A randomized, open-label, 5-period crossover study evaluating the pharmacokinetics and safety of a single dose of intranasal dihydroergotamine (DHE) powder (STS101), intramuscular DHE mesylate, and liquid nasal spray DHE in healthy adults.

OBJECTIVE: To compare the safety and pharmacokinetics (PK) of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), liquid nasal spray (LNS) DHE mesylate, and intramuscular (IM) DHE mesylate injection in healthy participants. BACKGROUND: DHE is an effective acute migraine treatment; however, self-administration difficulties have prevented its broader role in the management of migraine. METHODS: This randomized, active-controlled, five-period crossover study was conducted over 5 weeks separated by 1-week washout periods. Three STS101 dosage strengths (5.2, 7.0, 8.6 mg), and one dose each of LNS DHE 2.0 mg, and IM DHE 1.0 mg, were administered to 36 healthy participants. Liquid chromatography, tandem mass spectrometry was used to determine DHE (including its 8'OH-DHE metabolite) plasma levels and to calculate PK parameters (Cmax , Tmax , AUC0-2h , AUC0-last , AUC0-inf , and t1/2 ). Safety was evaluated by monitoring adverse events (AEs), vital signs, electrocardiograms, nasal examinations, and laboratory parameters. RESULTS: Thirty-six participants (mean age 36 years; 19% Hispanic Black and 81% Hispanic White) were enrolled. DHE plasma concentrations rose rapidly after STS101 5.2, 7.0, and 8.6 mg and IM DHE injection, with mean concentrations greater than 2000 pg/mL for all STS101 dose strengths at 20 min. All STS101 dose strengths showed approximately 3-fold higher Cmax , AUC0-2h , and AUC0-inf , than the LNS DHE. The mean AUC0-inf of STS101 7.0 and 8.6 mg were comparable to IM DHE (12,600 and 13,200 vs. 13,400 h × pg/mL). All STS101 dose strengths showed substantially lower variability (CV%) compared to LNS DHE for Cmax (35%-41% vs. 87%), and AUC0-inf (37%-46% vs. 65%). STS101 was well tolerated, and all treatment-emergent AEs were mild and transient. CONCLUSION: STS101 showed rapid absorption and was well tolerated with mild and transient treatment-emergent AEs. Achieving effective DHE plasma concentrations within 10 min, STS101 displayed a favorable PK profile relative to the LNS with higher Cmax , AUC0-2h , and AUC0inf , and with greater response consistency. The AUC0-inf was comparable to IM DHE.

Sustained severe intestinal edema after nafamostat mesilate-associated anaphylactic reaction during hemodialysis / Edema intestinal grave y prolongado después de reacción anafiláctica relacionada con nafamostat mesilato durante la hemodiálisis

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Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents.

The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum. We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 °C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.

High dose intravenous colistin methanesulfonate therapy is associated with high rates of nephrotoxicity; a prospective cohort study from Saudi Arabia.

