Speed of onset

Topical Application. Azelastine (11) and levocabastine (13) have been developed for topical appHcation (45). The topical antihistamines address the preference of some patients for a local treatment and allow adrninistration of dmg directly to the site requited. The advantage of this therapeutic approach is likely to be in the speed of onset of symptom rehef. In contrast to earlier reports of sensitization with older antihistamines locally apphed to the skin (46), sensitization has not been reported with local appHcation to the nose or eyes. 

Relating the Time-Course of Plasma Concentrations to the Time-Course of Effect A critical decision to be made after the first human study is whether the compound s speed of onset and duration of action are likely to be consistent with the desired clinical response. Speed of onset is clearly of interest for treatments which are taken intermittently for symptoms rehef, for example, acute treatments for migraine, analgesics, or antihistamines for hay fever. Duration of action phase I is particularly important when the therapeutic effect needs to be sustained continuously, such as for anticonvulsants. The first information on the probable time course of action often comes from the plasma pharmacokinetic profile. However, it has become increasingly evident that the kinetic profile alone may be misleading, with the concentration-time and the effect-time curves being substantially different. Some reasons for this, with examples, include... 

The phenomenon by which the speed of onset of inhalational anaesthetic agents is increased when they are administered with N20 as a carrier gas. 

Speed of onset is related to pKa. d Duration of action is related to protein binding. 

Table 9. Comparative values for 3 belladonnoids. Prolongation time = increase in duration by 2x ID50 Dose-Onset factor (Donjo) = increase in speed of onset by 2 x ID50 Safety Factor = LD50/ID50...

Transport of the benzodiazepines into the brain is rapid, the rate of uptake being determined by the physicochemical properties of the drug. Absorption from the gastrointestinal tract, or from an injection site, is the rate-limiting step governing the speed of onset of the therapeutic response. Oral absorption is more rapid when the drug is taken on an empty stomach. 

Although the cellular basis for the action of ethacrynic acid may not yet be established its micro-anatomical effects on the nephron are well attested. The speed of onset and intensity of action make the drug (like frusemide) a valuable addition to existing compounds, especially where diuresis is urgently needed (for example, pulmonary oedema) or in patients resistant to milder drugs of the thiazide type. 

After 6 weeks of treatment, 41 of 55 (75%) patients given fluoxetine plus pindolol versus 33 of 56 (59%) patients given fluoxetine plus placebo responded (F =. 04). Interestingly, no difference was found in the speed of onset of response. Although not limited to patients with TRD, these data do suggest a putative efficacy for patients who are nonresponsive to SSRls. 

Time Interval Until Euthymia Speed of Onset... 

No data link speed of onset during the acute episode with effectiveness in sustaining long-term maintenance, probably because most antidepressants are approximately equivalent in their speed of onset. 

A critical review by Olver et al. (2001) on so-called third-generation antidepressants (venlafaxine, reboxetine, nefazodone, mirtazapine) covered 30 controlled therapeutic trials and a number of relapse prevention studies. Questions addressed were overall efficacy, speed of onset and safety but, according to this review, none of the third-generation antidepressants was specifically tested with respect to its potential effects on cognitive function in depressed patients. 

The speed of onset of action, with the fastest typically being parenteral and the slowest transdermal ... 

Rocuronium is a desacetoxy analogue of vecuronium which is stable in solution and formulated as an aqueous ready-to-use solution. It was deliberately designed as a low-potency relaxant in an attempt to develop a non-depolarising agent which would have a fast onset of action, closer to that of suxamethonium. The basis for this development was the observation that potency and the speed of onset... 

Groups of 50 male and 50 female Fischer 344 rats were fed 0 or 2.36% acetamide in the diet for 12 months. Neoplastic nodules were seen in the liver in 0/50 and 1/47 control and treated males and in 0/49 and 3/48 control and treated females, respectively. Hepatocellular carcinomas were found in 0/50, 41/47, 0/49, 33/48 male controls, male treated, female controls and female treated rats, respectively. The incidence, speed of onset and frequency of metastases were greater in males than in females (Fleischman et al., 1980). 

Because faster onset of action is associated with higher potential for abuse, abuse-liability assessment should include consideration of whether a formulation can be altered to increase the speed of onset. There are numerous examples of abuse of a medication by a route other than that intended by the manufacturer. The sustained-release oral form of oxycodone, designed to deliver an initial rapid dose followed by slow release, has been widely abused by chewing the tablet, thus releasing the entire content of the tablet at once.65 There is also evidence for intravenous use of sublingual buprenorphine tablets.66 Transdermal systems developed to deliver medication slowly for extended periods of time have been prime targets for misuse,67 as discussed below in the case study of fentanyl. 

The feasibility of informative experiments, whether in vitro or, if necessary, in vivo will depend mainly on the availability of model systems that are sufficiently well understood, and the coverage of the broad types of investigation, as in conventional toxicity experiments where the objective is to try to detect any effect and subsequently to decide whether it is toxic or pharmacological . The need to explore such major features as the concentration-response or dose-response relationship, speed of onset, duration of action and reversibility of effects and their upstream and downstream consequences on other physiological mechanisms, potential interactions with the physiological and pathophysiological status of the patient, and other treatments administered at the same time, will all affect the nature and number of the most relevant experiments. 

Reduced effect of sublingual nitrates Increased plasma concentrations of tricyclic drugs Possible potentiation and/or increased speed of onset of antidepressant effect Enhanced cardiotoxic effects with thioridazine... 

Citalopram is a racemic bicyclic phthalane derivative and is a highly selective serotonin re-uptake inhibitor with minimal effects on noradrenaline and dopamine neuronal reuptake. Inhibition of 5-HT re-uptake by citalopram is primarily due to escitalopram, the active S-enantiomer of citalopram (1). One would expect escitalopram to be twice as potent as citalopram but otherwise not to differ significantly from the racemic mixture. However, escitalopram is marketed as being more efficacious than citalopram because, it is argued, the inactive R-isomer present in the racemate actually inhibits binding of the S-enantiomer to its site of action, the serotonin transporter. In some, but not all, clinical trials escitalopram has been statistically superior to citalopram in terms of speed of onset of therapeutic action and improvement on depression rating scales. The clinical significance of these differences is debatable (2). 

Delirium, toxic confusional state, metabolic encephalopathy or acute confusional state are terms that are used interchangeably and often loosely to describe a syndrome of acutely disordered cognition, sometimes associated with reduced level of consciousness and abnormal attention (see Table 32.1). The syndrome is very common, especially in the elderly and in patients with dementia, and presentations vary widely both in the speed of onset and severity (Siddiqi et al. 2006). The differential diagnosis is broad and includes almost any medical condition, but the commonest causes are sepsis, adverse drug reaction and metabolic derangement (Francis et al. 1990). 

DOMPERIDONE, METOCLOPRAMIDE OPIOIDS 1. i efficacy of domperidone on gut motility by opioids 2. Metodopramide T speed of onset and effect of oral morphine 1. Antagonist effect 2. Uncertain metodopramide may promote the absorption of morphine by increasing gastric emptying 1. Caution with co-administration 2. Be aware that the effects of oral morphine are T... 

Insulin cannot be taken as a pill as it is broken down during digestion, similar to protein in food. Therefore it is injected under the skin (subcutaneously). There are more than 20 different preparations of insulin available, but essentially there are four classes determined by the speed of onset, the time of reaching the peak plasma concentration and the duration of activity in the body ... 

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