Could a neurological disease be a part of Mozart’s pathography? [Neurološki aspekt Mozartove patografije]

As expected, since we recently celebrated the 250th anniversary of birth of Wolfgang Amadeus Mozart, there has been again a renewal of interest in his short but intensive life, as well as in the true reason of his untimely dead. Mozart lived and died in time when the medical knowledge was based mostly on subjective observations, without the established basics of standardized medical terminology and methodology. This leaves a great space for hypothesizing about his health problems, as well as about the cause of his death. The medical academic community attributed to Mozart approximately 150 different medical diagnoses. There is much speculation on the possible causes of Mozart’s death: uremia, infection, rheumatic fever, trichinellosis, etc. Recently some authors have raised the question about a possible concomitant neurological disease. According to available records, Mozart has shown some elements of cyclotimic disorder, epilepsy and Gilles de la Tourette syndrome. Furthermore, the finding of a temporal fracture on (allegedly) Mozart’s skull, gives a way to speculations about the possibility of a chronic subdural hematoma and its compressive effect on the temporal lobe. Despite numerous theories on Mozart’s pathography that also include a concomitant neurological disorder, the medical and history records about Mozart’s health status indicate that he probably had suffered from an infective illness, followed most likely by the reactivation of rheumatic fever, which was followed by strong immunologic reaction in the last days of his life. Taking all the above into consideration, it is reasonably to conclude that Mozart’s neurological disturbances were caused by the intensity of the infective disease, and not primarily by a neurological disease

Farmakogenetika citotoksičnog liječenja kolorektalnog karicinoma

Colorectal cancer is a relatively common tumor with incidence that has been increasing during recent decades. Despite the rapid advances in treatment of colorectal cancer, the best way to combine and sequence all available drugs to optimize treatment is not yet established. The majority of cytotoxic drugs used in therapy of colorectal cancer have a dose related effect and narrow therapeutic index. Hence, dosing of cytotoxic drugs is considered very important. Current modalities for therapy and dose selection give restricted possibilities to equalise inter-individual variations which are dependent on physiological, genetic and environmental factors. In this article, an overview of current possibilities of personalized medicine in therapy of colorectal cancer is presented. This includes review of the most important gene polymorphisms important for safety and efficacy of cytotoxic therapy in colorectal cancer, and evaluation of their importance for the current clinical practice. Despite raising knowledge, providing individual treatment with low toxicity and significant benefits is still an unsolved problem. Reasons for this are the lack of knowledge on distribution of these polymorphisms in the population, importance of non-genetic factors, price of genetic testing and still limited data from controlled clinical trials confirming the clinical usefulness of pharmacogenetic testing. Although the initial costs of cancer management and personalized medicine may be high, in the future they may result in significant benefits from both a clinical and economical perspective.Rak kolorektuma relativno je čest tumor s rastućom incidencijom zadnjih desetljeća. Unatoč brzom napretku u liječenju kolorektalnog raka, još nije jasno na koji način je najbolje kombinirati i kojim redoslijedom koristiti dostupne lijekove. Većina citotoksičnih lijekova koji se primjenjuju u liječenju kolorektalnog raka imaju učinak ovisan o dozi i malu terapijsku širinu te je određivanje doze lijeka vrlo značajno. Važeći načini izbora terapije i određivanja doze daju ograničene mogućnosti ublažavanja interindividualnih varijacija ovisnih o fiziološkim, genetičkim i okolišnim čimbenicima. U ovom članku dan je pregled trenutačnih mogućnosti individualiziranja liječenja kolorektalnog raka. To uključuje pregled najznačajnihih genetskih polimorfizama bitnih za sigurnost i učinkovitost citotoksične terapije u liječenju kolorektalnog raka te evaluaciju njihove značajnosti za trenutačnu kliničku praksu. Unatoč sve većem znanju, omogućavanje individualiziranog liječenja uz ograničavanje toksičnosti a potenciranje učinkovitosti još je neriješeni problem. Razlog za to su manjak znanja o distribuciji polimorfizama u populaciji, važnosti negenetičkih čimbenika, cijena genetičkog testiranja i još uvijek ograničeni podaci iz kontroliranih kliničkih studija koji bi potvrdili kliničku korisnost farmakogenetičkog testiranja. Iako inicijalni troškovi liječenja kolorektalnog raka i personalizirane medicine mogu biti visoki, u budućnosti bi kombinacija ovih pristupa mogla rezultirati značajnim prednostima iz kliničke i ekonomske perspektive

MASSIVE CLOZAPINE OVERDOSE: WHAT TO EXPECT?

