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Serum Antioxidant Enzymes and Malondialdehyde Levels in Patients with Premature Ejaculation Before and After Pharmacotherapy
Abstract
In our previous study, significantly higher antioxidant enzymes and malondialdehyde (MDA) levels in patients with premature ejaculation (PE) compared to healthy controls were found. In the present study, we planned to evaluate antioxidant enzymes and MDA levels of patients with PE before and after citalopram treatment.
The study comprised 30 patients with PE according to Diagnostic and Statistical Manual of Mental Disorders Fourth Version (DSM-IV) and 30 healthy controls. The patients were randomly assigned to two groups. Fifteen of them (group I) received 8 weeks of citalopram treatment but the remaining (group II) did not. The subjects were asked to determine the average intravaginal ejaculation latency time (IVELT). The fasting antioxidant enzymes and MDA levels were measured at baseline and after 8 weeks.
No statistically significant difference in the mean IVELT between groups at baseline was found. IVELT considerably elevated after 8 weeks of citalopram treatment in group I with a mean of 209 +/- 72.1 seconds but not in group II. Antioxidant enzymes and MDA levels did not differ between groups at baseline. At the evaluation of week 8, SOD, GSH-Px, and MDA levels significantly reduced during treatment in group I patients.
In conclusion, the results suggest that the ability for antioxidant enzymes and MDA to normalize through symptom alleviation reveals that they might be trait marker of PE. Further placebo-controlled studies are needed.
... The role of oxidative stress in the pathogenesis of PE hasn't been extensively studied; this is hardly surprising, considering that the exact pathophysiology of ejaculation is far from fully understood. It has been observed that nitric oxide (NO) levels in men with PE are signifi cantly lower than in healthy controls [ 44 ]; previous reports hinted at increased expression of antioxidant enzymes in patients compared to healthy subjects [ 3 ]. Evaluation in seminal plasma has shown lower magnesium concentrations in men with PE: hypothetically, this might result in decreased nitric oxide, in increased endothelial intracellular Ca 2+ , and ultimately in premature emission and ejaculation [ 43 ]. ...
Besides their widely discussed role in empirical therapy of male infertility, antioxidants have been used in experimental studies also for treating male sexual dysfunctions. Oxidative stress is clearly involved in the pathogenesis of infertility: less consisting evidence has been found in regard to its involvement in erectile and ejaculatory dysfunctions. Nitric oxide (NO) is an endothelium-derived relaxing factor, acting as a vasodilator and as an antioxidant: it is also the key molecule involved in obtaining and maintaining an erection. Administration of NO has been investigated as a substitute for phosphodiesterase type 5 (PDE-5) inhibitors or an additional treatment for nonresponders to standard treatments. Furthermore, a possible role for testosterone as a free radical scavenger has been postulated: testosterone replacement therapy might help prevent oxidative stress-related dysfunctions in several organs. Oxidative stress is also involved in some forms of priapism: antioxidants might therefore be helpful in preventing recurrences or in treating vascular damage resulting from ischemia-reperfusion injury.
... 13,14 Ranking SSRIs regarding their selectivity reveals citalopram, sertraline, paroxetine, fluvoxamine, and fluoxetine, in decreasing order. 15 Citalopram is an effective treatment with long-term benefit in patients with PE. 9,16 Citalopram is a chiral compound (ie, a 1:1 mixture of 2 enantiomers, R(-)-citalopram and S(+)-citalopram [escitalopram]). 17 Pharmacological studies, performed both in vitro and in vivo, have shown that the SSRI activity of citalopram resides almost exclusively in the S-enantiomer, escitalopram. ...
Purpose: To evaluate the efficacy and safety of most selective
serotonin reuptake inhibitor drug, escitalopram, in delaying
ejaculation in patients with premature ejaculation (PE).
Materials and Methods: A total of 276 married men (mean age,
34.4 years) with PE were randomly assigned to receive 10 mg of
escitalopram (n = 138; Group 1) or placebo (n = 138; Group 2) for
12 weeks. Pretreatment evaluation included history and physical
examination, intravaginal ejaculatory latency time (IELT), International
Index of Erectile Function (IIEF), and Meares-Stamey test.
