Sustained duration of action

Lercanidipine (Fig. 7.10) is one of the last dihydropyridines introduced into the market. Its high lipophilicity explains its long duration of action. Lercanidipine is extensively metabolized in the liver after oral administration, and is then retained by vascular cells to achieve a sustained duration of action. It is used in the treatment of hypertension and angina. like lacidipine, its smooth onset of action... 

The main objective of the project was to identify a new potent and selective dihydropyridine calcium antagonist which was endowed with a sustained duration of action and was amenable to become a once-daily antihypertensive drug. 

In vivo, lacidipine -when administered orally - was found to be an effective and potent antihypertensive agent in different animal models, including SHR (ED25 = 0.5 mg kg-1, per os) and renally hypertensive dogs (ED25 = 0.004 mg kg-1, i.v.) with a sustained duration of action [11,12]. Lacidipine was also found to possess coronary and cerebral vasodilatory activity [13]. 

In vivo studies for many of the Merck yS-lactam inactivators have been reported. In the cephem series, these reports have focused on the i.t. profile of (16-7) which was determined to possess the best overall properties for an aerosol drug candidate. This compound had an ED50 of 5 fig /animal in the AHA model when dosed i.t. 30 min. prior to HLE challenge. It showed sustained duration of action in the AHA model with a tjo (the pre-insult time... 

Recently, Mylari el a/, have prepared, according to Scheme 79, a novel sorbitol dehydrogenase inhibitor 351 that shows very high oral potency (50 rgkg ) in normalizing elevated fructose levels in the sciatic nerve of chronically diabetic rats and sustained duration of action (>24h) <2002JME4398>. 

Melatonin at doses of 0.5 to 5 mg taken at appropriate target bedtimes for east or west travel is becoming the drug of choice for jet lag. Melatonin significantly reduces jet lag and shortens sleep latency in travelers.50 Hypnotic agents with relatively short durations of action (3 to 5 hours) also may be used to sustain sleep during the initial adaptation to the new time zone. 

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... 

Melatonin does appear to initiate sleep effectively, but its extremely short duration of action raises questions about its ability to sustain sleep through the night. The effective dose of melatonin is not known. It has not yet been well studied in controlled clinical trials, and inaccuracies in the reported dosage of many dietary supplements remain a problem. 

Methylphenidate is readily absorbed and produces peak plasma levels in approximately 2 hr (immediate-release formulation). The duration of action is 3-6 hr for the immediate-release and 8 hr for the sustained-release formulation. Approximately 90% of methylphenidate is excreted in the urine as metabolites (80% is ritalinic acid) and the remainder as unchanged drug (26,36). 

Lente insulin is a mixture of 30% semilente (an amorphous precipitate of insulin with zinc ions in acetate buffer that has a relatively rapid onset of action) with 70% ultralente insulin (a poorly soluble crystal of zinc insulin that has a delayed onset and prolonged duration of action). These two components provide a combination of relatively rapid absorption with sustained long action, making lente insulin a useful therapeutic agent. As with regular insulin, the time of onset, time to peak, and duration of action are dose-dependent. 

To explore the utility of this approach, plasma samples obtained after injection of TACA into the posterior segment of the eye in pigs were analyzed [8], The objective of this therapeutic strategy was to achieve a local, sustained, pharmacologically active concentration in the eye, with minimal systemic concentrations. In this application, the low water solubility of TACA contributes to its prolonged duration of action at the injection site a previous human study showed that intraocular TACA maintained concentrations >100 ng/mL in the eye for at least 700 h after a single 4-mg intravitreal TACA treatment [9], However, TACA concentrations in plasma... 

The newer sustained release Metadate CD has an early peak and an 8-hour duration of action... 

The newer sustained release Concerta trilayer tablet has longest duration of action (12 hours)... 

Salmeterol is a selective beta2-adrenoceptor agonist that is more potent and has a significantly longer duration of action than salbutamol (SEDA-21, 184). It is used as a supplement to inhaled glucocorticoids for sustained bronchodUatation. It has a much slower onset of effect than salbutamol and is not effective in acute attacks of asthma. It is available as a multidose-pressurized aerosol 0.025 mg/puff, and as a dry powder, Diskhaler or Accuhaler 0.05 mg per dose. The adverse effects profile of salmeterol is the same as that of salbutamol and other betaz-agonists (SEDA-21, 185). 

---