BACKGROUND: Nephrotoxicity is an important adverse effect of colistin methanesulfonate (CMS) therapy. No data exist on rates and risk factors for colistin-related nephrotoxicity in Saudi Arabia (SA). We conducted a prospective cohort study to identify rates and risk factors for CMS nephrotoxicity in our patient population. METHODS: We prospectively included adult patients who received ≥48 hours of intravenous CMS therapy. Pregnant patients and those on renal replacement were excluded. Patients received 9 million units (mU) loading dose followed by 3 mU 8 hourly. In renal impairment, CMS dosing was adjusted according to calculated creatinine clearance (CrCl). Nephrotoxicity was defined as per RIFLE criteria (Risk, Injury, Failure, Loss and End-stage renal disease). Statistical analysis was performed using SPSS version 20.0 (IBM, Armonk, New York, USA). The study was approved by the institution's Research Ethics Committee. RESULTS: A total of 67 patients were included in the study. Mean (±standard deviation) age was 57.5 (±24.0) years, Charlson Co-morbidity Score 2.88 (±2.39), CrCl 133.60 (±92.54) mL/min and serum albumin 28.65 (±4.45) g/L. Mean CMS dose was 0.11 (±0.04) mU/kg/day and mean total CMS dose received was 101.21 (±47.37) mU. Fifty-one (76.1%) patients developed RIFLE-defined nephrotoxicity. Mean total CMS dose and duration of therapy before onset of nephrotoxicity were 66.71 (±43.45) mU and 8.70 (±6.70) days, respectively. In bivariate analysis, patients with nephrotoxicity were significantly older (P 0.013) and had lower baseline serum albumin (P 0.008). Multivariate logistic regression identified serum albumin [odds ratio (OR) 0.72; 95% confidence interval (CI) 0.57-0.93; P 0.010] and intensive care admission (OR 16.38; 95% CI 1.37-195.55; P 0.027) as independent risk factors for CMS nephrotoxicity. CONCLUSIONS: High dose intravenous CMS therapy is associated with high rates of nephrotoxicity in SA. Independent risk factors for colistin nephrotoxicity were baseline hypoalbuminemia and intensive care admission.

Pharmacokinetic properties of once-daily oral low-dose mesylate salt of paroxetine (LDMP 7.5 mg) following single and multiple doses in healthy postmenopausal women.

BACKGROUND: Low-dose mesylate salt of paroxetine (LDMP 7.5 mg) is being investigated for the treatment of vasomotor symptoms associated with menopause. OBJECTIVE: This Phase I, open-label, single- and multiple-dose study evaluated the pharmacokinetic properties, safety and tolerability of LDMP in postmenopausal, nonsmoking women aged ≥40 years. METHODS: After a 3-week screening period, subjects received LDMP 7.5-mg capsules as a single dose on day 1 and then as multiple doses (once daily for 14 days) on Days 6-19. Blood samples were collected predose and up to 120 hours postdose on day 1 (single-dose pharmacokinetic profile), at predose (after 12 doses) on day 18, and at predose and up to 24 hours postdose on day 19 (multiple-dose pharmacokinetic profile). Capsules were taken with 240 mL of water while subjects were fasted. Safety was evaluated throughout the study. RESULTS: Twenty-four women (mean age, 56 years) completed the study. On day 1, median Tmax was ~6 hours, and mean t1/2 was 17.30 hours. Mean plasma concentrations attained predose on days 18 and 19 (days 13 and 14 of multiple dosing) and at 24 hours postdose (day 20) were similar, suggesting that steady state was achieved by day 13 of multiple dosing after 12 daily doses. Mean AUC0-24 h at steady state (day 14 of multiple dosing) was ~3-fold greater than AUC0-∞ on day 1, indicating nonlinear pharmacokinetics. Mean Cmax on day 14 of multiple dosing was ~5-fold greater than that attained on day 1, and the accumulation index (AUCday 19/AUCday 1) at steady state was 9.71. Fluctuation index (calculated as [(Cmax - Cmin)/Cavg ss] × 100) was 75.8%. Most subjects (23/24 [95.8%]) experienced at least 1 treatment-emergent adverse event (AE); however, most AEs (67 events in 22/24 subjects [91.7%]) were mild, and the remainder were moderate. Seventeen subjects experienced 33 AEs that were deemed possibly or probably related to LDMP. No serious AEs were reported, and no clinically meaningful changes in laboratory values, vital signs, or ECGs were observed. CONCLUSIONS: On multiple dosing, LDMP exhibited nonlinear pharmacokinetics and was well tolerated in these healthy postmenopausal women; the extent of accumulation was consistent with data from the published literature.

Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design.

1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by GSK1292263, and a clinical drug interaction study investigated the effect of GSK1292263 (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, GSK1292263 demonstrated little/weak inhibition (IC50 values >30 µM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with GSK1292263, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, GSK1292263 did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by GSK1292263.

