Maximum useful dose

With some drugs, the point at which efficacy fails to improve is reached before the maximum tolerated dose is reached. In that case, the concept of the maximum useful dose (International Conference on Harmonisation, 1995) may be relevant, although this concept can also be ambiguous as it may be the dose for which some utility reflecting a trade-off between efficacy and tolerability is a maximum. (See section 20.2.13 for a discussion.)... 

Health and Safety Factors. Both pyromellitic acid and its dianhydride irritate skin, eyes, and mucous membranes, and they cause skin sensitization (156). When it comes in contact with moist tissue the dianhydride converts to the acid. Direct contact with should be avoided and protective clothing should be worn in areas where it is used. The LD q for intergastric administration in rats is 2.2—2.6 g/kg (157). In 6-mo experiments, the maximum nontoxic dose was 0.07 mg/kg/d, and it affected the fiver, kidney, and reproductive tract. Precautions against fire and dust explosions as explained in the terephthafic acid section should be foUowed. 

Savolainen, K. M. (1997). The use of maximum tolerated dose in rodent carcinogenicity bioas says and its relevance to human risk assessment. Hum. Exp. Toxicol. 16, 190-192. 

Numerous experimental therapeutics have shown potency in vitro however, when they are tested in vivo, they often lack significant efficacy. This is often attributed to unfavorable pharmacokinetic properties and systemic toxicity, which limit the maximum tolerated dose. These limitations can be overcome by use of drug carriers. Two general types of carrier systems have been designed drug conjugation to macromolecular carriers, such as polymers and proteins and drug encapsulation in nanocarriers, such as liposomes, polymersomes and micelles. 

Experiments were conducted in which purified trichloroethylene (1 mg in acetone) was applied to the shaved backs of female ICR/Ha Swiss mice (Van Duuren et al. 1979). In an initiation-promotion study, a single application of trichloroethylene was followed by repeated application of phorbol myristate acetate (PMA) promoter. In a second study, mice were treated with trichloroethylene three times per week without a promoter. No significant tumor incidences were observed in these studies. Doses used in these studies were well below the maximum tolerated dose, which is often not reached in dermal studies. 

Lutein produced negative results in several studies of genotoxicity in vitro and in vivo. Although the committee noted that the doses used in these tests were low, it recognized that maximum feasible doses were used. No evidence of tumor-promoting activity was noted in animal models. 

Cardiotoxicity is a serious, rare adverse effect of mitox-antrone. The incidence of congestive heart failure was 0.15% in patients with normal left ventricular ejection fraction and 2.18% in those who had asymptomatic left ventricular ejection fraction of less than 50% at baseline.46 Therefore, mitoxantrone should not be used in patients with baseline cardiomyopathy, even if asymptomatic. The risk of cardiotoxicity is dose-related. The maximum lifetime dose of mitoxantrone is 140 mg/m2, or about 3 years of MS therapy. The use of cyclooxygenase-2 inhibitors should be avoided in patients receiving mitoxantrone because of a potential for worsening cardiac toxicity.46... 

Opioids maybe administered in a variety of routes including oral (tablet and liquid), sublingual, rectal, transdermal, transmucosal, intravenous, subcutaneous, and intraspinal. While the oral and transdermal routes are most common, the method of administration is based on patient needs (severity of pain) and characteristics (swallowing difficulty and preference). Oral opioids have an onset of effect of 45 minutes, so intravenous or subcutaneous administration maybe preferred if more rapid relief is desired. Intramuscular injections are not recommended because of pain at the injection site and wide fluctuations in drug absorption and peak plasma concentrations achieved. More invasive routes of administration such as PCA and intraspinal (epidural and intrathecal) are primarily used postoperatively, but may also be used in refractory chronic pain situations. PCA delivers a self-administered dose via an infusion pump with a preprogrammed dose, minimum dosing interval, and maximum hourly dose. Morphine, fentanyl, and hydromorphone are commonly administered via PCA pumps by the intravenous route, but less frequently by the subcutaneous or epidural route. 