The efficacy of 2 treatments was assessed every 2 weeks during
treatment, at the end of study, and in 3- and 6-month follow-up
after cessation of treatment.
Results: At the end of 12-week treatment, the escitalopram group
had a 4.9-fold (95% confidence interval [CI], 3.14–6.12) increase of
the geometric mean IELT, whereas after placebo, the geometric
mean IELT did not increase significantly (1.4-fold increase; 95% CI,
0.86–1.68; P = 0.001). Baseline mean intercourse satisfaction
domain values of IIEF 10 and 11 reached to 16 and 10 at 12-
week treatment in Groups 1 and 2, respectively (P = 0.01). At the
end of 6-month follow-up period, the geometric mean IELT in
escitalopram and placebo group demonstrated 3.1- (95% CI,
2.16–4.4) and 1.3-fold (95% CI, 0.78–1.62) increase, respectively
(P = 0.001). Three- and 6-month intercourse satisfaction domain
values of IIEF were 15 and 14 in Groups 1 and 10 and 10 (P = 0.01)
in Group 2, respectively. Mean number of adverse events was 22
for escitalopram and 9 for placebo (P = 0.04).
Conclusions: Oral escitalopram is an effective treatment for PE with
long-term benefit for the patient after it is withdrawn. Further studies
are required to draw final conclusions on the efficacy of this drug in PE.
(J Clin Psychopharmacol 2007;27:444–450)
This book focuses on the use of various molecules with antioxidant properties in the treatment of major male genital tract disorders, especially male infertility, erectile dysfunction, and accessory gland infection. The coverage also includes discussion of pathophysiology, the molecular basis of male infertility, and the rationale for use of antioxidants, with particular attention to coenzyme Q10 and carnitine. Oxidative stress occurs when the production of reactive oxygen species, including free radicals, exceeds the body’s natural antioxidant defences, leading to cellular damage. Oxidative stress is present in about half of all infertile men, and reactive oxygen species can produce infertility both by damaging the sperm membrane, with consequences for sperm motility, and by altering the sperm DNA. There is consequently a clear rationale for the use of antioxidant treatments within andrology, and various in vitro and in vivo studies have indicated that many antioxidants indeed have beneficial impacts. In providing a detailed and up-to-date overview of the subject, this book will be of interest to both practitioners and researchers in andrology, endocrinology, and urology.
Aim. To provide an overview of current knowledge on pharmacotherapy of premature ejaculation (PE). Materials and Methods. A comprehensive review of the literature was conducted using MEDLINE and analysis of cross-references. The key points of methodology and pharmacology of various articles have been analysed and critically reviewed. Results. PE may have significant negative impact on quality of life. Various recommendations for drug treatment of PE have been found in the available literature, varying from anesthetic ointments to various antidepressants and phosphodiesterase inhibitors. Due to disturbing side effects, various drugs are not suitable for general use. On the other hand, topical anesthetics, clomipramine and some SSRIs have repeatedly been found safe and effective to delay ejaculation. Conclusions. Remarkable progress has been made in the treatment of PE. Further research into the neural, psychological and molecular mechanisms involved in PE will lead to the development of even safer, more effective and more convenient therapies for men with PE.
To evaluate the efficacy and safety of most selective serotonin reuptake inhibitor drug, escitalopram, in delaying ejaculation in patients with premature ejaculation (PE).
A total of 276 married men (mean age, 34.4 years) with PE were randomly assigned to receive 10 mg of escitalopram (n = 138; Group 1) or placebo (n = 138; Group 2) for 12 weeks. Pretreatment evaluation included history and physical examination, intravaginal ejaculatory latency time (IELT), International Index of Erectile Function (IIEF), and Meares-Stamey test. The efficacy of 2 treatments was assessed every 2 weeks during treatment, at the end of study, and in 3- and 6-month follow-up after cessation of treatment.
