Dragan R. Milovanovic

Effectiveness of clozapine, haloperidol and chlorpromazine in schizophrenia during a five-year period

OBJECTIVE The aim of our study was to evaluate the effects of low doses of clozapine in flexible regime in comparison with haloperidol and chlorpromazine in long term. METHOD The naturalistic study was prospective, active-controlled with 325 adult outpatients of both genders (140 females), with mean year age of 34.8 (range 21-57), suffering from chronic schizophrenia. The first onset of illness was at the mean of 27.9 years (range 17-38), and subjects had the mean year age of 4.1+/-0.5 previous relapses. The patients were allocated to receive haloperidol (105 subjects, dose range 2-15 mg), chlorpromazine (n=105, 100-400 mg) or clozapine (n=115, 75-600 mg). The scores of psychometric instruments (GWB, PANSS, CGI) were regularly assessed during 5 year period. RESULTS The sixty-six responders were included in per-protocol analysis: 12, 10 and 16 with positive and 7, 6 and 15 with negative schizophrenic syndrome in haloperidol, chlorpromazine and clozapine group, respectively. The statistically significant differences in all psychometric scores was found, for both schizophrenic syndromes, favoring clozapine. The distribution of eighteen different types of adverse events, which we noted, were significantly different among treatment groups ( chi2=315.7, df=34, p<0.001). Clozapine was safer and had fewer adverse effects (average of 0.9 adverse events per patient) than haloperidol (2.7) and chlorpromazine (3.2). CONCLUSIONS Clozapine, in low doses of flexible regime, in long term (five years) showed better effectiveness in chronic schizophrenics with positive and negative symptoms than typical antipsychotics.

The use of dry Jerusalem artichoke as a functional nutrient in developing extruded food with low glycaemic index

This study considers the use of dry Jerusalem artichoke (JA) as a functional nutrient in developing food products with enhanced nutritional characteristics and low glycaemic index (GI). Three different formulations based on buckwheat and JA were developed and processed using extrusion technology. Nutritional properties including the levels of total dietary fibre (TDF), protein, inulin, total carbohydrates and lipids were analysed. A clinical study was performed on ten healthy volunteers (aged between 21 and 56) to determine the level of GI and glycaemic load (GL). The results revealed that JA significantly (P<0.05) increased the levels of TDF and inulin whilst decreasing carbohydrates, lipids and proteins. The resulting products had a significant (P<0.05) effect on IAUC between reference food and extruded products, GI and GL. Samples containing 80% of Jerusalem artichoke were considered as a low GI food whilst samples containing 30% and 60% of Jerusalem artichoke as a medium GI food. A similar trend was seen in terms of GL.

Factors associated with severe postoperative pain in patients with total hip arthroplasty

OBJECTIVE The aim of this study was to determine the risk factors for the development of postoperative pain following total hip arthroplasty, particularly those connected with psychological distress and personality traits. METHODS The study included 90 patients with complaints of postoperative pain following cemented total hip replacement divided into two groups based on the intensity of postoperative pain as measured using the numerical rating scale (NRS). Patients with NRS scores of 5 or higher were included in the study group and those with NRS of less than 5 were included in the control group. The Hamilton scales for anxiety and depression and the DS14 test for the identification of Type D personality were used for psychological evaluation. RESULTS In the study group, more patients were female (29 vs. 13) and had more anxiety (13 vs. 3), depression symptoms (11 vs. 2), and Type D personality (18 vs. 9) than the control group. Mean preoperative NRS was 7.2 ± 1.7 in the study and 6.0 ± 1.2 in the control group (p<0.001). Factors associated with development of strong postoperative pain was female gender (OR=4.91, 95% CI=2.01 to 12.01, p<0.001), Type D personality (OR=2.81, CI=1.17 to 7.32, p=0.030), severe anxiety (OR=6.01, CI=1.58 to 22.90, p=0.009), depressive symptoms (OR=7.33, CI=1.52 to 35.34, p=0.013) and subjects with marked preoperative painful condition (OR=2.64, CI=1.17 to 5.44, p<0.001). CONCLUSION Patients with severe anxiety, depression and Type D personality appear to be at risk of developing severe postoperative pain. In addition, female gender and the intensity of pain immediately after procedure were found to be important risk factors.

Effect of exogenous glutamate and N-Methyl-D-aspartic acid on spontaneous activity of isolated human ureter

Objectives:  While the neurotransmitter role of glutamate in the gastrointestinal tract has been shown, its effects on smooth muscle of the human ureter have not previously been investigated. In our study we have investigated the effects of exogenous glutamate on the spontaneous activity of isolated human ureter, taken from 14 adult patients after nephrectomy.

