The median-effect equation derived from the mass-action law principle at equilibrium-steady state via mathematical induction and deduction for different reaction sequences and mechanisms and different types of inhibition has been shown to be the unified theory for the Michaelis-Menten equation, Hill equation, Henderson-Hasselbalch equation, and Scatchard equation. It is shown that dose and effect are interchangeable via defined parameters. This general equation for the single drug effect has been extended to the multiple drug effect equation for n drugs. These equations provide the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI 1 indicate synergism, additive effect, and antagonism, respectively. Based on these algorithms, computer software has been developed to allow automated simulation of synergism and antagonism at all dose or effect levels. It displays the dose-effect curve, median-effect plot, combination index plot, isobologram, dose-reduction index plot, and polygonogram for in vitro or in vivo studies. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation or carcinogen and radiation risk assessment, as well as for drug or other entity combinations in a vast field of disciplines of biomedical sciences. In this review, selected examples of applications are given, and step-by-step examples of experimental designs and real data analysis are also illustrated. The merging of the mass-action law principle with mathematical induction-deduction has been proven to be a unique and effective scientific method for general theory development. The median-effect principle and its mass-action law based computer software are gaining increased applications in biomedical sciences, from how to effectively evaluate a single compound or entity to how to beneficially use multiple drugs or modalities in combination therapies.

http://www.protocol-online.org/forums/uploads/monthly_09_2010/post-8165-008503000%201284677034.ipb

Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

The role of serotonin in antipsychotic drug action

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

• Cerebrospinal fluid concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) were measured in 30 psychiatric patients who had attempted suicide and 45 healthy volunteers. The suicide attempters had a significantly lower CSF 5-HIAA level than the controls, especially those who had made more violent attempts. After adjustment for differences in body height and age between controls and patients, the difference in 5-HIAA level became even more marked. Concentrations of 5-HIAA also were lower than normal in suicidal patients who were not diagnosed as depressed at the time of lumbar puncture, while HVA levels were lowered only in the depressives. A follow-up study of these and 89 more patients (depressed and/or suicidal) revealed a 20% mortality by suicide within a year after lumbar puncture in patients with a CSF 5-HIAA level below the median.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=psych&articleId=492558&pdfFileName=archpsyc_38_6_002.pdf

Monoamine metabolites in CSF and suicidal behavior.

Dopaminergic neuronal pathways arise from mesencephalic nuclei and project axons to the striatum, cortex, limbic system and hypothalamus. Through these pathways dopamine affects many physiological functions, such as the control of coordinated movement and hormone secretion. Here we have studied the physiological involvement of the dopamine D2 receptors in dopaminergic transmission, using homologous recombination to generate D2-receptor-deficient mice. Absence of D2 receptors leads to animals that are akinetic and bradykinetic in behavioural tests, and which show significantly reduced spontaneous movements. This phenotype presents analogies with symptoms characteristic of Parkinson's disease. Our study shows that D2 receptors have a key role in the dopaminergic control of nervous function. These mice have therapeutic potential as a model for investigating and correcting dysfunctions of the dopaminergic system.

Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors.

The inhibition of the uptake of /sup 3/H-(-)-noradrenaline (NA), /sup 3/H-dopamine and /sup 14/C-5-hydroxytryptamine (5-HT) in mouse brain slices by (Z)-3-dimethylamino-1-(4-bromophenyl)-1-(3-pyridyl)propene(H 102/09), desipramine and chlorimipramine and their releasing effect on the /sup 3/H-amines previously accumulated in the slices were examined. The interactions with reserpine produced hypothermia and sedation and the 5-hydroxytryptophan (5-HTP) syndrome in mice were also studied. Due to the poor inhibitory activity on the NA uptake H 102/09 was a more selective inhii.or of the 5-HT uptake than was chlorimipramine, particularly after administration in vivo, where it was as potent as chlorimipramine (ED50=19..mu..mol/kg intraperitoneally). In vitro chlorimipramine was 6 to 12 times more active than H 102/09. Desipramine was a very selective inhibitor of the NA uptake in vitro and in vivo. The compounds were generally more potent in inhibiting the uptake than in releasing the amines. However, in striatal slices the inhibition of DA uptake could be due to the releasing effect since the difference in potencies were small. The effect of desipramine on 5-HT uptake and that of H102/09 on NA uptake could also involve a release component. The 5-HTP syndrome was potentiated by H 102/09 and chlorimipramine but not by desipramine. The reserpine hypothermia but not the sedation was potently antagonized and reversed by desipramine and by chlorimipramine at high doses but not by H 102/09, suggested that NA but not 5-HT is involved in the hypothermic action of reserpine.

