Depression: prevalence, pathogenesis and treatment options

Depression represents a major public health problem that is characterized by disturbance of mood, poor concentration, loss of sense of control and a subjective experience of great distress. It affects the thinking and functioning processes of an individual, greatly diminishes his or her social role and productivity, even leading to suicide. The incidence of depression is gradually on a rise and afflicts all socioeconomic levels. Prevalence studies give very high figures of depression in all parts of the world. The pathogenesis of this mental health problem is very complex. Genetic factors greatly contribute in etiology of depression and the heritability of this illness is greater in females. Abnormalities in membrane bound signal transduction systems and intracellular signaling systems play an important role in the etiology of depression. Deregulation of the hypothalamic-pituitary-adrenal axis and altered levels of several brain neurotransmitters such as serotonin, norepinephrine, glutamate, gamma amino butyric acid and dopamine are also implicated in depression. The cause and effect relationshiop in this mental disorder still remains unclear. Therapies that are available to treat depression are limited and suboptimal with regard to their efficacy and tolerability. These therapies include pharmacotherapy, psychotherapy, exercise therapy, electro convulsive therapy, repetitive transcranial magnetic stimulation, phytotherapy, meditation, phototherapy and negative ion therapy

Interaction of amitriptyline and imipramine with serotonin receptors in rat uterus and stomach

Tricyclic antidepressants are known to bind with serotonin receptors in brain. We studied the in vitro interaction of amitriptyline and imipramine with serotonin receptors in rat uterus and stomach fundus preparations. In uterus, both amitriptyline and imipramine inhibited the contractile responses to serotonin. Similarly, in stomach, these antagonists also inhibited serotonin-induced contractions but blockade was seen only at very high concentrations of antagonists. Based on antagonist potencies, amitriptyline and imipramine were found to exhibit 150-500 fold higher affinity for uterine serotonin receptors than for those in the stomach. This suggests that these antidepressant drugs can discriminate between serotonin receptors located in uterus and stomach

Selective inhibition of prostaglandin biosynthesis by antipsychotic drugs

The effects of antipsychotic drugs on arachidonic acid metabolism via prostaglandin [PG] endoperoxide synthase and lipoxygenase pathways were determined. Chlorpromazine, thioridazine, fluphenazine, haloperidol, promethazine and cyclizine, in decreasing order of potency, inhibited PG endoperoxide synthase [thus PG biosynthesis] in a dose related manner. Conversely, anti-psychotic drugs either stimulated or had no effect on lipoxygenase activity. These results demonstrate that antipsychotic drugs selectively inhibit PG biosynthesis. Since administration of PGs in man produces emesis, and other untoward effects; our data is suggestive that the anti-emetic action of anti-psychotic drugs could be due to their inhibition of PG biosynthesis

Dimethyl sulphoxide inhibits platelet aggregation and alters arachidonic acid metabolism

Dimethylsulphoxide [DMSO] inhibits human platelet aggregation induced by adrenaline, ADP, arachidonic acid [AA] or collagen in a concentration-related manner. DMSO produced strongest inhibitory effects against ADP-induced aggregation whereas it was a weak inhibitor of AA-induced aggregation. DMSO did not protect rabbits against death from pulmonary platelet thrombosis induced by AA. On the other hand, DMSO exerted differential effects against AA metabolism. It stimulated PG endoperoxide synthase while DMSO inhibited lipoxygenase activity. Since lipoxygenase products play an important role in inflammation, it is possible that inhibition of lipoxygenase by DMSO could lead to beneficial anti-inflammatory activity by comparison with classical PG endoperoxide synthase inhibitors such as aspirin-like drugs

Prostaglandins, menstruation, and menstrual disorders

Prostaglandins play an important role in the mechanism of human menstruation. Furthermore aberrant prostaglandin production may be an intimate component of the pathogenesis of menstrual disorders such as dysmenorrhoea, menorrhagia and perhaps the premenstrual syndrome. Inhibitors of prostaglandin biosynthesis available today have proven universally useful in the treatment of dysmenorrhoea and menorrhagia. The development of such drugs and endogenous inhibitors of prostaglandin synthase [EIPS] with greater specificity and also perhaps antagonists of the actions of specific prostaglandins is currently a high priority. It may be anticipated that the development of these newer ranges of natural and synthetic drugs will allow treatments of menstrual disorders with greater efficacy, and reduced sideeffects