At the end of 12-week treatment, the escitalopram group had a 4.9-fold (95% confidence interval [CI], 3.14-6.12) increase of the geometric mean IELT, whereas after placebo, the geometric mean IELT did not increase significantly (1.4-fold increase; 95% CI, 0.86-1.68; P = 0.001). Baseline mean intercourse satisfaction domain values of IIEF 10 and 11 reached to 16 and 10 at 12-week treatment in Groups 1 and 2, respectively (P = 0.01). At the end of 6-month follow-up period, the geometric mean IELT in escitalopram and placebo group demonstrated 3.1- (95% CI, 2.16-4.4) and 1.3-fold (95% CI, 0.78-1.62) increase, respectively (P = 0.001). Three- and 6-month intercourse satisfaction domain values of IIEF were 15 and 14 in Groups 1 and 10 and 10 (P = 0.01) in Group 2, respectively. Mean number of adverse events was 22 for escitalopram and 9 for placebo (P = 0.04).
Oral escitalopram is an effective treatment for PE with long-term benefit for the patient after it is withdrawn. Further studies are required to draw final conclusions on the efficacy of this drug in PE.
Although magnesium is involved in many biological process and it is found higher levels in semen than serum, its role in human semen has not been elucidated. This investigation was conducted to evaluate the relationship between premature ejaculation and the levels of seminal magnesium. The levels of magnesium, zinc, copper, and selenium were evaluated with an atomic absorption spectrophotometer in serum and seminal plasma in 3 groups of men: (a) normal sperm parameters (15) (b) oligoasthenozoospermia (15), and genuine premature ejaculation (9). There were normal serum and semen levels of all the elements in the three groups, but significantly lower seminal plasma magnesium levels in men with premature ejaculation. The hormonal profile, body mass index (BMI) had no association with premature ejaculation. Decreased levels of magnesium gives rise to vasoconstriction from increased thromboxane level, increased endothelial intracellular Ca2+, and decreased nitric oxide. This may lead to premature emission and ejaculation processes. Magnesium is probably involved in semen transport. More research into the role of magnesium in the male physiology of reproductive tract, especially its association with premature ejaculation, is advocated.
Inhibition of human cytochrome P4502D6 (CYP2D6)-catalysed metabolism can lead to clinically significant alterations in pharmacokinetics. Since there is evidence that the selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs might inhibit CYP2D6, the effects of five SSRIs on human liver microsomal CYP2D6 activity were compared with each other and with three tricyclic antidepressant drugs. On a molar basis, paroxetine was the most potent of the SSRIs at inhibiting the CYP2D6-catalysed oxidation of sparteine (Ki = 0.15 microM), although fluoxetine (0.60 microM) and sertaline (0.70 microM) had Ki values in the same range. Fluvoxamine (8.2 microM) and citalopram (5.1 microM) also inhibited CYP2D6 activity. The major circulating metabolites of paroxetine in man produced negligible inhibition. In contrast, norfluoxetine the active metabolite of fluoxetine, was a potent CYP2D6 inhibitor (0.43 microM). CYP2D6 activity was also diminished by the tricyclic antidepressant drugs clomipramine (2.2 microM), desipramine (2.3 microM) and amitriptyline (4.0 microM). These findings suggest that compounds with SSRI activity are likely to interact with human CYP2D6 in vivo with the potential of causing drug interactions.
A new colorimetric method for quantitative analysis of serum lipid peroxide, free of interference from sialic acids, has been developed. We have used the thiobarbituric acid dissolved in sodium sulfate solution and both liberation of lipid peroxide and color reaction have been performed simultaneously by heating serum protein precipitate with this reagent in a weak acid solution. The new method is specific and facilitates the precise measurements of serum lipid peroxide. The average values determined by the new method increased slightly with age in healthy subjects. In patients with sequelae of cerebrovascular disorders, serum lipid peroxide values were higher than in healthy controls. These results may demonstrate the important role of lipid peroxide in aging and cerebrovascular disorders.
Nitric oxide has been identified as an endothelium-derived relaxing factor in blood vessels. We tried to determine whether it is involved in the relaxation of the corpus cavernosum that allows penile erection. The relaxation of this smooth muscle is known to occur in response to stimulation by nonadrenergic, noncholinergic neurons.