Decongestants such as OTC pseudoephedrine are sympathomimetic agents that constrict capacitance vessels in the nasal turbinates.17 Decongestants effectively reduce nasal congestion and to some extent rhinorrhea associated with AR.8,12 The recommended dose of pseudoephedrine is 30 to 60 mg every 4 to 6 hours for a maximum daily dose of 240 mg.15 Systemic adverse effects such as irritability, dizziness, headache, tremor, tachycardia, and insomnia can occur. Additionally, use is associated with increased blood pressure and intraocular pressure and urinary obstruction.8,12... 

Intravenous lipid emulsions are also a source of calories. The typical daily dose in adults is approximately 0.5 to 1 g/kg per day. In the absence of hypertriglyceridemia, substituting a portion of dextrose calories with lipid calories may be beneficial in situations where dextrose infusion may lead to complications (e.g., hyperglycemia). Some examples include patients with diabetes mellitus or pancreatic disease and patients under severe stress (e.g., trauma or burns) who are at risk for hyperglycemia. The maximum of dose of lipid emulsions is 2.5 g/kg per day,7 or 60% of total daily calories, although doses this high are used rarely in practice. 

In the current era with widespread problems of poor solubility [4] a compound (drug) with average permeability and a projected clinical potency of 1 mg kg-1 needs a minimum aqueous solubility of 50-100 jug mL-1 to avoid the use of nonstandard solubility fixing formulation technology. The guidelines published by Pfizer s Curatolo on maximum absorbable dose are an excellent guide for the combination of permeability, solubility and potency required in an orally active drug [8],... 

Rizatriptan 5 or 10 mg at onset as regular or orally disintegrating tablet can repeat after 2 hours if needed Optimal dose is 10 mg maximum daily dose is 30 mg onset of effect is similar with standard and orally disintegrating tablets use 5-mg dose (15 ms day max) in patients receiving propranolol... 

Nevertheless, this study had several limitations. Initial doses were not well tolerated because of exceedence of the Maximum Tolerated Dose (MTD) as indicated by excessive deaths. Doses were reduced 17-33% from initial doses once or twice during the experiment. During the final 75 days of treatment, high dose males received chlordecone on alternative weeks only. Doses above the MTD were used for 42-386 days. An unusually high mortality rate occurred in control animals also, and only pooled controls were used in this bioassay. 

Doses selected for safety pharmacology studies are typically based on the criteria established in the ICH S7A guidance.25 Doses should exceed those projected for clinical efficacy and at the upper limit be bound by (1) adverse pharmacodynamic effects in the safety pharmacology study (2) moderately adverse effects in other non-clinical studies that follow a similar route and duration of dosing or (3) limit of solubility/toxicity. In the absence of adverse effects, the maximum administrable dose can be used. If nonreusable animals enter the study, then the maximum tolerated dose may be appropriate. Most importantly, the doses/concentrations should establish the dose/concentration-response relationship of the adverse effect. 

Like fluphenazine, haloperidol is available in oral, injectable, and depot forms. In schizophrenia, haloperidol is begun at doses of 5 mg daily and increased as needed. Lower doses are used for most other indications. The depot form of haloperidol is initiated by administration of a 50mg test dose. Depot haloperidol is given monthly at about 20 times the daily dose of the oral form. The maximum depot dose is 200 mg per month. Dose dumping does not seem to be a problem with depot haloperidol. 

When used for detoxification, phenobarbital is given in equal doses four times a day. The maximum daily dose of phenobarbital is 600 mg, but much lower doses are usually sufficient. The phenobarbital dose is lowered (i.e., tapered) by about 20% per day. If the patient is too drowsy, then a dose should be skipped. If breakthrough withdrawal symptoms continue to occur, then the pace of the detoxification should be slowed. Before using phenobarbital, liver function tests should be obtained. All barbiturates depend greatly on the liver to be metabolized. Alcoholics with cirrhosis or other forms of liver impairment may have difficulty clearing phenobarbital. Phenobarbital should not be used in patients with poor liver function. In addition, the barbiturates can worsen a medical condition known as porphyria and should be avoided in those with this disorder. Phenobarbital, as noted, is seldom used today for alcohol detoxification. 

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