The delayed onset effect

The delayed onset effect was discovered experimentally by Ederer [180] in 1964 in the photoionisation spectrum of Xe gas. A more recent compilation of results for the same spectrum is presented in fig. 5.1. If one considers the ionisation continuum of H, then just above the ionisation threshold, there is a maximum in the cross section, which is followed by a monotonic decline with increasing energy. Such situations are illustrated in fig. 4.1 until the observations of Ederer, it had been believed that this would be the most general behaviour of continuum cross sections and that, apart from the Seaton-Cooper minima discussed in section 4.4, or the local influence of interchannel perturbations, revealed in spectra such as that of fig. 4.3, unperturbed continuum cross sections would usually follow a monotonic course of declining intensity comparable to that of H. 

The case of Xe demonstrated that this is definitely not the case. That this is a gross effect is apparent from the scale of energies involved the maximum in the cross section is delayed (in energy) by many eV above the associated threshold, which completely distorts the appearance of the photoionisation continuum. 

The delayed onset effect was soon explained in terms of a centrifugal 

This elegant and simple explanation was backed up by independent particle model calculations for a number of cases [186, 187], which demonstrated the effect semiquantitatively, and confirmed the observed dependences on atomic number for most elements. 

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Fig. 5.1. The spectrum of Xe above the 4d thresholds, showing the delayed onset effect. The dots are experimental results from [181], the open circles are from [182] and the triangles from [183], while the theoretical curves (Hartree-Fock length and velocity approximations - see equation (5.31)) are due to [184]. Note the logarithmic scales.

The LCso in mice for 60 minutes was 150 ppm effects were irritation of the eyes and nose and the delayed onset of labored breathing and lethargy autopsy findings included marked pulmonary congestion and hemorrhage. Mice exposed to sublethal concentrations had pulmonary irritation and delayed development of focal necrosis in the liver and kidneys. ... 

There may be an asymptomatic interval between recovery from initial symptoms and onset of delayed symptoms, which tend to develop 12-36 hours after exposure. Constrictive pain in the chest is characteristic of the delayed onset of pulmonary effects, followed by cough, hyperpnea, and cyanosis, leading to profound weakness. Except for the pronounced weakness and hyperpnea, the physical findings and symptoms resemble those of a viral or an influenzal pneumonia. 

Besides leukopenia, diarrhea is the major dose-limiting adverse effect of irinotecan (105,106). There are two different forms. The acute form occurs very early and is due to inhibition of acetylcholinesterase. The delayed-onset form occurs simultaneously with the leukocyte nadir and depends on the concentration of the active compound SN-38 in the plasma and bowel. 

Another incidence of neurodevelopmental effects occurring as a result of in utero exposure to methylmercury was reported by Cox et al. (1989) and WHO (1990). The effect of concern was the delayed onset of walking in offspring in Iraqi children whose mothers were exposed to methylmercury through the consumption of seed grain treated with methylmercury as a fungicide (Al-Mufti et al. 1976 Bakir et al. 1973 Cox etal. 1989 Marsh etal. 1981, 1987). 

Studies of many antidepressants have demonstrated that either desensitization or downregulation of NE receptors corresponds to a clinically relevant time course for antidepressant effects. Other studies have revealed downregulation of 5-HT2 receptors following chronic administration of antidepressants. Thus a theory based on postsynaptic changes in receptor sensitivity provides a cogent explanation of the delayed onset of activity of antidepressant drugs. ... 

Fig. 5.2. Explanation for the delayed onset of photoionisation and subsequent maximum in terms of spatial overlap between initial and final state wavefunctions and phase cancellation effects (see text). The spatial overlap between the 3d orbital and the ef orbital with e = 6 is shown as a hatched area, and corresponds to the maximum value of the cross section, just before phase cancellation sets in. (after S.T. Manson and J.W. Cooper [186]).

This class of drugs desensitizes serotonergic receptors, as well as adrenergic receptors. This may account for the delayed onset of therapeutic effects, as upregulation of receptors may result. 

Minoxidil is absorbed from the Gl tract and is metabolized to its active sulfate metabolite. Plasma concentrations for minoxidil sulfate peak within 1 hour and then decline rapidly. Following an oral dose of minoxidil, its hypotensive effect begins in 30 minutes, is maximal in 2 to 8 hours, and persists for approximately 2 to 5 days. The delayed onset of the hypotensive effect for minoxidil is attributed to its metabolism to its active metabolite. The drug is not bound to plasma proteins. The major metabolite for minoxidil is its N-O-glucuronide, which unlike the sulfate metabolite is inactive as a hypotensive agent. Approximately 10 to 20% of an oral dose of minoxidil is metabolized to its active metabolite, minoxidil O-sulfate, and approximately 20% of minoxidil is excreted unchanged. 

Another scientific argument for evaluating safety pharmacology effects on repeat-dosing is the phenomenon of delayed-onset effects that may be missed if just assessing the effects of a single administratiOTi. Mechanisms for delayed effects... 

Differences in the effects of acute and chronic treatment with imipramine and protriptyline on central NE metabolism in the rat have been observed. The turnover of NE was decreased after acute administration but increased during chronic administration of these drugs. The increase in NE turnover occurred sooner when thyroxine was administered with imipramine. It is suggested that these observations may help to explain the delayed onset of clinical antidepressive effects and the accelerating and enhancing effects of thyroid hormone on the clinical effects of imipramine. It has been suggested that thyroxine may exert some of its... 

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