We studied strips of corpus cavernosum tissue obtained from 21 men in whom penile prostheses were inserted because of impotence. The mounted smooth-muscle specimens were pretreated with guanethidine and atropine and submaximally contracted with phenylephrine. We then studied the smooth-muscle relaxant responses to stimulation by an electrical field and to nitric oxide.
Electrical-field stimulation caused a marked, transient, frequency-dependent relaxation of the corpus cavernosum that was inhibited in the presence of N-nitro-L-arginine and N-amino-L-arginine, which selectively inhibit the biosynthesis of nitric oxide from L-arginine. The addition of excess L-arginine, but not D-arginine, largely reversed these inhibitory effects. The specific liberation of nitric oxide (by S-nitroso-N-acetylpenicillamine) caused rapid, complete, and concentration-dependent relaxation of the corpus cavernosum. The relaxation caused by either electrical stimulation or nitric oxide was enhanced by a selective inhibitor of cyclic guanosine monophosphate (GMP) phosphodiesterase (M&B 22,948). Relaxation was inhibited by methylene blue, which inhibits cyclic GMP synthesis.
Our findings support the hypothesis that nitric oxide is involved in the nonadrenergic, noncholinergic neurotransmission that leads to the smooth-muscle relaxation in the corpus cavernosum that permits penile erection. Defects in this pathway may cause some forms of impotence.
Inhibition of human cytochrome P4502D6 (CYP2D6)-catalysed metabolism can lead to clinically significant alterations in pharmacokinetics. Since there is evidence that the selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs might inhibit CYP2D6, the effects of five SSRIs on human liver microsomal CYP2D6 activity were compared with each other and with three tricyclic antidepressant drugs. On a molar basis, paroxetine was the most potent of the SSRIs at inhibiting the CYP2D6-catalysed oxidation of sparteine (Ki = 0.15 microM), although fluoxetine (0.60 microM) and sertaline (0.70 microM) had Ki values in the same range. Fluvoxamine (8.2 microM) and citalopram (5.1 microM) also inhibited CYP2D6 activity. The major circulating metabolites of paroxetine in man produced negligible inhibition. In contrast, norfluoxetine the active metabolite of fluoxetine, was a potent CYP2D6 inhibitor (0.43 microM). CYP2D6 activity was also diminished by the tricyclic antidepressant drugs clomipramine (2.2 microM), desipramine (2.3 microM) and amitriptyline (4.0 microM). These findings suggest that compounds with SSRI activity are likely to interact with human CYP2D6 in vivo with the potential of causing drug interactions.
1. The aromatic 2-hydroxylation of imipramine was studied in microsomes from three human livers. The kinetics were best described by a biphasic enzyme model. The estimated values of Vmax and Km for the high affinity site ranged from 3.2 to 5.7 nmol mg-1 h-1 and from 25 to 31 microM, respectively. 2. Quinidine was a potent inhibitor of the high affinity site for the 2-hydroxylation of imipramine in microsomes from all three human livers, with apparent Ki-values ranging from 9 to 92 nM. This finding strongly suggests that the high affinity enzyme is CYP2D6, the source of the sparteine/debrisoquine oxidation polymorphism. 3. The selective serotonin reuptake inhibitors (SSRI), paroxetine, fluoxetine and norfluoxetine were potent inhibitors of the high affinity site having apparent Ki-values of 0.36, 0.92 and 0.33 microM, respectively. Three other SSRIs, citalopram, desmethylcitalopram and fluvoxamine, were less potent inhibitors of CYP2D6, with apparent Ki-values of 19, 1.3 and 3.9 microM, respectively. 4. Among 20 drugs screened, fluvoxamine was the only potent inhibitor of the N-demethylation of imipramine, with a Ki-value of 0.14 microM. 5. Neither mephenytoin, citalopram, diazepam, omeprazole or proguanil showed any inhibition of the N-demethylation of imipramine and the role of the S-mephenytoin hydroxylase for this oxidative pathway could not be confirmed.
