Direct metabolic effects

Figure 10.7 Direct metabolic effects of Leflunomide (A 77 1726) on glucose consumption and glycolysis. The upper chart shows that the drug suppresses both lactate production and glucose consumption. The lower chart shows that glutaminolysis is induced.

Sandor (SI) has investigated the effect of adrenaline on plasma proteins in the guinea pig. He found a rapid lowering of plasma albumin, with a frequent concomitant increase in -globulin levels. Although stimulation of ACTH may be involved he believes this to be largely a direct metabolic effect of the injected adrenaline. 

In examining the early inflammatory reaction after the implantation of pellets of plastic sponge in the rat, Saxena measured exudate formation and leucocytic infiltration. The cellular infiltration was significandy decreased by the CNS depressants morphine, pentobarbitone, meprobamate and chlorpromazine hydrochloride promethazine hydrochloride is ineffective. The extent to which this may be a direct metabolic effect of the drugs is not clear since the phagocytic activity of circulating leucocytes is decreased by chlorpromazine . 

AMP-activated Protein Kinase. Table 2 Metabolic effects of AMPK activation. In cases marked with an asterisk, there is evidence that AMPK mediates its effects by modulating the target named, although it is not yet clear whether the protein is directly phosphorylated by AMPK... 

A specific role for vitamin E in a required metabolic function has not been found. In addition to its direct antioxidant effects, a-tocopherol has been reported to have specific molecular functions. 

Interferon-a2b has diverse mechanisms of action, including antiviral activity, impact on cellular metabolism and differentiation, and antitumor activity.42 The antitumor activity is due to a combination of direct antiproliferative effect on tumor cells and indirect immune-mediated effects.42 Interferon-a2b is currently approved by the Food and Drug Administration (FDA) as adjuvant therapy for patients who are free of disease after curative surgical resection but are at high risk of MM recurrence. This includes patients with bulky disease or regional lymph node involvement such as stage IIB, IIC, or III disease.43 It is controversial if interferon-a2b (IFN) should be offered as adjuvant therapy for every high-risk MM patient. The reason is because clinical trials with different doses of IFN have not proved definitively that IFN improves overall patient survival. 

Coenzymes are densely functionalized organic cofactors capable of catalyzing numerous diverse chemical reactions. Nature exploits the intrinsic chemical reactivity of these molecules to extend the chemical fimctionaUty of enzymes well beyond the reactivity of the coded amino acids. When these constituents are incorporated via covalent or non-covalent interactions into coenzyme-depen-dent enzymes, the inherent reactivity of the co enzyme is augmented and directed to effect chemical transformations with substrate and product selectivities, rates, and yields that are unachievable by either the protein or coenzyme alone. Thus, coenzymes play a critical role in the execution of a large number of essential metabolic processes. 

Induction of enzymes involved in the metabolism of a test chemical is generally not a direct toxic effect exerted by the chemical, but a reaction toward a xenobiotic entering the body. 

A number of toxicological mechanisms have been proposed for hydrogen sulfide At extremely high concentrations it may exert a direct paralyzing effect on respiratory centers hydrogen sulfide is also known to inhibit cytochrome c oxidase, resulting in altered oxidative metabolism it can also disrupt critical disulfide bonds in essential cellular proteins. ... 

The observed ozone-induced growth reductions of roots could result from (a) a direct toxic effect of ozone on the root, (b) an ozone modification of the foliage metabolism which alters the quantity and/or quality of metabolites translocated to the roots, or (c) an alteration in soil chemistry. 

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. 

Procainamide INa (primary) and IKr (secondary) blockade Slows conduction velocity and pacemaker rate prolongs action potential duration and dissociates from INa channel with intermediate kinetics direct depressant effects on sinoatrial (SA) and atrioventricular (AV) nodes Most atrial and ventricular arrhythmias drug of second choice for most sustained ventricular arrhythmias associated with acute myocardial infarction Oral, IV, IM eliminated by hepatic metabolism to /V-acetylprocainamide (NAPA see text) and renal elimination NAPA implicated in torsade de pointes in patients with renal failure Toxicity Hypotension long-term therapy produces reversible lupus-related symptoms... 

Figure 4.72 The various possible consequences of metabolism of a foreign compound. The compound may undergo detoxication (2) metabolic activation (3), which leads to interaction with critical targets (6) and may cause toxic effects (8 A). Alternatively, the parent compound might cause a direct toxic effect (1 B). Formation of a stable metabolite (7) could cause atoxic effect (9 C). The stable metabolite could be further metabolized to atoxic metabolite (10) responsible for a different toxic effect to C. The reactive metabolite may be detoxified (4/5). The types of toxic effect caused by the metabolites would be one or more of the various types shown.

Evidence for consistent, positive metabolic effects of feeding antibiotics is fragmented and inconclusive. Direct measurement of increased uptake of nutrients, ie, in vivo amino acids, glucose, or volatile fatty acids in ruminants, have not been reported. 

No adverse effects are to be expected after a single injection of a high dose of a glucocorticoid, but some serious complications have been observed with repeated use, including both infections and the known direct adverse effects of glucocorticoids. Cases of ventricular dysrhythmias and atrial fibrillation have been reported (SEDA-18, 391). With pulse therapy, the nature of the injected glucocorticoid seems to be important for example, hydrocortisone, which is more rapidly metabolized, seems to be better tolerated than dexamethasone (SEDA-6, 331). 

Cyclofenil can cause reversible mild cholestatic jaundice. The authors of a review of 30 patients with hepatic reactions to cyclofenil concluded that liver derangement due to cyclofenil is probably related to metabolic hypersusceptibility rather than to a direct toxic effect (3). There is a surprising lack of such reports from countries where cyclofenil was widely used in France, at least, the number of cases of hepatitis occurring is known to have been much greater than that reported in print, and the drug was abandoned in that country in 1988. 

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