Desensitization duration

Aerosol adniinistration of isoproterenol produces a prompt (2—5 minutes) intense bronchodilatation of relatively short (1 h) duration. The lack of P2-selectivity leads, in many cases, to tachycardia and blood pressure elevation. Also, use of isoproterenol, like all other known P-agonists, results in a down-regulation, or desensitization, of P-adrenergic receptors. This desensitization is only partial, and after time (depending on dose, patient, and agent), a stable, less responsive state is achieved in which P-agonists remain effective. Isoproterenol has been widely used for many years. 

Some experts administer benzathine penicillin G 2.4 million units IM once per week for up to 3 weeks after completion of the neurosyphilis regimens to provide a total duration of therapy comparable to that used for late syphilis in the absence of neurosyphilis. For nonpregnant patients pregnant patients should be treated with penicillin after desensitization. 

Reitstetter R, Lukas RJ, Gruener R. (1999). Dependence of nicotinic acetylcholine receptor recovery from desensitization on the duration of agonist exposure. J Pharmacol Exp Ther. 289(2) 656-60. Ribeiro EB, Bettiker RL, Bogdanov M, Wurtman RJ. (1993). Effects of systemic nicotine on serotonin release in rat brain. Brain Res. 621(2) 311-18. 

Intermediate-duration studies suggest that longer term oral exposure can be tolerated by some nickel-sensitive individuals and may even serve to desensitize some individuals. Jordan and King (1979) found flaring of dermatitis in only 1/10 nickel-sensitive women given nickel sulfate at 0.007 mg/kg/day for 2 weeks. Patch test responses to nickel were reduced in nickel-sensitive women given one weekly dose of 0.05 or 0.07 (but not 0.007) mg nickel/kg as nickel sulfate for 6 weeks (Sjovall et al. 1987). 

Tolerance to nicotine s effects develops rapidly and most likely involves multiple processes, although the pattern and extent of tolerance development is not identical for all of nicotine s effects. It has been proposed that rapid tolerance or desensitization occurs to the behavioral or reinforcing effects of nicotine. These effects are of such a short duration that a smoker continually cycles between a sensitized and desensitized state. This notion is consistent with the fact that drugs with high abuse liability have a rapid onset and short duration of action. 

Clinical use Resiniferatoxin has been characterized as an ultrapotent sensory neuron desensitizing agent. It is 100 to 10,000 times more potent than capsaicin, has a longer duration of action, is much less irritating, and is substantially more effective in producing neural... 

For each study we specified the type of clinical study performed, the number of patients included, the duration of the study, its criteria for their inclusion, the methods employed to study the mite content of the environment when it was carried out (table 1), the therapeutic agents employed and the type of maintenance dose (table 2), the criteria chosen to assess the efficacy of sublingual desensitization, the results and adverse effects observed (table 3). 

Does sublingual desensitization preclude subsequent sensitizations Are the benefits of desensitization sustained for a long time after its discontinuation Is a maximum duration of 24 months justified by objective arguments As yet, no study has provided an answer to these questions concerning sublingual desensitization in mite allergy. 

The topical anesthetics in general use in the horse are 0.5% proxymetacaine (proparacaine) and 0.5% tetracaine (amethocaine). The rate of onset and duration of clinical anesthesia of the ocular surfaces using these agents in the horse is not known. However, in general, repeated instillations at 30-60 s intervals over a 5 min period will superficially desensitize the normal eye for around 15 min. In the presence of conjunctival hyperemia, there is likely to be accelerated loss of the drug into the systemic circulation and instillation of the anaesthetic agent at shorter intervals for a longer period may be necessary to desensitize the ocular surfaces effectively. 

Variations in the pharmacokinetics of the sulphonylureas are clinically relevant because of the differences in their rate of onset and their duration of action. Differences in the rate of onset are important because they relate to the capacity to reduce the delay in acute insulin release after nutritional challenge and therefore their capacity to reduce the evaluation and prolongation of the postprandial hyperglycaemia. Differences in the duration of action are important because they relate to the risk of causing chronic hyperin-sulinaemia, long-lasting hypoglycaemia, and possibly desensitization to sulphonylureas (Melander et al., 1990). 