Free radicals are reactive chemical species with an unpaired electron that are produced through a variety of physiologic and pathologic processes. Free radicals have been implicated in a variety of neuropsychiatric conditions, many of which are marked by the gradual development of psychopathologic symptoms and movement disorder. There is evidence that radical-induced damage may be important in Parkinson's disease, tardive dyskinesia, metal intoxication syndromes, and Down's syndrome, and possibly also in schizophrenia, Huntington's disease, and Alzheimer's disease. Although some of this evidence is highly speculative, it may offer an avenue for further understanding and treatment of these conditions.
Prostaglandin E2 (PGE2) microinjection (25 ng, 250 nl) into the preoptic area of the anterior hypothalamus (POAH) stimulated heat production in brown adipose tissue (BAT) and increased core temperature in urethane-anesthetized rats. These thermogenic and hyperthermic effects were attenuated by co-injection of NG-monomethyl-L-arginine (NMMA, 25 micrograms), a competitive inhibitor of nitric oxide (NO) production from L-arginine. Inclusion of L-arginine (50 micrograms), though not D-arginine (50 micrograms) reversed the inhibitory effect of NMMA (25 micrograms) on intra-POAH PGE2-induced increases in interscapular BAT (IBAT) and core temperatures. Intra-POAH injection of NMMA (25 micrograms) or L-arginine (50 micrograms) alone had no effect on IBAT and core temperatures. The results suggest that the effect on thermoregulation induced by action of PGE2 in the POAH is modulated by a local L-arginine-dependent and NMMA-sensitive NO-generating system.
The antioxidants in the aqueous phase of human plasma include ceruloplasmin, albumin (the protein itself and possibly also albumin-bound bilirubin), ascorbic acid, transferrin, haptoglobin, and hemopexin. Assays that attempt to answer the question "what is the most important antioxidant?" are compared, it being concluded that the answer is different depending on the nature of the prooxidant stress imposed in the assay.
The ejaculatory response and the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1 i.p.) were studied following acute and repeated treatment of rats with the selective uptake inhibitors of 5-HT, fluoxetine, zimeldine, alaproclate, and citalopram. The oral doses used were based on the respective ED50 values for uptake inhibition. Acute doses of fluoxetine and zimeldine significantly reduced the ejaculatory response when given 48 h before 5-MeODMT. This blockade was prevented by treatment of the rats with the postsynaptic 5-HT receptor antagonist methergoline. An acute dose of fluoxetine given 7 and 14 days before 5-MeODMT significantly enhanced the ejaculatory response. On day 24, the response returned to the control level. Repeated treatment every second day (5 times over 9 days and 10 times over 19 days) with fluoxetine caused a longer blockade of the ejaculatory response and the sensitization of the response came later than after an acute dose. Parallel with the ejaculatory response three other components of the 5-HT behavioural syndrome also decreased significantly. Acute doses of alaproclate and citalopram significantly blocked the ejaculatory response at 1 h, but they failed to affect the response at any other time point after either acute or repeated treatment. Neither did these drugs attentuate the 5-HT syndrome. It is concluded that acute and repeated treatment of rats with different selective 5-HT uptake inhibitors does not produce a common alteration in 5-HT2-receptor functions.
This assay for superoxide dismutase (SOD, EC 1.15.1.1) activity involves inhibition of nitroblue tetrazolium reduction, with xanthine-xanthine oxidase used as a superoxide generator. By using a reaction terminator, we can determine 40 samples within 55 min. One unit of activity of pure bovine liver Cu,ZnSOD and chicken liver MnSOD was expressed by 30 ng and 500 ng of protein, respectively. The mean concentrations of Cu,ZnSOD as measured by this method in blood from normal adults were 242 (SEM 4) mg/L in erythrocytes, 548 (SEM 20) micrograms/L in serum, and 173 (SEM 11) micrograms/L in plasma. The Cu,ZnSOD concentrations in serum and plasma of patients with cancer of the large intestine tended to be less and greater than these values, respectively, but not statistically significantly so.
An assay procedure is described in which blood cell glutathione peroxidase may be accurately measured by a direct spectrophotometric procedure. Glutathione peroxidase activity is found to be associated with a relatively stable, nondialyzable, heat-labile, intracellular component which is separable from hemoglobin, by gel filtration and ammonium sulfate precipitation. The activity appears to be dependent upon active sulfhydryl groups and is unaffected by low concentrations of azide, cyanide, or ferricyanide.
