Minimally effective dose

Other SERMs are currently under development. Diaz Curiel et al. (1998) have proved that a raloxifene analog, LY117018 HC1, is effective in reducing bone loss in OVX rats. In addition, the administration of the substance permits a significant reduction in the minimal effective dose of human parathyroid hormone (PTHh) required in the treatment of osteopenic rats (Hodsman et al. 1999a,b). Two more compounds, FC1271a 41 and HMR-3339 (Ammann et al. 2004), show promising results in preclinical studies. 

Various pyridazine-A-oxides (including cinnoline A-oxides) have been prepared as potential antitumour agents in Japan [276-278]. Among several 4-nitro-pyridazine 1-oxides tested for activity against rat ascites hepatoma AH-13, 3,6-dimethoxy-4-nitropyridazine 1-oxide (74) has been found to be the most potent compound a minimal effective dose of 5 mg/kg has been estimated [276], Also pyridazine A-oxides of type (75) bearing a bis(2-chloroethyl)ami-nomethyl side-chain at C-6 have been reported to be effective (0.5-5 mg/kg, i.p.) against AH-13 in rats [278]. Both types of compound (74), (75, R = H, Br), however, have been shown to be inactive against mouse lymphoid leukaemia L-1210. 

The initial testing was cautious, mainly establishing the minimal effective doses for each of a series of new belladonnoids. Sometimes, however, the quality and quantity of on-site staffing was not what it should have been. On one visit, I became quite upset with the prison staffs lack of expertise regarding psychoactive drug effects. Dr. Kligman came down to Edgewood to meet with some of us and discuss this problem. 

Minimal effective dose (MED50) - Lowest im dose required to produce 3 of 5 successive Number Facility (NF) scores below 75% of baseline. 

Minimal Effective Dose Medium Dose -Incapacitating Dose... 

NG EA 3580A Estimate of minimal effective dose in man. Edgewood Arsenal, MD. CRDL Technical Memorandum 2-12. 1965... 

Kitzes DL, Vancil ME. Estimate of Minimal Effective Doses of BZ by the Intramuscular Route in Man. Edgewood Arsenal Technical Memorandum 2-30, 1965. 

Charbonneau M, Perreault F, Greselin E, et ah Assessment of the minimal effective dose of acetone for potentiation of the hepatoxic-ity induced by trichloroethylene-carbon tetrachloride mixtures. Fundam Appl Toxicol 10 431-438, 1988... 

Moderate to severe vasomotor symptoms, vulvar/vaginal atrophy associated with menopause - Initiate treatment at the lowest dose. Titrate to determine the minimal effective dose for maintenance therapy. Administer micronized estradiol cyclically (eg, 3 weeks on and 1 week off). Administer estradiol acetate once daily. 

Hypoestrogenism caused by hypogonadism, castration, or primary ovarian failure-Treatment usually is initiated with a dose of 1 to 2 mg daily, adjusted as necessary to control presenting symptoms determine the minimal effective dose for maintenance therapy by titration. 

Renal impairment - Reduce initial dosage and use smaller increments for titration, which should be quite slow (1- to 2-week intervals). After the desired therapeutic effect is achieved, slowly back-titrate to the minimal effective dose. 

Initial therapy Give minimally effective dose (usually, 50 to 200 mg/day) on a continuous or intermittent dosage schedule to produce gradual weight loss of 2.2 to 4.4 kg/day (1 to 2 Ib/day). Adjust dose in 25 to 50 mg increments. Higher doses, up to 200 mg twice daily, achieved gradually, are most often required in patients with severe, refractory edema. 

All potencies are relative to a-MSH In dose-response assays. Relative potency cone, of a-MSH at 50Z responae/conc. of peptide at 50Z response. The cyclic peptides 11 and 12 have much higher minimal effective dose potencies ( 10,000) In the frog skin system. 

Acute toxicity studies have been performed in various animals mice, rats, rabbits, cats, dogs, and macaques.18,20,35,36,40,44 Lethal doses of DMHP are extremely high, in comparison with the small doses required to produce its pharmacodynamic effects. For instance, the intravenous LD50 in mice is 63 mg/kg, whereas the minimal effective dose in 50% of the animals (MED50) is 0.075 mg/kg, for a safety factor of 840. The dose required to produce tranquilization in the unanesthetized dog is 0.05 mg/kg, and the minimal lethal dose is 10 mg/kg by the same route. The margin of safety in the dog is about 200. By comparison, the margin of safety of reserplne is 5.0. 