(Z)-dimethylamino-1-(4-bromophenyl)-1-(3-pyridyl) propene (h 102/09), a new selective inhibitor of the neuronal 5-hydroxytryptamine uptake.

A series of alpha-amino acid esters of substituted phenethyl alcohols was prepared and tested as inhibitors of the neuronal reuptake of noradrenaline and 5-hydroxytryptamine. Some of the compounds are potent and very selective in blocking the 5-hydroxytryptamine uptake, as evidenced by biochemical data and behavioral tests. The most promising agent, alaproclate [2-(4-chlorophenyl)-1,1-dimethylethyl 2-aminopropanoate hydrochloride (I, IV)], was selected for further studies as a potential antidepressant agent. A discussion on structure--activity relationships (SAR) is given. In an attempt to explain the selective action on the mechanism of 5-hydroxytryptamine uptake by the new inhibitors, their structures are compared with those of the two neurotransmitters. From the tentative pharmacophore and conformations of transmitter (5-HT) and inhibitor (alaproclate) derived from SAR, a hypothetic carrier site for 5-HT uptake is deduced in terms of geometry and electronic properties.

Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by alpha-amino acid esters of phenethyl alcohols.

A series of substituted 6-methoxysalicylamides were synthesized from their corresponding 2,6-dimethoxybenzamides by demethylation of one methoxy group with boron tribromide. Substituted 6-methoxysalicylamides having a lipophilic aromatic substituent in the 3-position para with respect to the methoxy group, e.g. a bromo or an iodo atom or an ethyl or a propyl group, and having an (S)-N-(1-alkyl-2-pyrrolidinyl)methyl moiety as the side chain were found to be potent blockers of [3H]spiperone binding in vitro and potent inhibitors of the apomorphine syndrome in the rat. Similar to remoxipride but in contrast to haloperidol, some of the substituted salicylamides show a 10-20-fold separation between the dose that inhibits hyperactivity and that which inhibits stereotypy. It was concluded that, besides the requirement of a lipophilic substituent in the position para to the methoxy group for antidopamine activity in vivo, the formation of a coplanar six-membered pseudoring involving the amide moiety and the methoxy group is a structural requirement for activity in vitro.

Potential neuroleptic agents. 3. Chemistry and antidopaminergic properties of substituted 6-methoxysalicylamides.

D1- and D2-receptor antagonist induce catalepsy via different efferent. Striatal pathways

The effects of alaproclate and zimeldine on memory retrieval were examined in male Swiss Webster mice using a one-trial inhibitory avoidance task. All drugs were administered IP prior to the retention test 24 h after training. Both drugs were found to facilitate memory retrieval significantly in a dose-and time-dependent fashion that could not be explained in terms of non-specific effects of the drug (illness, lack of motility, etc.) at the time of the test. The temporal effects of alaproclate and zimeldine on memory closely followed their course of concentration of the drug within the blood stream. The facilitation of retrieval induced by alaproclate and zimeldine was blocked by the putative serotonergic receptor agonist quipazine but not blocked by the antagonist cyproheptadine. Pretreatment with quipazine alone in a group of animals trained to a shock level which normally results in high levels of suppression was not sufficient to produce memory impairment, suggesting that quipazine was probably antagonizing the facilitative effects of alaproclate and zimeldine directly, rather than overriding the facilitation through an indirect action on retrieval in general. The present results lend further support to the suggestion that serotonin plays a significant role in memory.

Sven Ove Ögren

Papers

(Z)-dimethylamino-1-(4-bromophenyl)-1-(3-pyridyl) propene (h 102/09), a new selective inhibitor of the neuronal 5-hydroxytryptamine uptake.

Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by alpha-amino acid esters of phenethyl alcohols.

Potential neuroleptic agents. 3. Chemistry and antidopaminergic properties of substituted 6-methoxysalicylamides.

D1- and D2-receptor antagonist induce catalepsy via different efferent. Striatal pathways

Role of serotonin in memory: facilitation by alaproclate and zimeldine.