Nitric oxide (NO) may mediate penile erection by inhibiting smooth muscle of the corpora cavernosa, thereby allowing vasodilation of the corpora. In order to test the role of NO in the sexual function of intact male rats, either the precursor of NO (L-arginine, L-Arg) or an inhibitor of its synthesis (NG-nitro-L-arginine methyl ester, NAME) was administered systemically before tests of copulation, ex copula genital reflexes, or sexual motivation/motor activity. NAME impaired copulation in a dose dependent manner. It also decreased the number of ex copula erections, but it increased the number of ex copula seminal emissions and decreased the latency to the first seminal emission. L-Arg marginally increased the number of penile reflexes, but had no other effects. NAME had no effect on sexual motivation or motor activity. The results indicate that nitric oxide promotes erection in intact male rats, probably by mediating filling of the corpora cavernosa. The data also suggest that NO inhibits seminal emission, probably by decreasing sympathetic nervous system activity; this may help prevent premature ejaculation.
The presently available selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, despite their common mechanism of action, differ in their chemical structure, metabolism and pharmacokinetics. From a clinical point of view, it is of relevance that potency to inhibit the cytochrome P450 isozyme CYP2D6 gradually decreases from paroxetine, fluoxetine, norfluoxetine, desmethylcitalopram, fluvoxamine, and sertraline down to citalopram, explaining to a great extent differences in pharmacokinetic interactions between the SSRIs and tricyclic antidepressants, which are metabolized by this enzyme. Fluvoxamine interacts with these drugs by a mechanism involving inhibition of CYP1A2, CYP3A4, and CYP2C19. Except for paroxetine, a substrate of CYP2D6, little is known about the enzymes implicated in the metabolism of SSRIs. Fluoxetine and citalopram are used as racemic drugs. Data on the stereoselectivity of their enantiomers in the inhibition of serotonin (5-HT) uptake in the animal brain, also those available on their metabolism and kinetics in humans, are presented. It may be concluded that for routine therapeutic drug monitoring, the plasma level measurement of the enantiomers of citalopram and fluoxetine is probably of little relevance. However, for the study of the structure-activity relationship between these drugs and the cerebral 5-HT transporter, the stereochemical differences of these enantiomers should be considered. In this sense, the enantiomers of these drugs could represent a promising tool to increase present knowledge.
Toxic oxygen radicals (collectively called reactive oxygen species, ROS) are intricately related to a vast number of disease processes including a variety of autoimmune and inflammatory disorders1. It is difficult to directly measure ROS because of their extremely short half-life. However, the reactions in which they participate often leave measurable markers (“footprints”) that reflect oxidant activity. Primarily four strategies have evolved to detect oxidant activity for diagnostic purposes:1) measuring products of oxidation, for example lipid peroxides or oxidized glutathione (GSSG); 2) measuring the release of products from damaged cells, for example the release of hepatic enzymes during acute hepatitis; 3) measuring antioxidant enzyme activities which may reflect the systemic compensation to oxidant stress; 4) ROS can be directly measured although the technology is complex and imperfect, the methodology somewhat complicated, and the equipment cost often prohibitive. In this review, I will discuss sources of selected oxidant markers, methodologies involved in their measurement, and their relevance to the diagnosis and management of several autoimmune and inflammatory diseases.
Nitric oxide (NO) is becoming recognized as an important intercellular messenger in the brain. The present experiment used microdialysis to examine the potential role of NO in the regulation of dopamine (DA) and serotonin (5-HT) release in the medial preoptic area (MPOA) of freely moving male rats. The NO precursor L-arginine (L-Arg, 100 microM), administered into the MPOA via the dialysis probe, increased extracellular levels of DA, 5-HT, and the major metabolites of DA. These increases were blocked by the coadministration of the NO synthase inhibitor N-monomethyl L-arginine (NMMA, 400 microM). The inactive isomer D-arginine (100 microM) was ineffective, and NMMA by itself decreased DA below baseline levels. Thus, NO may modulate the release of DA and 5-HT in the MPOA.
The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.