Impact of clinical pharmacology on health care: Serbian experience

Dear Sirs, During the recent 7th Congress of the European Association for Clinical Pharmacology and Therapeutics, held in Poznan, Poland, serious concerns were expressed by leading invited speakers on the future of clinical pharmacology as a discipline [1]. Their joint conclusion was that clinical pharmacologists in the majority of developed European countries are less and less involved in health care [2]. ‘‘It is the retreat from the bedside into the laboratory that is responsible’’ for the discipline’s decline, one of the speakers said ominously [3]. However, this trend is not taking place in all European countries. In some Eastern European countries, clinical pharmacology is still very much a patientbased discipline, with a significant impact on health care. It is that impact that keeps the discipline alive and prosperous, as can be seen from the Serbian experience. The status and impact of clinical pharmacology on health care in Serbia was investigated in two ways: by field survey and by questionnaire. In the field survey, 38 hospitals and health centers (two tertiary health care hospitals, three mixed tertiary/secondary health care hospitals, and 33 health centers, each consisting of a secondary care hospital plus a primary health care facility) were visited twice during the years 2002 to 2005, and the anonymous questionnaire was sent to 78 available clinical pharmacologists (out of 90 registered) from November 2004 to January 2005. While the field survey confirmed that the tertiary care and the mixed tertiary/secondary care hospitals had three to four clinical pharmacologists each, and four health centers had one clinical pharmacologist each, the questionnaire showed that 50% of the respondents (60 clinical pharmacologists) worked in the health care system, half of them as full-time employees. Both the field survey and the questionnaire indicated that the following services were given by clinical pharmacologists in the Serbian health care system: drug/patient problem consultations, drug information, chairing of drug and therapeutics committees, intensive monitoring of adverse drug effects, therapeutic drug monitoring, formulation of hospital drug policies, auditing of prescribing practice, design of postmarketing studies, continuing medical education, predispensing control of prescribing, and drug utilization analyses. The scope of health care services given by clinical pharmacologists was the largest in the two tertiary care hospitals with independent departments of clinical pharmacology. There is a growing trend in the number of services given, as can be seen from the data from the Center for Clinical and Experimental Pharmacology, Clinical Center ‘‘Kragujevac,’’ for a 10-year period (Fig. 1). Due to good organization of work within the departments, the drug management process in both hospitals was advanced (active drug and therapeutics committees, more than 60 local guidelines adopted), and the availability of all necessary drugs was achieved within the limits of modest drug budgets. Both hospitals had drug formularies completely agreed upon by other clinicians that yet were not far from the World Health Organization’s essential drugs model list (for instance, Clinical Center ‘‘Kragujevac’’ had 338 different drug entities and 584 formulations in total, with 6.08 euros spent for drugs per one bed-day in 2004; the available budget for 2004 was 5.94 euros per one bed-day). With predispensing control of prescribing (in Clinical Center ‘‘Kragujevac,’’ errors were found in about 12% of prescriptions, and drug dispensing was corrected appropriately), continuing medical education, and auditing of prescribing practice, clinical pharmacologists in these S. M. Jankovic (&) AE D. R. Milovanovic University of Kragujevac and Center for Clinical & Experimental Pharmacology, Clinical Center ‘‘Kragujevac’’, Kragujevac, Serbia & Montenegro

Predictors of surgical site infection in dirty urological surgery

Objectives:  Risk factors for surgical site infection (SSI) following urologic dirty operations have not been clearly identified. This study was conducted to describe incidence, potential risk factors and common causative pathogens of the SSI in such operations.

Parameters of Calcium Metabolism Fluctuated during Initiation or Changing of Antipsychotic Drugs.

Objective Serum parameters of calcium homeostasis were measured based on previously published evidence linking osteoporotic fractures and/or bone/mineral loss with antipsychotics. Methods Prospective, four-week, time-series trial was conducted and study population consisted of patients of both genders, aged 35-85 years, admitted within the routine practice, with acute psychotic symptoms, to whom an antipsychotic drug was either introduced or substituted. Serial measurements of serum calcium, phosphorous, magnesium, 25(OH)D, parathyroid hormone, calcitonin, osteocalcin and C-telopeptide were made from patient venous blood samples. Results Calcium serum concentrations significantly decreased from baseline to the fourth week (2.42±0.12 vs. 2.33±0.16 mmol/L, p=0.022, n=25). The mean of all calcemia changes from the baseline was -2.6±5.7% (-24.1 to 7.7) with more decreases than increases (78 vs. 49, p=0.010) and more patents having negative sum of calcemia changes from baseline (n=28) than positive ones (n=10) (p=0.004). There were simultaneous falls of calcium and magnesium from baseline (63/15 vs. 23/26, p<0.001; OR=4.75, 95% CI 2.14-10.51), phosphorous (45/33 vs. 9/40, p<0.001; 6.06, 2.59-14.20) and 25(OH)D concentrations (57/21 vs. 13/35, p<0.001; 7.31, 3.25-16.42), respectively. Calcemia positively correlated with magnesemia, phosphatemia and 25(OH)D values. Parathyroid hormone and C-telopeptide showed only subtle oscillations of their absolute concentrations or changes from baseline; calcitonin and osteocalcin did not change. Adjustment of final calcemia trend (depletion/accumulation) for relevant risk factors, generally, did not change the results. Conclusion In patients with psychotic disorders and several risks for bone metabolism disturbances antipsychotic treatment was associated with the decrease of calcemia and changes in levels of the associated ions.