Evaluation of drug effects on rabbit intestinal alkaline phosphatase activity

Alkaline phosphatase [AP] plays an important role in the availability and absorption of inorganic phosphate [Pi] through the intestine. In this study we have investigated the effects of various orally administered drugs on AP prepared from rabbit intestinal mucosa. The enzyme had a Km of 0.5 X 10-3 M at pH 10.5 and produced linear reaction rates both with respect to enzyme and substrate concentration. The AP was totally inhibited by 2.68 mM EDTA. An analysis of the effects of various drugs on AP showed that cysteine, aminophylline, neomycin, theophylline, pilocarpine, caffeine, aspirin and threonine, in descending order of potency, inhibited intestinal AP in a concentration-dependent manner. Acetylcholine, carbachol, alropine, hyoscine, ampicillin, isoniazide, polymyxin B, sulphamethoxazole, trimethoprim, indomethacin, p-acetamidophenol, papaverine, cyclazine, diphenhydramine, hydrocortisone, tyramine, streptomycin, and promethazine had no effect on intestinal AP. Our data showed that a number of drugs inhibited AP. It is tempting to speculate that the inhibition produced by various drugs may involve interference with absorption processes of Pi or the availability of Pi in the gastrointestinal tract

Decreased ability of human plasma to inhibit lipid peroxidation in uremia

Blood samples from normal healthy volunteers and uremic patients were obtained and plasma were prepared. The effects of these plasma samples on lipid peroxidation [LP] in rabbit homogenate were determined. Both plasma samples inhibited LP activity in our experiments. The percent inhibition of LP produced by normal plasma, concentration 1 and 10%, v/v, was 21.78 +/- 4.15 and 75.5 +/- 2.39 [Mean +/- S.E.M. n=20] respectively. The corresponding values of LP inhibition obtained using the uremic plasmas, concentrations 1 and 10% v/v, were 6.85 +/- 7.04 and 57.12 +/- 13.71 respectively. These data show that there was a significant reduction in LP inhibitory activity in plasma of uremic patients. This suggests that there may be an increased production of associative LP products in uremic patients. Since LP products profoundly affect blood clotting it can be inferred that aberrant levels of LP inhibitor in uremic plasma could contribute to increased bleeding in uremia

Endogenous inhibitor [S] of platelet aggregation

Human blood plasma contains an endogenous inhibitor [s] of platelet aggregation [EIPA]. The EIPA activity was found to be associated with alpha - globulin-rich and albumin-rich protein fractions of blood plasma. Data presented in this paper suggests that EIPA may regulate platelet aggregation associated with excessive production of arachidonic acid metabolites

Activity of endogenous inhibitor [s] of platelet aggregation in plasma of normal males, females and pregnant women

The EIPA activity in human plasmas obtained from adult males, females, pregnant females and foetal umbilical cord was determined. EIPA activity was highest in the following order of potency; adult females > adult males > pregnant females > foetal umbilical cord plasma. The data suggest the EIPA activity, is highest in females than in males and may vary according to sex or pregnancy in females

Endogenous inhibitors of cyclic nucleotide phosphodiesterase: isolation and partial characterization

We have developed an extraction procedure to isolate from mammalian organs and cells endogenous factors that inhibit cyclic nucleotide phosphodiesterase [PDE]. The procedure involves homogenization of an organ or cell type in HC1 followed by extraction with chloroform methanol. The aqueous-methanol phase is separated and lyophilised. This material containing PDE inhibitor activity is further purified by gel filtration chromatography on Sephadex G-25 and G-75 columns. In rat and bovine brain, calf thymus, guinea pig lungs and ileum, human stomach, rat peritoneal mast cells and mouse splenic lymphocytes, cAMP and cGMP dependent PDE activity was inhibited in dose dependent fashion by the lyophilised material derived from these tissues. In other experiments the material from calf thymus selectively inhibited the PDE of calf thymus and not of any other tissue. Preliminary investigation of the physico-chemical properties of rat and bovine extracts indicated that brain contained inhibitory peptides of low molecular weight whereas calf thymus extracts contained inhibitory peptides of both low and high molecular weights. This method therefore reveals the presence of endogenous inhibitors of PDE [EIPODS] in various mammalian organs and cells

Potential new uses of aspirin

Aspirin, the old standby, appears to have new potential in therapeutics as an inhibitor of prostaglandin biosynthesis. In the present review, we have identified new vistas on the use of aspirin in the treatment of various prostaglandin mediated disorders such as cardiac ischaemia, arrhythmias, shock, migraine and various ophthalmic conditions