Low molecular weight heparin and unfractionated heparin for prevention of thrombo-embolism in general surgery: a meta-analysis of randomised clinical trials

Low molecular weight heparin (LMWH), unfractionated heparin (UFH) and warfarin were compared with respect to efficacy and safety in the prevention of thrombo-embolism in general surgery. Meta-analysis (MA) with a priori definition of the MA protocol was used to combine the results from randomised trials with patients who underwent general surgery and deep-vein thrombosis (DVT) prophylaxis with LMWH, UFH or warfarin. Forty-four studies were identified for assessment and 33 were included, however, none for warfarin. For efficacy (DVT and pulmonary embolism) and major bleeding, no significant difference between the LMWH- and UFH-treated groups was demonstrated. The relative risk of minor bleedings for LMWH versus UFH was 0.75 (0.64-0.88; 95% confidence interval) and is significant (p < 0.05). Within the limitations of the MA, LMWH and UFH did not differ significantly in terms of prevention of thrombo-embolism, but LMWH had a significantly better safety profile. On this basis, LMWH may be preferable to UFH in the prevention of thrombo-embolism in general surgery.     

Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis after major surgical intervention: update of previous meta-analyses

BACKGROUND: Previous meta-analyses comparing low molecular weight heparin (LMWH) and unfractionated heparin for thrombosis prophylaxis after surgical interventions need updating. METHODS: This is a publication-based meta-analysis of 36 double-blind studies including 16583 patients. Main outcome measures are incidence of deep vein thrombosis (efficacy) and wound haematoma (safety). RESULTS: In general surgery there is no increased efficacy in favour of LMWH (odds ratio (OR) 0.88, 95 per cent confidence interval (c.i.) 0.60-1.30) but there exists a higher incidence of bleeding complications (OR 1.47, 95 per cent c.i. 1.07-2.01). Low-dose LMWH is equally efficacious (OR 1.03, 95 per cent c.i. 0.85-1.26) but safer than unfractionated heparin (OR 0.68, 95 per cent c.i. 0.56-0.82). In orthopaedic surgery there is a trend towards an increased efficacy for LMWH (OR 0.83, 95 per cent c.i. 0.68-1.02) with equivalent safety (OR 0.96, 95 per cent c.i. 0.68-1.36). CONCLUSION: A superiority of LMWH is suggested but heterogeneity might make generalizability to future patients questionable. A meta-analysis on individual patient data should be the next step before randomizing additional patients in future trials.     

Low molecular weight heparin: a critical analysis of clinical trials

LMWHs are an important new class of antithrombotic agents. They differ from UFH in having relatively more anti-Xa activity, greater bioavailability at low doses, longer half-life, and more predictable anticoagulant response when administered in fixed doses. These properties allow LMWHs to be administered QD or at most BID and without laboratory monitoring. The incidence of heparin-induced thrombocytopenia also appears to be lower with an LMWH than with heparin. Given their favorable pharmacological profile, it was of interest to critically appraise clinical trials of thromboprophylaxis and treatment with these new agents. In orthopedic trials, it was noted that LMWH provided safe and effective thromboprophylaxis for patients undergoing major orthopedic surgery of the lower limb. In those having hip arthroplasty, LMWH was as effective as low-intensity warfarin therapy, but its use was associated with more wound hematomas. In those having total knee arthroplasty, LMWH was more effective than warfarin and did not increase bleeding. However, the prevalence of DVTs complicating this procedure as well as acute hip fracture remains unacceptably high, and additional studies of LMWH in combination with other prophylactic methods, such as external pneumatic compression, are needed. Only one adequately designed trial found less bleeding resulted from LMWH prophylaxis administered at an equivalent antithrombotic dose to UFH. In general medical patients, LMWH appeared to be as effective as UFH and had the advantages of less frequent injections and fewer injection site hematomas. In general surgical patients, there was a lower risk of thromboembolism but a trend toward an increase in bleeding events. Subjects with strokes and spinal cord injuries benefited from fewer thrombotic events, and the latter had fewer bleeding complications. Other potential indications for LMWH, such as cardiopulmonary bypass, hemodialysis, and preservation of graft patency, are presently under study. Perhaps the most impressive benefits of LMWH will be realized when it is used for the treatment of venous thromboembolism. The meta-analysis presented in this review showed a trend toward greater efficacy with LMWH and fewer major bleeding events in comparison with adjusted-dose intravenous UFH. Also, during the months following the thrombotic event, there was significantly less mortality in patients receiving LMWH. A further advantage was the subcutaneous route of administration and lack of requirement for laboratory monitoring. Additional treatment trials are presently in progress and may establish LMWH as the treatment of choice for patients with thromboembolic disorders.     