Consulting clinical pharmacologist about treatment of inpatients in a tertiary hospital in Serbia

Dear Editor, Clinical pharmacology specialists give many services in various healthcare systems all over the world, but the most complex and responsible one is advising other specialties about treatment of difficult, and often critical, patients in tertiary care hospitals [1–3]. Usually, other clinical specialties call a clinical pharmacologist for a help only when they cannot see any further option to treat a patient who is either deteriorating or not improving as expected [3]. Since clinical pharmacology services are still developing in many regions, it is of interest to present experiences with effects of consulting clinical pharmacologist on treatment outcomes from places where such services have considerable history. Clinical pharmacology department in a tertiary care Clinical Center, Kragujevac, Serbia, was founded back in 1995 and have five fully employed specialists of clinical pharmacology, who on average give about 4000 consultations to other specialists annually. The department is funded by the National Health Insurance Fund, in the same manner as other specialty services, and it is integrated in postgraduate training of future clinical pharmacologists. During the 15-month period from January 2015 to March 2016, the clinical pharmacologists (CPs) were consulted 5137 times for 4692 patients (39 % females and 71 % males), whose average age was 61.67 ± 17.26 years. For 4176 patients, the CPs were consulted only once and for 516 patients, twice or more times. Daily workload per clinical pharmacologist on duty was between five and ten patients, and on average, 30 min was spent per consultation. Primary diagnoses of the patients are shown in the Table 1. After clinical examination of the patients for whom they were consulted and getting introduced with a patient’s history and files, the CPsmade certain interventions, which are shown in Table 2. The acceptance rate of the interventions by other clinical specialists who asked for consultation was 90.3 %. The outcome of the interventions suggested by the CPs and accepted by clinical specialists was improved in the patient’s status in 70.6 %, continuation of the same status in 0.9 %, and deterioration in 28.5 %. The vast majority of consultations was about the choice and/or dosing of antimicrobial drugs, and the most frequent infection sites in the patients were blood (55.4 %), respiratory tract (10.8 %), and skin and soft tissues (10.1 %). A few recent publications presented their experiences with consultations of clinical pharmacologists asked for by the other clinical specialists. In 1-year study from Udine, Italy, the focus was on consultations based on therapeutic monitoring of linezolid [4], and the CPs * Slobodan M. Janković slobnera@gmail.com

Micropapillary carcinoma of the bladder presented with spontaneous intraperitoneal bladder rupture

Spontaneous bladder perforation is a rare presenting feature of bladder malignancy. We describe an unusual case of a patient, admitted to emergency, with diffuse abdominal pain due to spontaneous bladder rupture in association with a micropapillary carcinoma. A diagnosis of an intraperitoneal bladder perforation was made during an emergency operation. Aspects of etiology, clinical presentation, diagnosis and management are described. Although cases of spontaneous carcinomatous bladder rupture are associated with high morbidity and mortality, prompt identification and treatment can lead to favourable outcomes.

Scoring System Development and Validation for Initial Treatment Failure in Suppurative Kidney Infections

BACKGROUND Suppurative kidney infections (SKIs) have potentially lethal implications and a high incidence of treatment-related morbidity and death. Until this point, there has been no study that has derived a prognostic model for adverse early outcomes in SKI. Therefore, our aim was to derive and validate a simple scoring system of early treatment failure in SKI. METHODS Logistic regression and bootstrap methods were used to create an integer score for estimating the risk of early treatment failure using patient characteristics, severity of disease, bacterial etiology, type of pathology, initial antibiotic therapy, and early urologic procedures. RESULTS This study included 92 adult patients with 104 SKIs. Early treatment failure was observed in 57 patients (54.8%). The length of the hospital stay and the treatment complications were significantly longer and more common, respectively, in patients with early treatment failure. The factors associated most strongly with early treatment outcome were whether there had been an early complete urologic procedure, the adequacy of early antibiotic therapy, and the presence or absence of sepsis syndrome. The total possible score ranged from 0 to 22 points, with a cut-off value of 5 points. A score of ≤ 5 points identified early success correctly in 85.3% of patients, whereas a score > 5 points correctly identified early failure in 93.2%. The scoring system retained its predictive ability on the validation set. CONCLUSION A scoring system was created to predict early treatment failure for a given patient with SKI. Although the system has good performance characteristics and provides a possible intervention measure, further studies should be performed before widespread implementation.