Avoiding concomitant prescription of drugs with a potential for interaction: mission impossible?

OBJECTIVE: The increased prevalence of multi-drug therapy increases the risk of drug interactions. We conducted a study with the aim of evaluating the prevalence of prescribing potentially interacting drug combinations, their severity, mechanism, and in particular, their clinical relevance, in medical inpatients at two Croatian university hospitals. METHODS: A cross-sectional study was conducted that included all medical inpatients receiving >= 2 drugs. Data were analyzed for 200 predefined drug-drug combinations compiled from the Micromedex data-base and literature. Two rating scales were used, one indicating the severity of a potential drug-drug interaction (pDDI) (minor, moderate, major), and the other assessing its clinical relevance (1: contraindicated; 2: avoidable; 3: consider risk-benefit ratio; 4: hardly avoidable). RESULTS: The prescribing patterns were similar between evaluated hospitals. The prevalence of pDDIs was 46%. The mean number of drugs prescribed per patient was 6.2 (± 95% CI 5.9 - 6.5). Out of 200 predefined pDDIs, 96 were found in our study population with mean 2.8 pDDIs per patient (± 95% CI 2.4 - 3.1). Out of 478 single identified pDDIs, most were of moderate and major severity (56% and 33%, respectively). However, only 9% out of them were considered completely avoidable, 57% were considered hardly avoidable, and for 35% the consideration of risk-benefit ratio was recommended. Most pDDIs were classified as pharmacodynamic by mechanism of interaction (45%). Age and number of prescribed drugs were significant risk factors for prescription of potentially interacting drug combinations (OR 1.01 (± 95% CI 1.001 - 1.03) and OR 1.46 (± 95% CI 1.33 - 1.59), respectively). CONCLUSIONS: Despite the high prevalence of pDDIs, only 1 in 10 was considered avoidable.

Cell cycle regulatory protein expression in fresh acute myeloid leukemia cells and after drug exposure.

Characteristics of treatment-induced cell cycle arrest are important for in vitro and in vivo sensitivity of acute myeloid leukemia (AML) cells to cytotoxic drugs. We analyzed the expression of the major G1 cell cycle regulators (p21Cip1, p27Kip1, cyclins D, cyclin E and pRb) in 41 fresh AML cell samples. The level of p27 expression was the only factor correlated with the response to chemotherapy, a high level of p27 expression being predictive of complete remission. There was a close relation between expression of pRb, cyclin D2 and FAB subtype, illustrated by the absence of both proteins in most samples having a monocytic component (M4, M5). We also assessed the expressions of pRb, cyclin E, p21 and p27 and the activity of cdk2, the major regulator of S-phase entry, after exposure to cytosine-arabinoside (AraC) and daunorubicin (DNR), and found these proteins could characterize time- and dose-dependent cellular response to each drug. We observed hyperphosphorylated pRb, increased levels of cyclin E and a high cdk2 activity, but no p21 induction, in AML cells exposed to 10(-6) M AraC. After exposure to 10(-5) M AraC, corresponding to the serum concentration reached in high-dose AraC regimens (HDAraC), a strong p21 induction was observed, associated with similarly overexpressed cyclin E and even higher cdk2 activity than after 10(-6) M AraC, while apoptosis was significantly increased. These data suggest that cdk2 activity is likely to play a role in AraC-induced apoptosis in AML cells. This mechanism may account for high efficacy of HDAraC in cells showing little sensitivity to conventional AraC doses.

Characterization of CD13 and CD33 surface antigen-negative acute myeloid leukemia.