Low plasma vitamin A concentrations in familial combined hyperlipidemia

As many as 20% of the survivors of acute myocardial infarction present with the heritable form of hyperlipidemia, termed familial combined hyperlipidemia (FCHL). Some of the genes reported to be involved in this disorder, such as those for lipoprotein lipase (LPL) and apolipoprotein (apo) C-III, are controlled by a peroxisome proliferator-activated receptor (PPAR)/retinoic acid receptor X (RXR) regulatory system, which is retinoic acid dependent. If, as we hypothesized, the availability of retinoic acid or its precursor retinol (vitamin A) could be altered in FCHL, this could help explain some aspects of the phenotypic expression of the disease. We therefore measured plasma retinol concentrations in 30 FCHL subjects and 56 controls. Plasma retinol concentrations in FCHL subjects were significantly lower than that of control subjects (1.96 +/- 0.83 mumol/L vs 2.91 +/- 1.23 mumol/L, respectively; P < 0.0001). This novel finding of significantly decreased concentrations of plasma retinol in FCHL relative to control subjects gives support to the hypothesis that vitamin A might be involved in the expression of this disorder.     

Postoperative plasma concentrations of procalcitonin after different types of surgery

Transforming growth factor (TGF)-beta 1 is an important cytokine involved in the pathobiology of tissue fibrosis through its stimulation of the production of, and inhibition of the degradation of, extracellular matrix proteins. We examined the clinical usefulness of plasma TGF-beta 1 concentration as a marker of fibrogenesis in patients with chronic viral hepatitis. Thirty-five patients, 11 with minimal chronic hepatitis, 14 with mild chronic hepatitis and 10 with moderate chronic hepatitis and 20 healthy subjects were studied. Transforming growth factor-beta 1 concentrations in platelet-poor plasma were measured with a TGF-beta 1 enzyme-linked immunosorbent assay system kit after acid-ethanol extraction. Plasma TGF-beta 1 levels were significantly elevated in patients with mild and moderate chronic hepatitis, but not in those with minimal chronic hepatitis, compared with the levels in the controls. Plasma TGF-beta 1 levels were increased in parallel with the histological degree of necroinflammation and of liver fibrosis. Plasma TGF-beta 1 levels were positively correlated with blood levels of procollagen type III N-peptide, and 7S fragment and central triple-helix of type IV collagen. These results suggest that plasma TGF-beta 1 level is a useful marker in assessing the situation of liver active fibrogenesis in patients with chronic viral hepatitis.     

Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: effect of smoking

Concentrations in plasma of clozapine and norclozapine, the major metabolite of clozapine, were measured in 59 treatment-resistant schizophrenic patients at a random time period during the course of treatment. A lower sum of the concentrations of clozapine and norclozapine or either alone predicted less improvement in the Brief Psychiatric Rating Scale (BPRS) Total and Positive symptoms in a multivariate analysis that controlled for baseline BPRS rating and dose. The mean doses of clozapine after 6 months of treatment and at the time of blood sampling were not significantly different in 30 responders and 29 nonresponders to clozapine, on the basis of the decrease in BPRS Total scores, whereas the concentrations in plasma in clozapine of norclozapine and the sum of their concentrations were significantly higher in responders. Clozapine and norclozapine concentrations in plasma correlated both with dose at the time of sampling and with dose at 6 months. A clozapine concentration of 370 ng/ml was the optimal cutoff for distinguishing responders from nonresponders. Clozapine and norclozapine concentrations did not differ in male smokers and nonsmokers.     

