Clinical relevance

Numerous physiological and clinical conditions are associated with hypoxemia, ranging from acute episodes of hypoxia (asthma) to chronic sustained hypoxia (ascent to high altitude, COPD) or chronic intermittent hypoxia (OSA). During these episodes of hypoxia, activation of both peripheral and central sites likely occurs, with the net response refiecting a coordination of these drives by the pattern-generating network. 

Marcel Dekker, L c. 270 Madison Avenne, New Yodc, New Yoifc 10016 

In addition to the potential for adaptations in the eentral oxygen sensors during chronic sustained hypoxia, it is likely that adaptations occur in these central cardiorespiratory oxygen sensors during chronic intermittent hypoxia as well. Of particular interest is understanding what the impact of chronic intermittent hypoxia is on the cardiorespiratory responses and the particular adaptive or maladaptive changes in the cellular processing of the hypoxic stimulus (128-130). For example, how much of the clinical sequalae associated with OSA can be attributed to the responses to hypoxia  

---

P-Adrenoceptors have been subdivided into P - and P2-adrenoceptors. A third subset called nontypical P-adrenoceptors or P -adrenoceptors have been described but are stiU the subject of debate. In terms of the interactions with various subsets of P-adrenoceptors, some antagonists are nonselective in that they antagonize the effects of activation of both P - and P2-adrenoceptors, whereas others are selective for either P - or P2-adrenoceptors. P - and P2-adrenoceptors coexist in almost all organs but generally, one type predominates. The focus herein is on the clinically relevant P -adrenoceptor-mediated effects on heart and on P2-adrenoceptor-mediated effects on smooth muscles of blood vessels and bronchioles, the insulin-secreting tissue of the pancreas, and skeletal muscle glycogenolysis for side effects profile (36). 

Hydrolysis of macrolides by products of the ere genes detected in enterobacteria is only of scientific interest, while esterases VGB-A and VGB-B encoded by the vgb type genes mediate clinically relevant resistance in staphylococci to the B compound (quinupristin) of the streptogramin combination quinu-pristin-dalfopristin. 

In contrast to macrolides, the targets of (3-lactams, the penicillin binding proteins (PBPs) require several mutations in order to become resistant while simultaneously maintaining their viable function as cell wall transpeptidases/transglycosidases. Thus, in order to achieve clinically relevant resistance Streptococcus pneumoniae uses a unique strategy to rapidly accumulate several point mutations. Due to its natural competence for transformation during respiratory tract... 

Acquired resistance has been observed by constitutive upregulation of mdr efflux pump expression due to a mutation inactivating a respective repressor or inducibly, caused by molecules transiently inactivating repressor molecules upon binding. Depending upon the substrate spectra of the respective subset of efflux pumps upregulated, a multiple drug resistance (mdr) phenotype is expressed, which in combination with a specific resistance mechanism can contribute to a clinically relevant level of resistance. 

Na+ channels at clinically relevant concentrations (carbamazepine, phenytoin, lamotrigine). Most of these anticonvulsant dtugs display three distinct effects on Na+ channels ... 

Any protein whose function is believed to be clinically relevant and suitable for modulation by a drug can be considered a drug target. Targets may be grouped... 

Furthermore, there is some evidence for pleiotrophic effects (e.g., effects on hemostasis, vascular function, anti-inflammatory effects, and stabilizing effects on atherosclerotic plaques) of statins. The clinical relevance of this (and the potential difference between the various statins) is at present uncertain but subject to intense investigation. 

It has been shown that an AAC enzyme variant (AAC (6 )-Ib-cr, cr for ciprofloxacin resistance) found in various Enterobacteriaceae is capable of A-acetylating fluoroquinolones with an unmodified piperazinyl substituent at the amino nitrogen. Although the increase in MIC is low, this plasmid encoded quinolone resistance determinant can augment further development of clinically relevant resistance. 