From a cohort of 220 adults with newly diagnosed acute myeloid leukemia (AML), 8 (3.6%) exhibited a rare variant of aberrant membrane phenotype. It was characterized with typical myeloid morphologic and cytochemical patterns and absence of myeloid associated antigens (CD13, CD33, CD14, glycophorin A, CD61). According to the French-American-British criteria, disease in 5 patients was classified as M1 and in 3 patients as M2. CD34, CD38, HLA-DR, and CD45 were strongly expressed in 4 of 5, 3 of 3, 8 of 8, and 3 of 3 analyzed cases, respectively. CD7 antigen was strongly expressed in 4 of 6 patients. Except for predominance of male sex and high frequency of CD7 antigen expression, no other remarkable clinical or biologic characteristics were noted. Detected variant of AML with the unusual membrane phenotype (CD34+, HLA-DR-positive, CD38+, CD45+, CD7+) might represent an example of extreme asynchrony in sequences of morphologic and immunologic maturation or abnormal epitope expression on leukemic cell membrane molecules CD13 and CD33. Although the clinical significance of this AML variant is unclear, the existence of such cases demonstrates the continued need for simultaneous cytochemical and immunologic studies in the evaluation of acute leukemias.

Antimicrobial drug use in hospitalised paediatric patients: a cross-national comparison between Germany and Croatia.

PURPOSE: To compare the utilisation of systemic antimicrobials at the paediatric units of the university hospitals in Marburg (Germany) and Rijeka (Croatia). METHODS: A prospective, observational analysis of hospital records from 300 incident users of antimicrobials in each study centre that were younger than 19 years. Antimicrobial utilisation was analysed in six gender-specific age groups with respect to drug choice, duration of treatment and hospital stay, indication and route of administration. The extent of antimicrobial drug use was assessed by the number of treatment courses. RESULTS: In each hospital, more than 1/3 of the patients were younger than 1 year. The duration of hospital stay was about two-fold longer in Rijeka (18.5 +/- 5.8 days) than in Marburg (8.6 +/- 3.8 days). Pneumonia and other respiratory tract infections were the most common indications in Marburg (38.6%) and Rijeka (58.7%). The cumulative percentage of patients treated with an equal number of different antimicrobials was lower in Rijeka than in Marburg. The most commonly used antimicrobials were ampicillin (40.3%) and cefuroxim (35.9%) in Marburg, but ceftriaxone (43.3%) and cefotaxim (14.0%) in Rijeka. CONCLUSIONS: A shorter treatment duration, less variation in the prescribing pattern and a greater adherence to the use of recommended antimicrobials argue for a more rational antimicrobial drug use in Marburg than in Rijeka. However, a further identification of drug choice determinants is warranted.

Coexistent Polycythemia Vera and Chronic Lymphocytic Leukemia: Down-Regulation of Myeloid Clone by the Lymphoid Clone?

Coexistence of polycythemia vera (PV) and chronic lymphocytic leukemia (CLL) is a rare association. The clinical course in all cases has been remarkably mild, thus suggesting suppression and/or control of each disease by the other. We have studied a patient who exhibited a typical feature of PV for 6 years. After 3 years of remission, induced by (32)P, a mild form of PV reappeared in association with B-CLL. In order to investigate the possible influence of CLL to the mild expression of PV, we have performed several in vitro colony assays and the tumor necrosis factor (TNF) assay. Colony formation by patient's bone marrow hematopoietic progenitor cells showed "spontaneous" BFU-E and CFU-E. In addition, patient's plasma selectively inhibited growth of normal BFU-E and CFU-E colony formation. TNF bioactivity, analysed during the course of the disease, was reduced. These findings suggested the existence of an inhibitor of erythropoiesis that could be involved in a down regulation of the myeloid clone by the lymphoid clone in this patient.

[Immunophenotyping of leukemic cells in the diagnosis of hairy cell leukemia]. / Znacaj imunofenotipizacije leukemijskih celija za dijagnostiku leukemije vlasastih (hairy) celija.