Ocorrência de múltiplas neoplasias em paciente portador de leucemia mieloide crônica: relato de caso / Occurence of multiple neoplasms in patient with chronic myeloid leukemia: case report

Introdução: A leucemia mieloide crônica é um distúrbio mieloproliferativo clonal com uma anormalidade citogenética específica, resultante da translocação entre os cromossomos 9 e 22 com consequente produção de uma proteína com atividade tirosina quinase alterada. Tratamentos históricos com drogas como bussulfan, hidroxiureia e interferon passaram a ser pouco utilizados devido ao surgimento dos inibidores de tirosina quinase, cujo principal representante é o mesilato de imatinibe. Esse fármaco é a terapia de primeira linha, sendo bem tolerado pelos pacientes e com baixo risco de eventos adversos severos. Entretanto, com cerca de dez anos de uso, ainda há preocupação com efeitos colaterais em longo prazo, tais como o desenvolvimento de segunda neoplasia. Objetivo: Descrever a ocorrência de múltiplas neoplasias em um portador de leucemia mieloide crônica. Método: Relata-se o caso de um paciente com leucemia mieloide crônica há 13 anos, tendo utilizado hidroxiureia e interferon como terapias prévias e em uso de mesilato de imatinibe há nove anos. Resultados: Há dois anos, o paciente apresentou dois nódulos em coxa esquerda que foram totalmente ressecados. Diagnosticou-se lipossarcoma mixoide e o paciente foi submetido à radioterapia. A tomografia computadorizada do abdomên de controle aos seis meses detectou nódulo espiculado na gordura mesenquimal adjacente ao jejuno/íleo. Feita laparotomia exploradora e ressecção, o anatomopatológico demonstrou fibromatose desmoide. Conclusão: O portador de tumor maligno tem risco aumentado de desenvolver uma segunda neoplasia, que pode dessa forma ocorrer nos portadores de leucemia mieloide crônica. Essa associação pode estar relacionada aos fármacos usados no tratamento da mesma.

In vitro and in vivo investigation of the efficacy of arylimidamide DB1831 and its mesylated salt form--DB1965--against Trypanosoma cruzi infection.

Chagas disease is caused by infection with the intracellular protozoan parasite Trypanosoma cruzi. At present, nifurtimox and benznidazole, both compounds developed empirically over four decades ago, represent the chemotherapeutic arsenal for treating this highly neglected disease. However, both drugs present variable efficacy depending on the geographical area and the occurrence of natural resistance, and are poorly effective against the later chronic stage. As a part of a search for new therapeutic opportunities to treat chagasic patients, pre-clinical studies were performed to characterize the activity of a novel arylimidamide (AIA--DB1831 (hydrochloride salt) and DB1965 (mesylate salt)) against T. cruzi. These AIAs displayed a high trypanocidal effect in vitro against both relevant forms in mammalian hosts, exhibiting a high selectivity index and a very high efficacy (IC(50) value/48 h of 5-40 nM) against intracellular parasites. DB1965 shows high activity in vivo in acute experimental models (mouse) of T. cruzi, showing a similar effect to benznidazole (Bz) when compared under a scheme of 10 daily consecutive doses with 12.5 mg/kg. Although no parasitological cure was observed after treating with 20 daily consecutive doses, a combined dosage of DB1965 (5 mg/kg) with Bz (50 mg/kg) resulted in parasitaemia clearance and 100% animal survival. In summary, our present data confirmed that aryimidamides represent promising new chemical entities against T. cruzi in therapeutic schemes using the AIA alone or in combination with other drugs, like benznidazole.

Allelic ratios and the mutational landscape reveal biologically significant heterozygous SNVs.

