Drug effects biphasic

COMMENT/QUESTION 1 was very intrigued by your substitution data from the drug discrimination paradigm. But my question is not unlike Lou Seiden s. For with substances that are characterized by tremendously qualitatively different effects, biphasic in nature, and in many functional... 

Dose-effect curve for a biphasic drug effect... 

Gallium nitrate is approved for treating cancer-related hypercalcemia. It showed antitumor activity fur putienb with lymphoma in phase II trials. - Gallium nitrate probably works in hypercalcemia by inhibiting calcium resorption from bone, although the precise mechanism is unknown. Major side effects include hypocalcemia and nephrotoxicity. On continuous infusion, the drug exhibits biphasic elimination with an a half-life of 8.3 to 26 minutes and a half-life of 6.3 to 95 hours. Between 69 and 91% of the dnsc was recovered in the urine. ... 

Pharmacokinetic analysis revealed R115777 to be rapidly absorbed with peak plasma concentrations being reached by 3 to 4 h and steady state levels after 3 days. The degree of bioavailability and the steady state levels attained were sufficient pharmacologically for antitumor effects as predicted by preclinical experiments. The drug exhibits biphasic elimination with half-lives of 4 h and 16 h. 

There are similarities between the biological actions of inhalants and those of alcohol and barbiturates (Bowen et al. 1996b). For example, acute administration of inhalants affects motor coordination (Moser and Balster 1981) and induces anxiolysis, whereas chronic administration is associated with physical dependence and withdrawal (Bowen et al. 1996a Evans and Balster 1991, 1993). In addition, some inhalant drugs have anticonvulsant properties (Wood et al. 1984). Like other CNS-depressant agents, inhalants have biphasic effects on spontaneous locomotor activity in rodents, with increased activity seen at lower doses and diminished locomotion seen at higher doses (Cause et al. 1985 Kjellstrand et al. 1985). 

Excretion - Following discontinuation of chronic oral therapy, amiodarone has a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 107 days. A much slower terminal plasma elimination phase shows a half-life of the parent compound of approximately 53 days. For the metabolite, mean plasma elimination half-life was approximately 61 days. Antiarrhythmic effects persist for weeks or months after the drug is discontinued. 

Distribution of etomidate is rapid, with a biphasic plasma concentration curve showing initial and intermediate distribution half-lives of 3 and 29 minutes, respectively. Redistribution of the drug from brain to highly perfused tissues appears to be responsible for the relatively short duration of its anesthetic effects. Etomidate is extensively metabolized in the liver and plasma to inactive metabolites, with only 2% of the drug excreted unchanged in the urine. 

The function r (E) can take various forms describing the natural growth of the cell population in the absence of drug [372,445], while g (c) can be either linear or nonlinear [435,446,447]. Due to the competitive character of the functions r (E) and g (c), the cell number vs. time plots are usually biphasic with the minimum effective concentration of drug being the major determinant for the killing or regrowth phases of the plot. 

In spite of its apparent straightforwardness, drug self-administration is affected by serious interpretative difficulties that limit its usefulness in the study of the basic mechanisms of drug motivated behavior. These difficulties are mainly related to the biphasic nature of the dose-effect relationship. In the following example we will consider the case of cocaine i.v. self-administration. 

A recent study by Xi et al. (1998) utilized single carbon fiber instead of multiple fiber electrodes and a fast-scan voltammetry instead of chronoamperometry. An additional difference was that the rats were first trained to acquire stable rates of heroin selfadministration and then were implanted with the electrodes. Under these conditions 60% of the rats responded to self-injection of 0.06A).l mg/kg of heroin with a monophasic increase, 20% with a biphasic increase/decrease and 20% with a biphasic decrease/ increase of the electrochemical signal (Xi et al., 1998). Only monophasic increases were observed with doses of 0.2 mg/kg of heroin. Tonic monophasic increases in signal were observed also by chronoamperometry with stearate-coated electrodes in a comparative study of cocaine and amphetamine self-administration in parallel with microdialyis (Di Ciano et al., 1995). From this study, however, it appears that, although the effect of drug self-injection on dialysate DA and on the tonic voltammetric signal is qualitatively... 

Microdialysis allows direct intracerebral administration of the drugs that normally do not cross the blood-brain barrier (BBB) or are metabolized in the circulation. It was demonstrated earlier (Ozaki et al., 1988 Westerink et al., 1990) that MPP+, a toxic metabolite of 1-methyl-4-phenyl-l, 2,3,6-tetrahydropyridine (MPTP), has a biphasic effect on TH activity when infused via the microdialysis probe for 20 minutes. Since, however, this drug does not penetrate the BBB, it was difficult to investigate its effects in vivo. Microdialysis overcomes this problem and has enabled the testing of a range of other modulators that previously could be studied only on in vitro preparations. 

Nicotine is called a biphasic drug because at low doses it stimulates ACH receptors but at higher doses it retards neural transmission (Taylor, 2001). This biphasic action partly e. plains the complex effects that humans perceive when they ingest nicotine, which we discuss shortly. 

Nicotine is classified as a stimulant drug, but people who use it often report decreased arousal. That is, the perception is that nicotine has a calming effect, and nicotine users find this effeet reinforcing (Todd, 2004). The reasons for this perception of lowered arousal are complex. One factor may be nicotine s acute effect of relaxing the skeletal muscles (see Table 7.5 also see Jones, 1987b). Another pharmacological reason is nicotine s biphasic action at higher doses its effects are more depressant. 

The phenothiazines have a long duration of effect compared with many of the other sedative-tranquillizers used in horses. The onset of effect is relatively slow after i.v. administration and the maximum clinical effect occurs 20-30 min after i.v. administration. Peak plasma drug levels occur 30 min after the i.m. injection of acepromazine (Chou et al 1998). Acepromazine has a biphasic concentration decay pattern after i.v. administration (Marroum et al 1994). The distribution half-life is 3-5 min (Ballard et al 1982, Marroum et al 1994) and the elimination half-life is 2-3 h. The terminal half-life of acepromazine after oral administration is approximately 6h. Acepromazine is highly protein bound in the plasma (>99%) with a large apparent volume of distribution (Vj, 6.61/kg) (Ballard et al 1982). 

The treatment of HBV with lamivudine (LMV) and famciclovir (FCV) therapy also exhibits a biphasic decline in viral load with an initial rapid decline during the first 2 days representing both the clearance of free virus rate (cV) and the effectiveness of drugs (e) followed by a slower decline representing the clearance of infected cells (S) (13, 59, 60). Lewin et al. (60) and Nowak et al. (13) proposed that during LMV and FCV therapy, the production rate of new virus (pi) was decreased by a factor (1 - e) and de novo infection rate (pVT) was decreased by a factor (1 - rj). Therefore, Eqs. (22.14)-(22.16) can be modified as follows ... 

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