All of the inhalational agents augment both the degree and duration of the neuromuscular blockade induced by the nondepolarizing muscle relaxants. Possible mechanisms by which they exert their effect include depression of the central nervous system, presynaptic inhibition of acetylcholine mobihzation and release, postsynaptic receptor desensitization, or an action imposed on the muscle at some point distal to the chohnergic receptor. 

REFRACTORINESS TO CATECHOLAMINES Exposure of catecholamine-sensitive cells and tissues to adrenergic agonists causes a progressive diminution in their capacity to respond to such agents. This phenomenon, variously termed refractoriness, desensitization, downregula-tion, or tachyphylaxis, can limit the therapeutic efficacy and duration of action of catecholamines and other agents see Chapter 1). 

Therapy of syphilis with penicillin G is highly effective. Primary, secondary, and latent syphilis of <1 year s duration may be treated with penicillin G procaine (2.4 million units per day intramuscularly), plus probenecid (1.0 g/day orally) to prolong the tj for 10 days or with 1—3 weekly intramuscular doses of 2.4 million units of penicillin G benzathine (three doses in patients with HIV infection). Patients with neurosyphilis or cardiovascular syphilis typically receive intensive therapy with 20 million units of penicillin G daily for 10 days. Since there are no proven alternatives for treating syphilis in pregnant women, penicillin-allergic individuals must be acutely desensitized to prevent anaphylaxis. 

Fig. 8.9. Square-wave signal considered for the response to pulsatile stimulation in the general model based on receptor desensitization. The duration of stimulation and the interval between successive stimuli are denoted by t, and tq, respectively (Li Goldbeter, 1989b).

Fig. 8.15. Optimal pattern of cell responsiveness observed at three increasing magnitudes of stimulation in the general model based on receptor desensitization. The variation in cell responsiveness defined by eqn (8.13), is determined numerically as a function of the duration of stimulation, t, and the interval between two stimuli, % for = 0.1 (a), 1 (b) and 10 (c) the basal value of the normalized ligand level, is equal to 0.001. The optimum (tj, tq ) as well as the absolute value of are seen to vary with the amplitude of the pulsatile stimulus (Li Goldbeter, 1992).

To determine quantitatively how the response of the signalling system varies with the pattern of periodic stimulation, it is useful to consider first the total amount of intracellular cAMP, Pj, synthesized above the basal level over a period once a constant amplitude has been reached in response to pulsatile stimulation (dashed area in fig. 8.16). How this quantity varies with the duration Ti and interval To is shown in fig. 8.17. At very large values of To the response increases and later saturates as the duration of stimulation increases. At lower values of Tq, the response passes through a maximum as Ti rises the increase in response due to prolonged stimulation is indeed counterbalanced by enhanced receptor desensitization. 

Whatever the details of the molecular mechanism of desensitization, the results on the existence of an optimal pattern of stimulation by GnRH pulses is confirmed not only by in vivo observations in the rhesus monkey (see above), but also by the systematic experiments of McIntosh McIntosh (1986) and Liu Jackson (1984) on the effect of different patterns of pulsatile stimulation by GnRH on the secretion of gonadotropic hormones in cultures of pituitary cells. The response of pituitary cells as a function of the duration of the stimulus and of the interval between successive stimuli (fig. 8.20) - which parameters correspond to the quantities ti and Tq in the simulations presented in fig. 8.13... 

Li Goldbeter (1992) carried out a detailed analysis of the general model based on receptor desensitization (see section 8.4), in which the duration Tj and/or the pulse interval Tq of the square-wave stimulus were varied in a random manner or chaotically. The latter, aperiodic variations were generated by means of the logistic map. In each case... 

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