Dose dependence

The more variable responses with growing catde appear to result from lower doses, nutritional constraints, or lesser responsiveness of younger animals, ie, veal calves. A dose-dependent reduction in feed intake in finishing cattle, which also reduced average daily gain, has been observed (84). However, carcass composition was improved in a dose-dependent manner. 

As a therapeutic class, hypnotics are nonselective CNS depressants that eflcit drowsiness and a natural sleep state from which the individual can be aroused. The effects of hypnotics are generally dose-dependent. 

Reproductive System. The primary PGs are intimately involved in reproductive physiology (67). PGE2 and PGP2Q, are potent contractors of the pregnant utems and intravenous infusion of either of these compounds to pregnant humans produces a dose-dependent increase in frequency and force of uterine contraction. PGI2 and TXA2 have mild relaxant and stimulatory effects, respectively, on uterine tissue. The primary PGs also play a role in parturition, ovulation, luteolysis, and lactation and have been impHcated in male infertility. 

Side Effects and Toxicity. Adverse effects to the tricycHc antidepressants, primarily the result of the actions of these compounds on either the autonomic, cardiovascular, or central nervous systems, are summarized in Table 3. The most serious side effects of the tricycHcs concern the cardiovascular system. Arrhythmias, which are dose-dependent and rarely occur at therapeutic plasma levels, can be life-threatening. In order to prevent adverse effects, as weU as to be certain that the patient has taken enough dmg to be effective, the steady-state semm levels of tricycHc antidepressant dmgs are monitored as a matter of good practice. A comprehensive review of stmcture—activity relationships among the tricycHc antidepressants is available (42). 

Subcutaneous injection of 100—750 mg/kg sulfolane at an ambient temperature of 10°C also caused a dose-dependent decrease in colonic temperature of rabbits. MetaboHc rate remained unchanged during the initial phase of the hypothermia for all dose groups but peripheral vasodilatation, as indicated by an increase in ear skin temperature, was seen at the higher dose levels (29). 

The first human kidney and bone marrow transplants using cyclosporine were reported in 1978. Oral or intravenous cyclosporine is an immunosuppressant for transplantation of these and other organs and investigations are underway for its possible use in a variety of autoimmune diseases including rheumatoid arthritis, severe psoriasis, and Crohn s disease. Dose-dependent nephrotoxicity (261—264) remains the primary limitation of the dmg and necessitates close monitoring of patients, including measurement of dmg levels in blood. Cyclosporine research has been reviewed (265—274). 

Nicardipine is almost completely absorbed after po adrninistration. Administration of food decreases absorption. It undergoes extensive first-pass metaboHsm in the Hver. Systemic availabiHty is dose-dependent because of saturation of hepatic metaboHc pathways. A 30 mg dose is - 35% bioavailable. Nicardipine is highly protein bound (>95%). Peak plasma concentrations are achieved in 0.5—2.0 h. The principal path of elimination is by hepatic metaboHsm by hydrolysis and oxidation. The metaboHtes are relatively inactive and exert no pharmacological activity. The elimination half-life is 8.6 h. About 60% of the dose is excreted in the urine as metaboHtes (<1% as intact dmg) and 35% as metaboHtes in the feces (1,2,98,99). 

In long-term treatment, the thia2ides may produce hypokalemia, hyperglycemia, hypemricemia, and a 5% increase in plasma cholesterol indapamide has been shown not to increase plasma cholesterol or Hpids at therapeutic doses (21—23). The decrease of plasma potassium, ie, hypokalemic effect, is dose-dependent, and can be avoided if high doses are avoided (24,25). Thia2ides can cause hyponatremia in patients with large water intake while on the dmg (26,27) hyponatremia may be associated with nausea, vomiting, and headaches. 

Cu/ Zn0/Si02 catalyst reduced at 700 K [3.147]. These LEIS spectra were obtained at three different ion doses - 3 x 3.41 x 10 and 8.67 x 10 Ne" cm . Because of the use of isotopically enriched Cu and Zn, and of Ne" ions as projectiles, Cu and Zn can clearly be separated in the LEIS spectrum. Strong dose-dependence is apparent. Eig. 3.60b shows the dose-dependent surface concentrations of Cu and Zn. At low doses (<1.5 x lO " Ne cm ) the Zn concentration remains constant whereas the Cu concentration increases. At these low doses a hydroxyl layer on top of the catalyst is sputtered. The Zn signal stays constant despite removal of the adsorbate, indicating that at the virgin surface the Zn concentration was even higher. 

Sulfuric acid (H1SO4) and ammonium bisulfate (NH4HSO4) contribute importantly to ambient acid aerosols, particularly in geographic locations where sulfur-rich coal is used for power plant fuel, such as the eastern United States.Studies on animals and human subjects have shown that H2SO4 and NH4HSO4 alter mucociliary transport in a dose-dependent fashion and... 

Dose-dependent Response to applied stimuli directly proportional to con-... 

Constitutive receptor activity, receptors spontaneously produce conformations that activate G-proteins in the absence of agonists. This activity, referred to as constitutive activity, can be observed in systems in which the receptor expression levels are high and the resulting levels of spontaneously activating receptor species produce a visible physiological response. An inverse agonist reverses this constitutivie activity and thus reduces, in a dose-dependent... 

In general, systemic treatment with ASON is well-tolerated and side effects are dose-dependent. Among those, thrombocytopenia, hypotension, fever, increasing liver enzymes, and complement activation were most frequently seen. 

Vertex also put in clinical trial VX-765, another caspase-1 -specific, YVAD-derived peptidomimetic that is in vitro slightly more potent then pralnacasan (IC50 0.8 nM). Evaluation of VX-765 in a mouse model of oxazolone-induced dermatitis showed a dose-dependent (10-100 mg/kg) inhibition of ear inflammation. Consequently, VX-765 was enrolled in a 4-week phase Ila safety and pharmacokinetic study for psoriasis. However, Vertex has not communicated any results yet. 

Clinical studies, available only for entacapone and tolcapone, support preclinical findings. A dose-dependent (100-800 mg) inhibition of the COMT activity of the erythrocytes can be seen after nitrocatechols. However, effective and sufficient dose levels of both entacapone and tolcapone, given concomitantly with L-dopa and DDC inhibitors to patients with Parkinson s disease, appear to be 100-200 mg. However, the treatment strategies of entacapone and tolcapone differ entacapone is a short-acting compound that is given with each dose of L-dopa, and COMT activity may even... 

A lead is a hit compound that displays specificity and potency against a target in a library screen and continues to show the initial positive dose-dependent response in more complex models such as cells and animals. 

Psychotomimetic drags can be defined as chemical agents that reliably and dose-dependently induce a psychosis, often including hallucinations and delusions in normal individuals. Implicit in this term is a mimicking of naturally occulting psychosis. 

One of the chief adverse reactions associated with the amphetamines and anorexiants is overstimulation of the CNS, which may result in a variety of adverse reactions, including insomnia, tachycardia, nervousness, headache, anorexia, dizziness, and excitement. In some instances, die intensity of diese reactions is dose dependent, but some individuals may experience an intense degree of diese symptoms even widi low doses. Odier individuals experience few symptoms of CNS stimulation. 

As with the barbiturates, the most common adverse reaction seen with the use of clonazepam (Klonopin), clorazepate (Tranxene), and diazepam (Valium) is sedation in varying degrees. Additional adverse effects may include anorexia, constipation, or diarrhea. Some adverse reactions are dose dependent, whereas others may diminish in intensity or cause few problems after several weeks of therapy. 

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