More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT

This study was designed to determine whether the maintenance of higher than usual patient-specific heparin concentrations during cardiopulmonary bypass (CPB) was associated with more effective suppression of hemostasis system activation. Thirty-one patients scheduled for repeat cardiac surgery or combined procedures (i.e., coronary revascularization + valve repair/replacement) were consented and enrolled in this study. All patients received porcine heparin and protamine and were randomly assigned to monitoring of anticoagulation by either celite ACT alone (Control, n = 16) or by kaolin ACT combined with on-site measurements of whole blood heparin concentration (Intervention, n = 15). Blood specimens collected before administration of heparin, before weaning from CPB and after administration of protamine were analyzed with a battery of coagulation assays. Patients in the intervention cohort received appreciably greater heparin doses than control patients, resulting in higher anti-Xa heparin levels at the end of CPB. Fibrinopeptide A and D-dimer levels were higher in the control group before discontinuation of CPB. Percent decrease during CPB were greater in the control group for factors V and VIII, fibrinogen and antithrombin III. Percent decrease in complement 3 was greater in the control group after protamine and bleeding times measured in the Intensive Care Unit were significantly more prolonged in this group. Maintenance of higher patient-specific heparin concentrations during CPB more effectively suppresses excessive hemostatic system activation than do standard heparin doses chosen based on measurement of ACT. These findings may explain, at least in part, the significant reduction in perioperative blood loss and blood product use when higher heparin concentrations are maintained.     

Use of single dose low-molecular-weight heparin in long hemodialysis

BACKGROUND AND OBJECTIVES: Granuloma Inguinale (GI) is an endemic sexually transmitted disease (STD) in India. With increasing prevalence of human immunodeficiency virus (HIV) among patients with STD at a clinic in Mumbai, a study was conducted to determine clinico-epidemiologic features of GI and HIV. GOAL: To determine possible interaction between GI and HIV. STUDY DESIGN: Prospective follow-up of 21 consecutive cases (GI in HIV-seropositive individuals) and 29 controls (GI in HIV-seronegative individuals) to determine time to heal. All cases and controls received a standard treatment regimen of erythromycin, 2 g po daily, under supervision until healing occurred. RESULTS: Although GI ulcers at recruitment were not significantly larger among HIV-seropositive individuals as compared with those seen among HIV-seronegative individuals (mean size 4.4 cm2 vs. 3.6 sq2; odds ratio [OR] 1.22, confidence interval [CI] .95, 0.63, 2.40; p = 0.52), the former took longer time to heal completely (mean 25.7 days vs. 16.8 days; OR 1.82, CI .95, 0.99, 3.36; p = 0.03) and tended to produce greater tissue destruction (as included in results). CONCLUSION: These findings are important because slow-healing GI ulcers with underlying HIV infection, which may be caused by their interaction, will lead to increased transmission of both the infections.     

Bleeding classification in clinical trials: observer variability and clinical relevance

To evaluate the bleeding classification in a recent trial on venous thrombosis treatment, a selection of reported bleeding episodes was adjudicated twice by an independent committee and graded by the treating physician and independent clinical experts on the clinical severity and impact on the patient's life. The kappa values for the dichotomy major bleeding versus minor or no bleeding were 0.79 (95% CI, 0.57-1.0) for the agreement between the two members of the adjudication committee and 0.77 (95% CI, 0.52-1.0) for the agreement between both adjudication sessions. The kappa values for the dichotomy major or minor bleeding versus no bleeding were 0.42 and 0.44. The weighted kappa values for the agreement between the treating physician and the independent experts were 0.76 for the clinical severity and 0.79 for the impact on the patient's life (95% CI, 0.63-0.88 and 0.70-0.89). The association between the adjudication result expressed as major bleeding or minor or no bleeding and the clinical grading by the treating physician resulted in an ROC curve with an area under the curve of 0.98 for the clinical severity and 0.99 for the impact on the patient's life. The dichotomy major or minor bleeding versus no bleeding resulted in areas under the curve of 0.70 and 0.66. In conclusion, the applied criteria for major bleeding are reproducible and clinically relevant. The criteria for minor bleeding are not reproducible and are less associated with the observed clinical relevance.     

Haloperidol and reduced haloperidol plasma concentrations after a loading dose regimen with haloperidol decanoate

1. Haloperidol and reduced haloperidol plasma levels were measured in schizophrenic patients who received both oral (10 mg, N=16 and 20 mg, N=4) and depot haloperidol treatment 2. Patients were of Asian ethnicity and were safely and effectively converted from oral to depot therapy using a loading dose regimen using a 100 mg weekly injection interval for 4 weeks, biweekly for one month and then monthly. 3. Significant correlations were found for plasma haloperidol and reduced haloperidol levels and reduced haloperidol/haloperidol ratios between oral and depot therapy in these non-smoking patients. 4. A loading dose regimen is needed due to the long elimination half-life of decanoate of 26 days otherwise steady-state condition will not occur until 34 months of therapy. 5. Patients were maintained on monthly depot treatment for 40 weeks after the loading dose regimen and only one patient relapsed during treatment despite dosage increases. 6. The formation of reduced haloperidol remained consistent for oral and depot haloperidol treatment.     