The issue of heterozygosity continues to be a challenge in the analysis of genome sequences. In this article, we describe the use of allele ratios to distinguish biologically significant single-nucleotide variants from background noise. An application of this approach is the identification of lethal mutations in Caenorhabditis elegans essential genes, which must be maintained by the presence of a wild-type allele on a balancer. The h448 allele of let-504 is rescued by the duplication balancer sDp2. We readily identified the extent of the duplication when the percentage of read support for the lesion was between 70 and 80%. Examination of the EMS-induced changes throughout the genome revealed that these mutations exist in contiguous blocks. During early embryonic division in self-fertilizing C. elegans, alkylated guanines pair with thymines. As a result, EMS-induced changes become fixed as either G→A or C→T changes along the length of the chromosome. Thus, examination of the distribution of EMS-induced changes revealed the mutational and recombinational history of the chromosome, even generations later. We identified the mutational change responsible for the h448 mutation and sequenced PCR products for an additional four alleles, correlating let-504 with the DNA-coding region for an ortholog of a NFκB-activating protein, NKAP. Our results confirm that whole-genome sequencing is an efficient and inexpensive way of identifying nucleotide alterations responsible for lethal phenotypes and can be applied on a large scale to identify the molecular basis of essential genes.

Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes.

BACKGROUND: Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs, inducing cell-cycle arrest and tumour regression in preclinical models. We assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma. METHODS: In this non-randomised multicentre phase 2 study, patients were included if they had progressive or high-grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease. They were stratified by the type of soft-tissue sarcoma they had. Eribulin was given intravenously at a concentration of 1·4 mg/m(2) over 2-5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks (RECIST 1.0), which we evaluated in all patients who started treatment. Safety analyses were done in all patients who started treatment. This trial is registered at ClinicalTrials.gov, number NCT00413192. FINDINGS: Of 128 patients included, 37 had adipocytic sarcoma, 40 had leiomyosarcoma, 19 had synovial sarcoma, and 32 had other sarcomas. 12 (31·6%) of 38 patients with leiomyosarcoma evaluable for the primary endpoint, 15 (46·9%) of 32 patients with adipocytic sarcoma, four (21·1%) of 19 with synovial sarcoma, and five (19·2%) of 26 in other sarcomas were progression-free at 12 weeks. The most common grade 3-4 adverse events were neutropenia (66 [52%] of 127 patients evaluable for safety), leucopenia (44 [35%]), anaemia (nine [7%]), fatigue (nine [7%]), febrile neutropenia (eight [6%]), abnormal alanine aminotransferase concentrations (six [5%]), mucositis (four [3%]), and sensory neuropathy (four [3%]). INTERPRETATION: Eribulin deserves further study in this setting, based on progression-free survival at 12 weeks in leiomyosarcoma and adipocytic sarcoma. FUNDING: Eisai Limited, Hatfield, UK.

Vasodilatation produced by fasudil mesylate in vivo and in vitro.

To investigate the vasorelaxant effect of fasudil mesylate (FM) in vivo and in vitro. The relaxation effect of FM was studied using cerebral vasospasm (CVS) model in vivo and isolated aortic rings in vitro. FM (0.35, 1.2, 3.5 mg·kg⁻¹) increased cerebrovascular flow (CVF) and femoral blood flow (FBF) dose-dependently in vivo, however, the relaxation effects of FM on cerebral vessels were much stronger than on peripheral vessels; FM showed dose-dependent relaxation of isolated aortic rings contracted by Methoxamine (Met) or KCl in vitro. The relaxation IC50 of FM and Prasozin (Pra) to the rabbit aortic rings contracted by Met are 27.54 µM and 0.01 µM respectively, and the relaxation IC50 of FM to the rabbit and rat aortic rings contracted by KCl are 37.15 µM and 0.74 µM respectively. In addition, there is no obvious difference between endothelium-intact and endothelium-removal groups. The Met dose-effect relationship curve was significantly shifted to right by FM (0.3, 3 µM), and E(max) was decreased (P<0.05). The relaxation effect of FM on cerebral vessels was much stronger than on peripheral vessels in vivo, and the action is in an endothelium-independent manner.

Eribulin mesylate (Halaven) for breast cancer.