Clozapine is an atypical antipsychotic drug indicated for treatment-resistant schizophrenia. Despite its superior clinical efficacy, many deleterious adverse events, including agranulocytosis, have resulted in its more judicious use (Asenjo Lobos et al. 2010). The most frequently reported symptoms of clozapine intoxication are impaired alertness and tachycardia; other symptoms include: hyperthermia, alterations in consciousness, dysarthria, ataxia, seizures, cardiac arrhythmias, excessive bronchial mucus, hypersalivation, miosis, blood dyscrasias, pancreatitis and hepatitis (Le Blaye et al. 1992, Krämer et al. 2010). Studies that evaluated the case fatality rate with various antipsychotics concluded that clozapine was far more toxic than other antipsychotics (Ferrey 2018). To the best of our knowledge, this is the fist case report describing treatment and outcomes following a massive overdose of clozapine, amounting to 46.7 times the recommended patient’s daily dose of clozapine

Drugs and Pregnancy

Znanje o sigurnosti lijekova primijenjenih tijekom trudnoće vrlo je važno za sve liječnike kliničare. S obzirom na to da je 50-ak posto trudnoća neplanirano, učestalo se javlja pitanje učinka ekspozicije lijekovima u ranom i najosjetljivijem razdoblju još neotkrivene trudnoće. S druge strane, mnogo žena s bolestima koje treba liječiti kroničnom terapijom planira trudnoću. Iako je malen broj lijekova čija je primjena u trudnoći kontraindicirana zbog dokazanih štetnih utjecaja na majku i dijete, općenito postoji velik strah od primjene lijekova u trudnoći, što kao problem donosi nedovoljno ili neadekvatno ili pak pretjerano propisivanje lijekova. Neprimjerene preporuke mogu dovesti do nepotrebnog prekida ili neprimjerenog liječenja kroničnih ili akutnih bolesti tijekom trudnoće, što može povisiti rizik od njezina nepovoljnog ishoda. Kod odluke o primjeni lijekova u trudnice treba provesti ovaj pristup: 1. procijeniti potrebu za primjenom lijeka; 2. izabrati najsigurniji lijek; 3. pratiti primjenu lijeka; 4. dati specifične upute o primjeni (npr., izbjegavati određene kombinacije lijekova); 5. tražiti savjet kliničkog farmakologa ako je potrebno. U članku se daje pregled racionalne terapije najčešćih bolesti i stanja tijekom trudnoće i dojenja.Knowledge about safety and efficacy of drugs prescribed during pregnancy and lactation is important for every clinician. Due to the fact that approximately 50% of pregnancies are unplanned, there is concern about possible adverse drug reactions (ADR) of drugs taken during the early and most vulnerable stage of pregnancy. Furthermore, many women with chronic illnesses that require treatment are planning to become pregnant. Although there is limited number of drugs that are contraindicated during pregnancy due to their teratogenic or other ADR, there is much fear about prescribing drugs to pregnant women. This raises as much concern about under prescribing drugs as overprescribing them. Inadequate recommendations on drug use during pregnancy may lead to unnecessary therapy cessation or inadequate therapy of chronic or acute illnesses leading to increased risk for adverse pregnancy outcomes. When consulting on pharmacotherapy during pregnancy, physicians should take the following approach: 1. Determine if drug therapy is necessary; 2. Choose the safest drug available; 3. Monitoring drug therapy (e.g. measurement of plasma drug concentration, ADR); 4. Advice on drug use (e.g. avoiding specific drug-drug combinations); 5. Seek advice from clinical pharmacologist. This article provides a review of rational pharmacotherapy for the most common clinical conditions during pregnancy

Use of gastroprotective agents in recommended doses in hospitalized patients receiving NSAIDs: a drug utilization study