Major depression and dysthymia (chronic, low grade depression) were associated with an increase in the number of CD16/56 (natural killer; NK) cells in blood, whereas other lymphocyte subsets (CD3, CD4, CD8, CD19, and the CD4/CD8 ratio) did not differ from control subjects. After treatment with a specific serotonin reuptake inhibitor, the symptoms of depression were alleviated in both the major depressive and dysthymic patients. Likewise, NK cell numbers declined to control values in these treated groups. Among the major depressive patients, the NK cell number reached control values within 4 weeks, whereas 6 months of treatment was required for such an effect to be achieved in the dysthymic patients. Although plasma levels of epinephrine, norepinephrine, cortisol, and ACTH were not different between groups, among the major depressive patients ACTH was inversely correlated with total lymphocytes, CD3, and CD19, and epinephrine was directly related to the CD4 and CD4/CD8 ratio. Among dysthymics, ACTH was unrelated to any of the lymphocyte subsets, but norepinephrine was directly related to total lymphocytes, CD3, CD4, and NK cells. The data are interpreted in terms of stress perception among major depressive and dysthymic patients and the potential impact of stressor experiences on immune processes.
The efficacy of the selective serotonin re-uptake inhibitor fluoxetine in the treatment of premature ejaculation was examined.
The study comprised 17 patients with premature ejaculation who presented to the urology clinic of our medical school. In this double-blind study the patients were randomized into treatment groups receiving 20 mg. fluoxetine daily for 1 week and 40 mg. daily afterward (group 1) or 1 capsule placebo daily for 1 week and 2 capsules daily afterward (group 2). The groups were evaluated according to the latent period of intravaginal ejaculation.
The latent period of intravaginal ejaculation in group 1 was significantly longer than that in group 2. Nausea, headache and insomnia were reported side effects.
Fluoxetine may be regarded as a safe and effective alternative in the treatment of premature ejaculation.
Reactive oxygen species (ROS) may play a role in some neuropsychiatric disorders. There is some evidence that the activation of immune-inflammatory process, increase of monoamines catabolism, and abnormalities in lipid compounds may cause overproduction of ROS and, in turn, antioxidative enzyme activities (AEAs) and lipid peroxidation (LP), and that these phenomena may be related to pathophysiology of major depression.
The aims of this study were (i) to examine the AEAs and LP levels of the major depressed (MD) patients, and to compare these with healthy controls; and (ii) to investigate the effect of subchronic treatment with selective serotonin reuptake inhibitors (SSRIs) on AEAs and LP levels in MD subjects. Thirty MD patients, and 32 healthy controls (HC) participated in this study. AEAs and LP levels were determined by measuring several antioxidative enzymes and malondialdehyde (MDA) levels in plasma and/or in red blood cells.
Major depressed patients, especially melancholic patients, had higher AEA and LP levels than those of healthy controls. After treatment for 3 months with SSRIs, AEA and LP levels of the patients were significantly decreased to normal levels.
These findings suggest that (i) major depression, especially with melancholia, is associated with elevated AEAs and LP, and that (ii) subchronic treatment with SSRIs may have a suppressive effect on AEA and LP. CLINICAL IMPLICATION AND LIMITATION: AEAs might be used for monitoring SSRIs effects.
Citalopram is a selective serotonin re-uptake inhibitor that has demonstrated antidepressant efficacy in numerous controlled clinical trials. Additional studies have shown that the drug benefits patients with other illnesses that are related in some way to serotonergic dysfunction, including anxiety, panic disorder, obsessive-compulsive disorder, premenstrual dysphoria, alcohol dependence and the behavioural disturbances of dementia. This paper reviews the full spectrum of citalopram's clinical efficacy, as well as its safety and tolerability, in a range of patients.
Data showing the neurobiological background of rapid ejaculation was reviewed. In addition, new hypotheses to integrate clinical symptomatology, psychopharmacotherapy and psychotherapy of rapid ejaculation with brain function are provided.
A computerized MEDLINE search, and manual bibliographic review of cross-references and neurobiological animal studies were performed. These reports were analyzed, summarized and compared with the studies performed by the author.