Acetylsalicylic acid irreversibly inhibits both COX-1 and COX-2 by acetylating the enzymes. Since mature platelets lack a nucleus, they are unable to synthesise new enzyme. The anti-platelet effects of acetylsalicylic acid persist therefore throughout the lifetime of the platelet and the half-life of this effect is thus being much longer than the elimination half-life of acetylsalicylic acid (15 min). Since new platelets are continuously launched into the circulation, the clinically relevant anti-platelet effect of aspirin lasts for up to five days. This is the reason why low doses of acetylsalicylic acid (ca. 100 mg per day) are sufficient in the prophylaxis of heart attacks. 

Oxicams, e.g. piroxicam, tenoxicam, meloxicam and lornoxicam are non-specific inhibitors of COX. Like diclofenac, meloxicam inhibits COX-2 ten times more potently than COX-1. This property can be exploited clinically with doses up to 7.5 mg per day, but at higher doses COX-1-inhibition becomes clinically relevant. Since the dose of meloxicam commonly used is 15 mg daily, this agent cannot be regarded as a COX-2-selective NS AID and considerable caution needs to be exercised when making comparisons between the actions of meloxicam and those of other conventional NSAIDs. The average daily dose in anti-rheumatic therapy is 20 mg for piroxicam and tenoxicam, 7.5-15 mg for meloxicam and 12-16 mg for lornoxicam. Oxicams have long elimination half-lives (lornoxicam 3-5 h, meloxicam - 20 h, piroxicam 40 h and tenoxicam 70 h). 

Benet LZ, Hoener BA (2002) Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 71(3) 115—121... 

An initial examination of the extent to which lithium may prevent cannabis withdrawal in rats was conducted by Cui et al. (2001), who reported that, at clinically relevant serum levels, lithium prevented the appearance of the cannabis withdrawal syndrome. The authors also noted that these effects were accompanied by a release of oxytocin, which they conclude is responsible for suppression of the withdrawal signs. 

Roessler, Wilke A, Griss PM, and Kienapfel H. Missing osteoconductive effect of a resorbable PEO/PBT copolymer in human bone defects A clinically relevant pilot study with contrary results to previous animal studies. Biomed Mater Res (Appl Biomater), 2000, 53, 167-173. 

The clinical relevance of this finding was suggested by the observation that mice were more susceptible to sepsis following infection with Streptococcus pneumoniae when basophils were depleted before the second vaccination with pneumoccocal antigen [22]. Antigen-specific IgG antibodies produced after the second vaccination were significantly lower in the basophil-depleted mice than in control mice. Thus, basophils are important contributors to humoral memory immune responses. 

We have identified mast cells around blood vessels and between myocardial fibers in all sections of human hearts [16,17]. These cells are also seen in normal and atherosclerotic human arterial intima [ 18-21 ]. In situ electron microscopy of cardiac mast cells revealed a small percentage (about 5%) of activated, i.e. partially degranulated mast cells [16,22]. This is clinically relevant because it implies that immunologic and non-immunologic stimuli can activate HHMC to release vasoactive and proinflammatory mediators [23]. 

HHMC can also be activated by a variety of non-immunological stimuli. Some have clinical relevance because they might explain certain adverse effects observed in vivo when these compoimds are used for diagnostic (contrast media, etc.) or therapeutic... 

Two immunoassays have been developed to measure tryptase in human fluids, one that measures mature a/(3-tryptases, i.e. total tryptase, available commercially, and one developed by Schwartz et al. [7] that measures both mature (3-tryptase and immature a/(3-tryptases. This distinction is of clinical relevance since immature tryptases reflect mast cell burden whereas mature tryptases indicate mast cell activation. Thus, for the diagnosis of anaphylaxis it would be extremely important to be able to differentiate between acute anaphylaxis and increases in tryptase due to increase in numbers of mast cells as happens in mastocytosis. Total tryptase would be high in both conditions, whereas mature tryptase will be only high in anaphylaxis but negligible in mastocytosis. 

Simons FE Comparative pharmacology of 62 Hi-antihistamines clinical relevance. Am J Med 2002 113(suppl9A) 38-46. 

---