INTRODUCTION: It is established that immunophenotyping constitutes a useful method in the diagnosis of hairy cell leukaemia. However, no single marker is specific for hairy cell leukaemia. Two-color-flow cytometry can aid in the diagnosis by showing coexpression of CD11c, HC2 or CD25 with pan B cell markers. Recently, Matutes E. et al. [17] proposed a scoring system of immunophenotypic markers, which could be used to evaluate the diagnosis of hairy cell leukaemia. AIM OF THE STUDY: The aim of the study was to: a) confirm previous observations of immunophenotypic characteristics of hairy cell leukaemia; b) identify antibody combinations of two-color immunofluorescence staining that are most useful in the diagnosis of hairy cell leukaemia; c) examine the value of a scoring system of immunophenotypic markers in the diagnosis of hairy cell leukaemia. METHODS: We analyzed peripheral blood of 46 patients with hairy cell leukaemia using indirect immunofluorescence flow cytometry (EPICS-Coulter) with an extended panel of monoclonal antibodies: CD19, CD2O, CD22, CD24, CD10, HLA-DR, CD11c, CD25, HC2, Slg, kappa and lambda light chains. The diagnosis of hairy cell leukaemia in all patients was made using conventional criteria based on cell morphology, TRAP cytochemistry and bone marrow histology. One fourth of patients were also analyzed using two-color flow cytometry with three antibody combinations as follows: CD19 + CD11c, CD19 + CD25 and CD19 + HC2. RESULTS: Our results showed that hairy cells of our patients had a uniform and unique immunophenotype with expression of the following markers: CD19, CD22, CD2O, CD11c and HLA-DR in 100% of patients, CD24 in 93%, CD25 in 88%, Slg in 82%, HC2 in 67%, CD1O in 50%, kappa light chains in 38% and lambda light chains in 35% of patients (Table 1). The level of detectable circulating hairy cells varied widely, from 2% to 93% of total lymphocytes, and 12 patients (26%) with less than 5% of detectable hairy cells were excluded from analysis. Two-color cytometry showed that antibody combination CD19 + CD11c was coexpressed in 100% of patients, CD19 + CD25 in 78% of patients and CD19 + HC2 in 57% of patients (Table 2). Only patients with 5% or more double colored hairy cells for one antibody combination, were included in the analysis. On the basis of our results of in immunophenotyping of hairy cell leukaemia patients and results of other authors (17), we made our scoring system which considers the reactivity with the following markers: CD19, CD11c, CD25 and HC2. Each marker gives 1 point if positive and 0 point if negative. Score 4 had 83% of patients, score 3 had 14% of patients, score 2 had 3% of patients and no patient had score 1 or 0 (Table 3). CONCLUSION: Our results demonstrated that immunophenotyping with a selective panel of monoclonal antibodies could significantly increase the accuracy in diagnosis of hairy cell leukaemia. Two-color flow cytometry with antibody combination CD19 + CD11c showed coexpression of hairy cells in 100% of our patients. The scoring system for hairy cell leukaemia used in our patients showed that high scores 3 and 4 had 97% of patients.

[Leukemic infiltration of gastrointestinal system: unusual complication of hairy cell leukemia]. / Leukemijska infiltracija gastrointestinumskog trakta: neuobicajena pojava u toku leukemije s vlasastim celijama.

Hairy cell leukemia is a rare chronic lymphoproliferative disease, characterized by pancytopenia, splenomegaly and infiltration of the bone marrow and peripheral blood by abnormal lymphoid cells with unique morphology and specific cytochemical staining for the tartarate resistant isoenzyme of acid phosphatase. Leukemic infiltration of the gastrointestinal system is an extremely rare (less than 1%) complication during the course of the hairy cell leukemia. The authors presented a patient in whom the correct diagnosis of this unusual complication was of particular importance for the initiation of alpha interferon therapy. After successful treatment with alpha interferon the patient died, few months later, from unrelated disease-acute anteroseptal myocardial infarction.

[Results of treatment in patients with hairy cell leukemia with splenectomy, alpha-interferon and deoxycoformycin]. / Rezultati lecenja bolesnika s leukemijom vlasastih celija primenom splenektomije, alfa-interferona i deoksikoformicina.