Nyberg S, Eriksson B, Oxenstierna G, et al. Suggested minimal effective dose of risperidone based on PET-measured D 2 and 5-HT2g receptor occupancy in schizophrenic patients. Am J Psychiatry 1999 156 869-875. 

To supplement depot medication, oral preparations can be used when early warning signals of an impending relapse occur because the pharmacokinetics of depot preparations require months to reach steady-state (see also Pharmacokinetics/Plasma Levels later in this chapter). By contrast, oral administration brings about an altered steady state in several days. We recommend treating most patients with the minimally effective dose to avoid more serious adverse effects, even at the cost of a few more relapses, provided this strategy does not lead to rehospitalization or produce serious impairment in functioning. 

Possible usefulness in helping to establish the minimally effective dose... 

Neurotoxic reactions have been periodically reported with lithium alone or in combination with antipsychotics, CBZ, verapamil, or methyidopa, with the elderly probably at much greater risk for such events (Table 10-21). Although such drug combinations are often necessary and usually well tolerated, common clinical sense dictates that only the minimally effective doses be prescribed. It is also advised that patients carry or wear some form of identification indicating that they are receiving... 

The primary cardiovascular effects of muscarinic agonists are reduction in peripheral vascular resistance and changes in heart rate. The direct effects listed in Table 7-3 are modified by important homeostatic reflexes, as described in Chapter 6 and depicted in Figure 6-7. Intravenous infusions of minimally effective doses of acetylcholine in humans (eg, 20-50 mcg/min) cause vasodilation, resulting in a reduction in blood pressure, often accompanied by a reflex increase in heart rate. Larger doses of acetylcholine produce bradycardia and decrease atrioventricular node conduction velocity in addition to hypotension. 

Intracavernosal injection or urethral suppository therapy with alprostadil (PGE1) is a second-line treatment for erectile dysfunction. Doses of 2.5-25 meg are used. Penile pain is a frequent side effect, which may be related to the algesic effects of PGE derivatives however, only a few patients discontinue the use because of pain. Prolonged erection and priapism are side effects that occur in less than 4% of patients and are minimized by careful titration to the minimal effective dose. When given by injection, alprostadil may be used as monotherapy or in combination with either papaverine or phentolamine. 

Minimally effective dose, [a] unpublished data of the author s group. 

With long-term treatment, IgG subclass deficiencies can become marked (312). There is suppression of the antigen-antibody reaction, and since this reaction itself normally results in liberation of kinins, the latter is also suppressed. Failure of kinin liberation leads in turn to inhibition of invasion of sensitized leukocytes and reduced production and maturation of phagocytes. Undoubtedly, it is true that using minimal effective doses will avoid the most serious consequences, but the problem cannot be fully circumvented, since the antiinflammatory effects themselves involve some inhibition of the migration of leukocytes and phagocytosis. 

Regarding the efficacy of hypnotics when used long-term, there is evidence that sleep latency shows more tolerance than sleep time. Furthermore, it is generally accepted that each hypnotic has a minimal effective dose and that increasing this does little to improve the duration of sleep but is more likely to increase the side effects. 

These parameters include, but are not limited to, establishment of a minimal effective dose (MED), a no observable dose (NOEL), a no observable adverse effect dose (NOAEL), and a maximum tolerated dose (MTD). From the standpoint of our antibody-coated stent model, and antibody dose, it is possible that the product (device) labeling could limit the dose of mAb a patient is allowed to receive to how much protein is able to be coated onto just one stent. Alternatively, since stents are made in various lengths in order to match the length of the lesion, the longer the stent, the more antibodies that can be delivered. 

Locomotor activity can be quantified in rodents by a variety of means. The method described below uses interruptions of photoelectric beams. The difference between Irwin estimations of drug effects on spontaneous activity and activity meter tests is mainly a question of quantification. Activity meter tests are generally carried out using automated apparatus with a larger number of animals, and are therefore less labor intensive but permit more precise statistical analyses. The quantitative data obtained enable the generation of dose-response curves and more precise estimations of the minimal effective dose (MED) or the dose which increases or decreases locomotion by 50 % (ED50). 

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