OBJECTIVE: In recent years, studies investigated to what extend recommendations for co-prescribing gastroprotective agents in prevention of NSAID-induced gastrointestinal complications are followed in clinical practice. However, only a few studies have also taken into consideration the recommended dose of gastroprotectives prescribed in NSAID-induced ulcer prophylaxis. The aim of our study was to evaluate the prevalence of concomitant use of gastroprotectives with NSAIDs in hospitalized patients, with emphasis on the recommended dose of gastroprotectives for ulcer prophylaxis. - - - - - METHOD: This observational, cross-sectional, drug utilization study included all adult patients receiving NSAIDs hospitalized in the Clinical Hospital Center Zagreb on the day of the study. Data on age, sex, comorbidities, indications for NSAID use, type/dose of NSAIDs and gastroprotectives, history of gastrointestinal events, active gastrointestinal symptoms and risk factors were evaluated. - - - - - MAIN OUTCOME MEASURE: Study outcomes were: (1) prevalence of prescription of gastroprotectives among NSAID-users at risk; (2) prevalence of prescription of gastroprotective in recommended dose; (3) association between risk factors and prescription of GPAs. - - - - - RESULTS: The rates of gastroprotectives prescription were significantly higher in NSAID-users with concomitant risk factors as compared to patients without risk factors [47/70 (67.1%) and 8/22 (36.4%), respectively; p = 0.01072]. However, gastroprotection in recommended ulcer-preventive dose was low in both groups [8/70 (11.4%) and 9/92 (9.8%), respectively]. The number of concomitant risk factors did not increase the odds of receiving anti-ulcer therapy (odds ratio 0.7279). Thirty-three percent of patients with concomitant risk factors were not prescribed gastroprotectives. Ibuprofen, NSAID with the lowest risk of inducing gastrointestinal complications, was prescribed in only two patients. - - - - - CONCLUSION: The results indicate high awareness among hospital physicians about possible NSAID-induced gastrointestinal complications, but insufficient knowledge about risk factors related to NSAID-induced gastrointestinal toxicity, recommended dose of gastroprotectives in NSAID-induced ulcer prophylaxis and gastrointestinal toxicity of different types of NSAIDs

Distributed lags time series analysis versus linear correlation analysis (Pearson's r) in identifying the relationship between antipseudomonal antibiotic consumption and the susceptibility of Pseudomonas aeruginosa isolates in a single Intensive Care Unit of a tertiary hospital

The relationship between antibiotic consumption and selection of resistant strains has been studied mainly by employing conventional statistical methods. A time delay in effect must be anticipated and this has rarely been taken into account in previous studies. Therefore, distributed lags time series analysis and simple linear correlation were compared in their ability to evaluate this relationship. Data on monthly antibiotic consumption for ciprofloxacin, piperacillin/tazobactam, carbapenems and cefepime as well as Pseudomonas aeruginosa susceptibility were retrospectively collected for the period April 2006 to July 2007. Using distributed lags analysis, a significant temporal relationship was identified between ciprofloxacin, meropenem and cefepime consumption and the resistance rates of P. aeruginosa isolates to these antibiotics. This effect was lagged for ciprofloxacin and cefepime [1 month (R=0.827, P=0.039) and 2 months (R=0.962, P=0.001), respectively] and was simultaneous for meropenem (lag 0, R=0.876, P=0.002). Furthermore, a significant concomitant effect of meropenem consumption on the appearance of multidrug-resistant P. aeruginosa strains (resistant to three or more representatives of classes of antibiotics) was identified (lag 0, R=0.992, P<0.001). This effect was not delayed and it was therefore identified both by distributed lags analysis and the Pearson's correlation coefficient. Correlation coefficient analysis was not able to identify relationships between antibiotic consumption and bacterial resistance when the effect was delayed. These results indicate that the use of diverse statistical methods can yield significantly different results, thus leading to the introduction of possibly inappropriate infection control measures

Pain Relief in Medical Patients: Does Clinical Judgment and Prescribing Knowledge Suffice?

The aim of this study was to evaluate the quality of pain management in hospitalised patients. A cross-sectional study design that included all medical patients experiencing pain was used. Out of 167 patients hospitalized at the Department of Medicine at the University Hospital Zagreb, 41 patients were experiencing pain and 40 out of them received analgesics. Twenty-two out of 38 patients were treated for malignant pain, 16 for non-malignant pain, and 2 patients could not be classified. Adequate pain relief was reported in less than 25% of patients in both groups. Our study revealed under-prescribing of combination therapy, low utilization rates of strong opioids and prevailing »as needed« prescribing practice. In conclusion, unsatisfactory pain management in medical patients is often present if left solely to the clinical judgement and knowledge of the prescribing physician. Regular pain assessment, evidence-based guidelines, education and regular audits of implementation of these measures are a prerequisite for effective pain treatment, and should all be employed in patients experiencing pain

Antibiotic Use Optimization Program in the Largest Croatian University Hospital – Benefits of Restrictions on Unlimited Antibiotic Use