INTRODUCTION: The ability of interferon alpha and purine analogues to induce long-lasting remissions in the majority of patients with hairy cell leukaemia has revolutionized the treatment [16, 17, 24, 25], but also provoked dilemma and different opinions about the initial treatment or first line therapy. Splenotomy, the first standard treatment, increases peripheral blood counts but half of the patients require a later systemic therapy because of progressive cytopenia. On the other hand, it has been shown that splenotomy performed after achieving complete remission with interferon alpha or purine analogues contributed to spleen infiltration with hairy cells [37, 38]. PATIENTS AND METHODS: In our study we analysed results of treatment of 44 patients with hairy cell leukaemia who were followed-up for 8 years. Patients were treated with three treatment modalities, mostly successively. Splenotomy++ was performed in 34 patients as a first line therapy (Group I); interferon alpha in 24 patients; in 10 patients as a first line therapy without splenotomy (Group II) and in 14 patients as a second line therapy after splenotomy (Group III). Deoxycoformycin was given to 5 patients as a third line therapy. RESULTS: Our results showed that 20 patients (59 percent) treated only with splenotomy were in haematological remission (Group I). The analysis of prognostic variables demonstrated that at diagnosis patients from Group I, treated only with splenotomy, had at diagnosis higher levels of haemoglobin and thrombocyte counts and a lesser degree of bone marrow (b.m.) infiltration with hairy cells (HCs) than they were found in the other two groups of patients (median Hb = 11.3 g/dL, Plt = 133 x 10(9)/L, HCs in b.m. = 77%). Group II had median Hb = 8.6 g/dl, Plt = 72 x 10(9)/L, HCs in b.m. = 88%, and Group III had median Hb = 9.2 10(9)/L, Plt = 61 x 10(9)/L and HCs in b.m = 90%. Survival curves (Kaplan-Meier method) and Log Rank Statistics showed a significant difference in survival-time (Figure 4) among patients groups (p = 0.0427). Group I had median survival of 270 months; Group II 80 months; and Group III 140 months. Our results demonstrated that different prognostic risk groups existed among hairy cell leukaemia patients and could be identified on the basis of Hb level, Plt count and percent of infiltration of hairy cells into bone marrow. At diagnosis the low risk group of patients (Table 1) had levels of haemoglobin more than 11.3 g/dL; platelet counts more than 72 x 10(9)/L; percent of bone marrow infiltration with hairy cells less than 70%, and expression of lambda type of light chains on leukaemic cells. This group of patients was treated only with splenotomy without systemic therapy. In high risk group of patients the levels of haemoglobin were lower than 8.6 g/dL; platelet counts lower than 60 x 10(9)/L; percent of bone marrow infiltration with hairy cells more than 90% and expression of kappa type of light chains on leukaemic cells. The survival of this group of patients, in spite of initial treatment with systemic therapy with interferon alpha, was shorter. Results of treatment with interferon alpha (Group II and Group III) have demonstrated that the duration of remission in patients who were initially splenectomized and later treated with interferon alpha, was longer (median 31 months) than in patients who were treated with interferon alpha without splenotomy (median duration of remission = 13 months) (Table 3). Results of treatment with deoxycoformycin (Table 4) showed that 3/5 of patients achieved complete remission and 2/5 patients achieved partial remission. Four patients were initially splenectomised and att five patients were treated with interferon alpha before deoxycoformycin. CONCLUSION: On the basis of our results, splenotomy can be recommended as the first-line therapy for low risk patients with hairy cell leukaemia; interferon alpha should be the first-line therapy in high risk patients, and the second-line therapy in l

Megakaryocyte progenitors in paroxysmal nocturnal haemoglobinuria are sensitive to complement.

