoinvestigation ewe responses to lambs, including tongue-manipulation of palate [c.f. Fig. 7.6(d)], procaine = MOE inhibition, a sign, versus control (from Booth and Katz, 2000).

Figure 4 Sequential assignment of the backbone atoms for the segment Pro-109 to Val-113 of inhibited sfSTR by 4-D HCANNH and 4-D HCA(CO)NNH. Four planes are shown from each spectrum. The assigned backbone atoms are indicated in (A). In (B) the upper four planes in solid lines are from the 4-D HCANNH and the lower four planes in dashed lines are from the 4-D HCA(CO)NNH. The chemical shifts for the four correlated nuclei in each case are shown. The correlations continue for the segment Pro-109 to Pro-129. As Pro lacks a protonated N, this residue serves as a "stop" signal. The correlation of 19 residues with Pro at the N- and C-terminal ends is unique for this segment in the sequence of sfSTR, therefore these backbone atoms are specifically assigned without having to further assign side chain atoms. (From Ref. 5.)...

Occupational exposure to carbamate insecticides may be monitored by measuring RBC-ACHE and/or PCHE. However, given the low cholinesterase inhibition levels and the short time duration of this effect, ACHE inhibition can generally be used as a biomarker of exposure only when exposure levels are high. Three sequential samples are recommended to establish an individual baseline before exposure. In exposed workers, blood sampling and analysis should be carried out soon after the end of exposure (WHO, 1986). 

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