Apoptosis: clinical relevance and pharmacological manipulation

Apoptosis, often synonymously used with the term 'programmed cell death', is an active, genetically controlled process that removes unwanted or damaged cells. Suppression, overexpression or mutation of a number of genes which orchestrate the apoptotic process are associated with disease. The diseases in which apoptosis has been implicated can be grouped into 2 broad groups: those in which there is increased cell survival (i.e. associated with inhibition of apoptosis) and those in which there is excess cell death (where apoptosis is overactive). Diseases in which there is an excessive accumulation of cells include cancer, autoimmune disorders and viral infections. Deprivation of trophic factors is known to induce apoptosis in cells dependent on them for survival. This fact has been exploited in the use of antiandrogens or antiestrogens in the management of prostate or breast cancer. Haemopoietic growth factors like granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin-3 prevent apoptosis in target cells and modulation of levels of these factors has been tried in the prevention of chemotherapy-induced myelosuppression. Until recently, it was thought that cytotoxic drugs killed target cells directly by interfering with some life-maintaining function. However, of late, it has been shown that exposure to several cytotoxic drugs with disparate mechanisms of action induces apoptosis in both malignant and normal cells. Physiological regulation of cell death is essential for the removal of potentially autoreactive lymphocytes during development and the removal of excess cells after the completion of an immune response. Recent work has clearly demonstrated that dysregulation of apoptosis may underlie the pathogenesis of autoimmune diseases by allowing abnormal autoreactive lymphocytes to survive. AIDS and neurodegenerative disorders like Alzheimer's or Parkinson's disease represent the most widely studied group of disorders where an excess of apoptosis has been implicated. Amyotrophic lateral sclerosis, retinitis pigmentosa, epilepsy and alcoholic brain damage are other neurological disorders in which apoptosis has been implicated. Apoptosis has been reported to occur in conditions characterised by ischaemia, e.g. myocardial infarction and stroke. The liver is a site where apoptosis occurs normally. This process has also been implicated in a number of liver disorders including obstructive jaundice. Hepatic damage due to toxins and drugs is also associated with apoptosis in hepatocytes. Apoptosis has also been identified as a key phenomenon in some diseases of the kidney, i.e. polycystic kidney, as well as in disorders of the pancreas like alcohol-induced pancreatitis and diabetes.     

Fentanyl plasma concentrations maintained by a simple infusion scheme in patients undergoing cardiac surgery

The mean response of body protein accretion in growing animals to their amino acid intake is sometimes described by a rectilinear ("broken-line") model and sometimes by a curvilinear model. The response of a population may be curvilinear as a result of averaging individual rectilinear responses or because individual responses are themselves curvilinear. This experiment was undertaken to distinguish these possibilities by examining the responses of individual animals. Eighteen pigs with a mean initial weight of 35 kg and a mean final weight of 73 kg were each fed, in a different sequence, six diets providing a daily nitrogen intake of 0.5, 1.5, 1.83, 2.17, 2.5 or 3.5 g/kg body wt0.75. Each diet was given for 10 d, with complete collections of feces over the last 6 d and of urine over the last 4 d. Rates of nitrogen retention (expressed per kg0.75 per day) were related to rates of nitrogen intake (in the same units) using a rectilinear (broken line), an exponential or a saturation kinetics model. Mean square errors were significantly larger for the rectilinear model than for either of the curvilinear models and were slightly but not significantly less for the saturation kinetics model than for the exponential model.     

Effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia

Triglyceride levels and free fatty acid metabolism are influenced by body fat distribution. To test whether the pattern of fat distribution in obese subjects results in distinct insulin mediated suppression of non-esterified fatty acids which could account for differences in plasma triglycerides, we studied 59 obese subjects who were classified according to waist-to-hip ratio. Non-esterified fatty acids and insulin response to a 75 g oral glucose tolerance test were higher in abdominal obesity. Total non-esterified fatty acids response, after adjustment for sex, showed a positive association with waist-to hip ratio (r = 0.292; p < 0.05). The abdominal obese group had higher fasting triglycerides (1.74+/-0.83 versus 1.11+/-0.71 mmol/L; p = 0.003) and lower glucose/insulin ratio (5.2+/-2.3 versus 7.1+/-2.4; p = 0.003). Stepwise multiple regression analysis showed that triglyceride levels are explained by fasting and 120 min non-esterified fatty acids and by glucose/insulin ratio. We conclude that abdominal obesity is associated with a higher resistance to insulin mediated suppression of non-esterified fatty acids in obese subjects. Variation of triglyceride concentrations in obesity is dependent on both fasting and 120 min non-esterified fatty acids as well as on insulin sensitivity to glucose utilization.     

The clinical relevance of biomechanics

Most neurologists are familiar with biomechanics but may be unsure of the relevance of this field to their practice. Actually those involved in musculoskeletal problems are undoubtedly using biomechanical principles. This article is limited to the spine, but the basic principles of biomechanics are applicable to other parts of the body. In this article, we describe the spine and trunk as a biomechanical organ, the biomechanical principles behind back injuries and their importance, the role of biomechanical issues in pain, the utility of clinical tests based on biomechanical principles, the effects of aging, and the future directions in spine biomechanical research.     

Retropsoas positioned bowel: incidence and clinical relevance

PURPOSE: Our goal was to assess the incidence of retropsoas positioned large or small bowel in the population and to examine factors predisposing to its formation. METHOD: The presence of retropsoas positioned bowel was retrospectively studied in 1,852 abdominal CT examinations of 1,055 men and 797 women, 648 younger and 1,204 older than 50 years. All examinations were considered normal or demonstrated findings that were unrelated to the position of the bowel. RESULTS: Retropsoas positioned colon (RPC) was observed in 51 (2.8%) cases for the ascending and 45 (2.3%) for the descending colon. RPC appeared more frequently in younger (< 50 years) than older patients and in individuals with decreased amount of retroperitoneal fat. Retropsoas position of small bowel loops was observed in 11 (0.6%) patients, all exhibiting paucity of retroperitoneal fat. CONCLUSION: Because of its prevalence, retropsoas positioned bowel should be considered when performing percutaneous diskectomy or other interventional procedures in the posterior retroperitoneum.     

Removal of heparin and protamine from plasma

A simple chromatographic technique for rapid adsorption of heparin and protamine from plasma samples is described, allowing accurate interpretation of coagulation screening tests and specific clotting factor assays. With the use of columns of ECTEOLA-cellulose, up to 300 U. of heparin could be completely adsorbed from a 1 ml. plasma sample. When citrated nonheparinized plasma was passed over the ECTEOLA-cellulose columns, the thrombin, prothrombin, and partial thromboplastin times were unaffected. Levels of fibrinogen, prothrombin, and factors V, VII, VIII, IX, and XI average within 90 per cent of control, nonchromatographed samples. When heparinized plasma samples (0.1 and 1.0 U. per milliliter) were passed over columns, heparin was completely removed and the results of the screening tests and the specific factor assays were the same as for the chromatographed nonheparinized samples. In addition, heparinized samples with decreased factor VIII activity maintained their pretreatment factor VII activities after heparin removal. Blood samples containing heparin were obtained from two patients during open-heart surgery. Following heparin adsorption on ECTEOLA-cellulose columns, factor VIII activity levels remained above 60 per cent during cardiopulmonary by-pass. The presence of protamine sulfate in plasma samples prolonged the prothrombin and partial thromboplastin times while slightly shortening the thrombin time. The protamine effect persisted after ECTEOLA-cellulose, but could be removed by a similar column of carboxymethyl-cellulose. The latter resin had no effect on screening tests or on assays of factors VIII or IX activity. The combination of the two resins was then used to remove the separate inhibitory effects from heparinized plasma samples to which protamine had been added.     