We have investigated growth in vitro of bone marrow megakaryocytic progenitors (CFU-Mk) in 7 patients with paroxysmal nocturnal haemoglobinuria (PNH) to determine the sensitivity of CFU-Mk to complement. Bone marrow light density mononuclear cells were exposed to fresh or heat-inactivated AB human serum in the presence of medium or isotonic sucrose solution. We found that the proliferative activity of bone marrow CFU-Mk in PNH patients was significantly lower than in controls. In addition, the number of CFU-Mk in PNH bone marrow cells exposed to isotonic sucrose and complement was reduced to 25% of that in PNH cells exposed to isotonic sucrose without complement. In conclusion, our finding showed an increased sensitivity of CFU-Mk in PNH bone marrow cells to complement, supporting the hypothesis that the PNH defect is present at the level of CFU-Mk.

[Results of treatment of patients with advanced multiple myeloma with the vincristine-adriamycin-dexamethasone protocol]. / Rezultati lecenja bolesnika s napredovalim multipnim mijelomom primenom protokola vinkristin-adriablastin-deksametazon.

UNLABELLED: A very few treatment regimens have shown a benefit in patients with multiple myeloma resistant to conventional melphalan/prednosone therapy or similar combinations. The first "biologically designed" protocol for the treatment of advanced, refractory myeloma was a combination of vincristine, doxorubicin and intermittent high-dose dexamethasone, so called VAD regimen. This report summarizes our experience in VAD regimen in the treatment of advanced, refractory myeloma patients, initially treated with melphalan-based chemotherapy. METHODS: Between July 1989 and July 1995, 27 patients with high-tumour-mass stage (Durie Salmon staging system) of the disease were treated with VAD combination. Clinical characteristics of patients are shown in Table 1. There were 17 pts who never responded (9 pts) of who progressed during induction therapy (8 pts). The second group of 10 pts responded to induction therapy and relapsed. Five pts (four with progressive and one with resistant myeloma) were treated with VAD therapy particularly due to significant extramedullary infiltrates. All pts in this study were initially treated with VMCP induction therapy. Seven of them were additionally treated with ABP combination, and this subgroup of pts was characterized as "resistant to melphalan and doxorubicin". The VAD regimen consisted of four-day continuous infusions of vincristine (0.4 mg per day) and doxorubicin (9 mg/m2 per day) in addition to dexamethasone in a dose of 40 mg for four days, beginning od days 1.9 and 17 of each cycle. The response was defined as a reduction of serum myeloma-protein concentration exceeding 75 per cent, with disappearance of Bence-Jones protein excretion. RESULTS: "Good" response to VAD regimen was achieved in 12 of 27 pts (44 per cent), mainly after three cycles of chemotherapy (Table 2). The tumour reduction occurred rapidly (Table 3), without significant myelosuppression. Response-rate was significantly higher in relapsing myeloma pts than in pts with progressive or resistant disease (chi 2 = 4.2; p < 0.05). Neither previous treatment (Table 2) nor the type or paraprotein concentration, degree of marrow infiltration and cytologic type of plasma cells affected the response to VAD. Among 15 pts with "bad" response to VAD, seven died during first four months of treatment. All pts with significant extramedullary infiltrates failed to respond to VAD (chi 2 = 4.91; p < 0.05). Median survival of all pts was 16 months. In responsive pts remissions were of good quality and survival was significantly longer that that in whom treatment failed (Figure 1, left). In responsive pts the median duration of "plateau-phase" was 11 months (Figure 1, right). In three pts who relapsed after the treatment, reinstitution of VAD regimen restored the "plateau-phase". The most important complications of treatment with VAD combination were infections (8 pts) but, fortunately, serious forms (i.e. pneumonia) were observed only in two pts. DISCUSSION: The antitumour effect of VAD regimen originates from a combined effect of doxorubicin and vincristine continuous infusions and intermittent pulses of high-dose corticosteroids. The rationale for protracted administration of vincristine and doxorubicin was based on long generation time and low growth fraction of plasma cells in most patients, while the use of high-dose dexamethasone was based on well-known dose-depend antimyeloma effect of corticosteroids. Using this chemotherapy schedule, significant prolongation of survival was achieved in our responding patients comparing to patients with VAD-resistant myeloma. The major toxic effect of treatment was infection, which was attributed in part to intensive steroid program. Relapse of the disease could be expected about one year after completion of VAD therapy. Nevertheless, the second "plateau-phase" can be obtained upon reinitiation of VAD (ABSTRACT TRUNCATED).