The literature on premature ejaculation published between 1887 and 2001 was reviewed. It appeared that the various psychological hypotheses and psychotherapies have not adequately been investigated. In contrast, psychopharmacological treatment studies, animal research data and stopwatch assessments in men with rapid (premature) ejaculation indicate that lifelong rapid ejaculation is a neurobiological phenomenon related to central serotonergic neurotransmission and likely influenced by hereditary factors.
Basic and clinical psychopharmacological studies suggest that premature ejaculation is a not a psychological disturbance but a neurobiological phenomenon.
To evaluate serum leptin levels (an adipocyte hormone involved in the suppression of appetite) in patients with premature ejaculation before and after treatment with citalopram, a selective serotonin reuptake inhibitor, with the hypothesis that leptin levels might become normal during this treatment.
The inhibitory effect of serotonin on libido, ejaculation and orgasm is well documented. Although there is no direct evidence of an association involving brain pathways which are related to sexual behaviour, there is an interaction between leptinergic and serotonergic systems. In a previous study serum leptin levels were high in patients with premature ejaculation. The present study comprised 30 patients with premature ejaculation according to the Diagnostic and Statistical Manual of Mental Disorders Third Revised Version. Fifteen patients (group I) were randomly assigned to 8 weeks of citalopram treatment and the remainder (15, group II) received no therapy. The patients were asked to determine the average intravaginal ejaculation latency time, and their fasting serum leptin levels were measured at baseline and after 8 weeks.
There was no significant difference in the mean intravaginal ejaculation latency time between the groups at baseline; it increased after 8 weeks of treatment with citalopram in group I, to a mean (sd) of 209 (72.1) s, but not in group II. No difference was detected in leptin levels between the groups at baseline, but at 8 weeks they were lower in group I.
As hypothesized, leptin levels decreased in patients with premature ejaculation after treatment with citalopram, and this decrease seemed to be linked to the therapeutic effect. Further experimental studies are needed.
Defective neutrophil function in schizophrenic patients has recently been reported. There are several lines of evidence to support the contribution of oxygen free radicals in schizophrenia, including increased lipid peroxidation, fatty acids and alterations in blood levels of anti-oxidant enzymes. Eighteen schizophrenic patients (DSM-IV) and 15 healthy controls were studied. Neutrophil chemotaxis, superoxide production and bactericidal activity were investigated. A statistically significant increase of superoxide anion release was found in schizophrenic patients compared with controls (mean+/-S.E.M., patients: 6.89+/-0.30 nmol O2-/10(6) cells/min, controls: 5.13+/-0.55 nmol O2-/10(6) cells/min). Moreover, a significant positive correlation between superoxide production and negative symptoms as assessed by the Positive and Negative Syndrome Scale was demonstrated. No differences were detected in chemotaxis and phagocytosis between schizophrenic patients and healthy controls. The present findings of a positive correlation between superoxide generation and negative symptoms in schizophrenic patients support the hypothesis that superoxide anion may participate in the pathogenesis of schizophrenia, as an excess of free radicals could contribute to the deterioration phase of the disease. Further studies are required to establish the role of oxidative stress in the ethiopathogenesis of schizophrenia.
Abstracts of the 149th Annual Meeting of the American Psychiatric Association
- Zemishlany Z
The effect of selective 5HT re-uptake inhibitors on 5-methoxy-N,N-dimethyltriptamine induced ejaculation in the rat
- Remy
Remy L. The effect of selective 5HT re-uptake
inhibitors on 5-methoxy-N,N-dimethyltriptamine
induced ejaculation in the rat. Br J Pharmacol
1986;87:639-48.
The effects of methylenedioxymethamphetamine
- Z Zemishlany
Zemishlany Z. The effects of methylenedioxymethamphetamine ("Ecstasy") on human sexual
function. In: Abstracts of the 149th Annual
Meeting of the American Psychiatric Association.
Washington, DC: American Psychiatric Association; 1996:265.
The effects of methylenedioxy-methamphetamine (“Ecstasy”) on human sexual function
- Zemishlany
Antioxidative enzyme activities and lipid peroxidation in major depression: Alterations by antidepressant treatments
- Bilici
Citalopram: A detailed evaluation
- Pollock