Hydroxyethyl starch antibodies in humans: incidence and clinical relevance

Hydroxyethyl starch (HES) is a plasma expander used for perioperative i.v. fluid management, as well as for resuscitation from trauma and shock. HES is very well tolerated, and the incidence of anaphylactic reactions is lower than with dextran or gelatin. Dextran anaphylaxis is caused by circulating dextran-reactive antibodies (ABs) of the immunoglobin G (IgG) class found in most adults. Histamine release from mast cells induces adverse reactions after gelatin infusion. The cause of adverse reactions due to HES is not yet clear. To investigate AB formation due to HES, we collected sera of 1004 patients at least 14 days after starch administration. Using a highly sensitive enzyme-linked immunoabsorbent assay technique, we found one patient with a low 1:10 titer of HES-reactive ABs (immunoglobin M [IgM] class). Despite repeated HES infusions, no clinical reaction could be detected in this patient. On the basis of a binomial distribution, a one-tailed confidence interval (99%) was used to calculate the percentage of the occurrence of ABs in general with maximum of 33 in 10,000 persons (IgM) and 23 in 10,000 persons (IgG). We suggest that HES-reactive ABs are extremely rare and that they do not necessarily induce anaphylaxis. Other mechanisms may be responsible for adverse reactions due to HES. Implications: The frequency of antibody formation due to hydroxyethyl starch, a commonly used plasma expander, was prospectively investigated in 1004 patients. Only one patient showed transient antibody formation, which was not harmful to the patient. This low antigenicity could explain the excellent tolerance of hydroxyethyl starch compared with other plasma expanders.     

Serum and tissue CEA in colorectal cancer: clinical relevance

PURPOSE: This article is an analysis of the information derived from the determination of tumor-tissue concentration of CEA in patients with colorectal cancer. To ascertain the relationship between tumor marker content with the histologic aspects and serologic levels of CEA of this neoplam. MATERIALS AND METHODS: 136 patients with colorectal adenocarcinoma and 41 with colorectal benign processes are analyzed and followed during an average time of 27 months. The CEA of the serum were obtained preoperatively and postoperatively and measured by radioimmunoassay (RIA). Tissular CEA levels were determined with RIA. The histological characteristics are analyzed (Dukes classification, grade of differentiation, index of atypia, microscopic vascular and lymphatic involvement. RESULTS: 1) The cut off point of the tissular CEA with the best sensitivity and specificity for the diagnosis of normal mucosa is 386 ng/mg and for tumoral tissue is 1160 ng/mg. 2) There is no correlation between tissue and serologic CEA value. 3) The tissular level of CEA have a significant statistical correlation with Dukes stage (p < 0.003); other histological characteristics were no significative. 4) There are significant statistical correlations between serologic CEA and relapse but no with survival rates. CONCLUSIONS: 1) Serologic CEA levels depend on numerous factors. 2) There aren't correlations between preoperative serologic levels and tissular CEA levels. 3) Tissular CEA do not predict what patients will have an elevated serologic CEA level in relapse.     

Metabolism of psychotropic drugs: pharmacological and clinical relevance

Cytochrome P-450 (CYP) catalyzes phase I metabolic reactions of psychotropic drugs. The main isoenzymes responsible for their biotransformation are CYP1A2, CYP2D6, CYP3A4 and these of the subfamily CYP2C. The majority of metabolites of psychotropic drugs are biologically active. Some of them retain pharmacological properties of parent compounds (eg. selective serotonin reuptake inhibitors, risperidone, carbamazepine, benzodiazepines), but others display quite different (eg. amitriptyline, buspirone) or even opposite (trazodone) profiles. They are present in vivo in concentrations high enough to contribute to pharmacological and clinical effects of the administrated drugs. Active metabolites of psychotropics are also characterized by pharmacokinetic properties different from their parent compounds, e.g. half-life time, plasma protein binding, blood-brain-barrier penetration, the cerebrospinal fluid (CSF) protein binding and tissue binding. These properties lead, in turn, to differences in the brain/plasma and the CSF/plasma concentration ratios between a drug and its metabolites. Therefore studies relating a pharmacological or therapeutic response of psychotropic drug to its plasma concentrations should not disregard the presence of its active metabolites, considering their distinct pharmacological and pharmacokinetic properties. With regard to a low therapeutic index of psychotropics, interindividual differences in the rate of their metabolism, genetic polymorphism of their main metabolic pathways and metabolic interactions in clinical drug combinations, the phenotyping of patients at the beginning of therapy and a control of drug concentrations (and its active metabolites) at a steady state and during coadministration of another drug, may increase the efficiency and safety of the pharmacotherapy of psychiatric disorders.