[Sezary's syndrome (case report)]. / Sezarijev sindrom (prikaz bolesnika)

The Sezary's syndrome is a lymphoproliferative disorder from the group of chronical lymphocytic leukaemia originated from the T-cell lineage. Authors are presenting the patient with Sezary's syndrome for the first time ever diagnosed in the Institute of Haematology. The patient, 58 years old got ill in summer 1989. with the symptoms of strong itch and erythematous papullas over the sin. In April 1990. he came to the Institute of Hematology where he was diagnosed as a Sezary's syndrome case on the evidence of generalized erythrodermia, identification of lymphocytes with cerebriform nucleus in peripheral blood and membrane-marker analysis that showed aberant post-thymic proliferation of T-lymphocytes in bone marrow. The patient wastreated with a polychemiotherapy and with "electron beam" therapy with temporary improvement, but died in January 1991 with sepsis and a hepathorenal syndrome.

Two outbreaks of typhoid fever related to the war in Bosnia and Herzegovina.

Two outbreaks of typhoid fever caused by Salmonella typhi of the same phagotype (A, biotype II), and antibiotic susceptibility are reported. Both occurred during the war in Bosnia and Herzegovina. The first outbreak appeared among the refugees from the town of Jajce. The second outbreak appeared among the inhabitants in the village of Vidosi near Livno. This report describes main clinical, epidemiological and laboratory findings for 22 patients treated in Split University Hospital, Croatia, in the period November 1992-January 1993. Possible epidemiological connections between those two outbreaks are discussed.

Three monoclonal IgG components, an IgG4(lambda), an IgG2(kappa) and an IgG1/IgG3 (kappa) Gm(f,b) hybrid, in a single myeloma patient.

An unusual triclonal IgG combination in the serum of a 56-year old male with clinical stage IIIB multiple myeloma is reported. The patient initially had an IgG4(lambda) monoclonal protein in his serum and later developed an IgG2(kappa) and an IgG (kappa) which possessed the characteristics of both IgG1 and IgG3 subclasses with an unusual combination of allotypic markers. Three M-proteins did not share idiotypic determinants. A rare class-switch recombination followed by mutation has been considered as a possible mechanism leading to this combination.

Lyn is required for normal stem cell factor-induced proliferation and chemotaxis of primary hematopoietic cells.

Stem cell factor (SCF) binds to c-Kit and is an important mediator of survival, growth, and function of hematopoietic progenitor cells and mast cells. Lyn and other Src family members are activated by SCF and associate with phosphorylated tyrosine residues in the c-Kit juxtamembrane region. However, studies using c-Kit mutants incapable of directly recruiting Src family members suggest this kinase family plays a minimal role in c-Kit stimulus-response coupling mechanisms. The objective of this study was to specifically target Lyn and subsequently address its role in SCF-mediated responses of primary hematopoietic progenitor cells and mast cells. To this end, a dominant-inhibitory Lyn mutant and Lyn-deficient mice were used. Transfection of normal murine mast cells with kinase-inactive Lyn impaired SCF-induced growth. Further, SCF-induced proliferation and chemotaxis of Lyn-deficient mast cells were less than for wild-type mast cells. SCF-induced growth of progenitor cells lacking Lyn was also reduced compared with that of wild-type progenitor cells. Impairment of SCF-mediated responses of Lyn-deficient mast cells and progenitor cells did not result from reductions in surface expression of c-Kit. These studies demonstrate that Lyn is required for normal SCF-mediated responses of primary progenitors and for a differentiated lineage.