The aim of this study was to obtain the relevant information on antibiotic use in a 750-bed Croatian university hospital. The study has been designed as a 2-point prevalence interventional analysis. For each patient on antibiotic therapy, diagnosis, indication for treatment, antibiotic therapy, dosage and route of administration together with the results of microbiological studies (if available) were obtained. After the first prevalence analysis in 2001, a restriction on unlimited antibiotic use was introduced. The second analysis, performed in 2002, after restrictions on antibiotic use, revealed reductions in the rates of restricted release antibiotics and overall antibiotic use with decreases from 38.6% to 36.9% and 23.4% to 23.2% respectively (p=0.87). The first survey showed that the 5 most often prescribed antibiotics in the therapy of bacterial infections were: gentamicin, other aminoglycosides, carbapenems, amoxycillin+clavulanate and vancomycin with proportions of 14.8%, 10.3%, 8.2%, 7% and 7% respectively. In the year 2002, the most prescribed antimicrobial drugs in the therapy of bacterial infections were: gentamicin, quinolones, vancomycin, carbapenems and cefuroxime with proportions of 18.6%, 11.4%, 9.7%, 9.3% and 8% respectively. A reduction in the proportions of doubtful antibiotic therapy, from 24.6% before the intervention, to 24.2% after the restrictions, accompanied by a 0.4% rise in the rates of indicated antibiotic therapy was also observed (p=0.93). Our study shows that restrictions on formerly unlimited use of antimicrobials, even when leading to an improvement in their prescribing, do not necessarily cause rapid and significant reduction in the overall use of antibiotics or explicit positive financial effects

Two-year Rehospitalization Rates of Patients with Newly Diagnosed or Chronic Schizophrenia on Atypical or Typical Antipsychotic Drugs: Retrospective Cohort Study

Cilj Odrediti smanjuju li atipični antipsihotički lijekovi stopu rehospitalizacije bolesnika s novodijagnosticiranom ili kroničnom shizofrenijom više nego tipični lijekovi. Postupci Od 1. siječnja 2003. do 31. prosinca 2004. retrospektivno smo uspoređivali dvogodišnje stope rehospitalizacije 135 bolesnika s novodijagnosticiranom i 398 bolesnika s kroničnom shizofrenijom (62%, odnosno 65% muškaraca) koji su otpušteni s liječenja u Psihijatrijskoj bolnici Vrapče u Zagrebu u razdoblju između 1. siječnja 2002. do 31. prosinca 2002. a bili su im prepisani atipični (olanzapin, risperidon ili klozapin) ili tipični (haloperidol ili flufenazin) antipsihotici. Vrijeme do ponovnog primanja u bolnicu određeno je Kaplan-Meierovom formulom za analizu preživljenja. Rezultati Za vrijeme dvije godine koliko je trajalo praćenje rehospitalizirana su 52 (39%) bolesnika s novodijagnosticiranom i 197 (47%) bolesnika s kroničnom shizofrenijom. Nije bilo značajnih razlika u vremenu do rehospitalizacije s obzirom na vrstu uzimanog lijeka između bolesnika s novodijagnosticiranom (P=0,378) i bolesnika s kroničnom shizofrenijom (P=0,531). Zaključak. Stopa rehospitalizacije u bolesnika kojima su prepisani atipični antipsihotici bila je slična stopi u bolesnika kojima su prepisani tipični antipsihotici i za bolesnike s novodijagnosticiranom i za bolesnike s kroničnom shizofrenijom.Aim To determine if atypical antipsychotic agents reduce the rehospitalization rates of patients with newly diagnosed or chronic schizophrenia in comparison with typical antipsychotic drugs. Methods From January 1, 2003, to December 31, 2004, we retrospectively compared two-year rehospitalization rates of 135 patients with newly diagnosed schizophrenia and 398 patients with chronic schizophrenia (62% and 65% men, respectively), who were initially discharged from Vrapče Psychiatric Hospital, Zagreb, with the prescription of atypical (olanzapine, risperidone or clozapine) or typical (haloperidol or fluphenazine) antipsychotic treatment between January 1, 2002 and December 31, 2002. Time-to-readmission was determined with Kaplan-Meier formula for survival analysis. Results In the two-year follow-up, 52 (39%) newly diagnosed patients and 197 (47%) patients with chronic schizophrenia were rehospitalized. No significant differences in time-to-rehospitalization were observed with respect to the type of medications in patients with newly diagnosed schizophrenia (P = 0.378) or patients with chronic schizophrenia (P = 0.531). Conclusions. Rehospitalization rates of patients who were prescribed atypical antipsychotic drugs were similar to those of patients who were prescribed typical antipsychotic drugs for both the group with the first psychotic episode and group with chronic schizophrenia