Eribulin mesylate (Halaven-Eisai) has been approved by the FDA for treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapy regimens for metastatic cancer. Prior therapy should have included an anthracycline and a taxane in either an adjuvant or metastatic setting. Other drugs used to treat anthracycline- and taxane-refractory metastatic breast cancer include capecitabine (Xeloda), gemcitabine (Gemzar, and others) and vinorelbine (Navelbine, and others).

Eribulin mesylate: a promising new antineoplastic agent for locally advanced or metastatic breast cancer.

More than one million women worldwide are diagnosed with breast cancer every year. For those diagnosed with metastatic breast cancer, the 5-year survival rates are low as, ultimately, patients develop tumors that become refractory to treatment. In clinical trials, eribulin mesylate (E7389) - a novel nontaxane microtubule dynamics inhibitor - demonstrated efficacy in patients with various solid tumors, in particular, those with heavily pretreated metastatic breast cancer. The Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389 (EMBRACE) study observed a significant increase in overall survival with eribulin compared with treatment of physician's choice (median: 13.1 vs 10.6 months, respectively). Based on these results, eribulin recently received approval by the US FDA for the treatment of patients with metastatic breast cancer who have received at least two prior chemotherapeutic regimens including an anthracyline and a taxane. In addition, eribulin has a manageable tolerability profile, requires no premedication and has shorter infusion times than most other microtubule-targeted agents.

Reacciones adversas del imatinib como droga de segunda línea en pacientes con leucemia mieloide crónica / Adverse reactions to imatinib as second-line drug in patients with chronic myeloid leukemia

El imatinib es un inhibidor sintético de la tirosina cinasa usado en el tratamiento de la leucemia mieloide crónica (LMC) y considerado como la droga de primera línea para el tratamiento de la enfermedad. Los efectos adversos más comunes son: náuseas, dolores musculoesqueléticos, diarrea, erupción cutánea, fatiga y mielosupresión, a expensas, fundamentalmente, de la línea granulopoyética. Se realizó un estudio en 43 pacientes adultos (23 femeninos y 20 masculinos) con LMC Ph+ en fase crónica, atendidos en el Instituto de Hematología e Inmunología y en otros servicios de hematología del país. Todos los casos presentaron resistencia o intolerancia al tratamiento con interferón alfa recombinante (INFα) y recibieron terapia con imatinib (400mg/día) en el período comprendido entre abril del 2003 hasta julio del 2008. El 48,8 por ciento de los pacientes no tuvieron reacciones adversas. Dentro de los efectos adversos no hematológicos, los más frecuentes fueron: 23,3 por ciento dolores óseos, musculares o ambos; 23,3 por ciento edemas; 20,9 por ciento hipopigmentación de la piel; y 11,6 por ciento nódulos subcutáneos. Dentro de las reacciones hematológicas, en el 14 por ciento se diagnosticó la anemia hemolítica inmune por droga; en el 11,6 por ciento la trombocitopenia inmune por droga; y en el 9,3 por ciento bicitopenia(AU)

Imatinib is a synthetic inhibitor of kinase-tyrosine used in the treatment of chronic myeloid leukemia (CML) and also is considered as the first-line drug for the treatment of this entity. The commonest side effects include: nausea, musculoskeletal pains, diarrhea, cutaneous eruption, fatigue and myelosuppression mainly at the expense of granulopoiesis line. A study was conducted in 43 adult patients (23 females and 20 males) presenting with CML pH+ in chronic phase, seen in the Hematology and Immunology Institute and in other Hematology services in our country. All cases showed resistance and intolerance to treatment with recombinant Alfa-Interferon (INFα) and Imatinib therapy (400 mg/day) from April, 2003 to July, 2008. The 48,8 percent of patients have not adverse reactions. The more frequent non-hematologic side effects include bone, muscular or both pain (23 percent), edema (23,3 percent); skin hypopigmentation (20,9 percent), and subcutaneous nodules (11,6 percent). In hematological reactions are included the drug-hemolytic anemia (14 percent) drug-immune anemia, drug immune thrombocytopenia (11,6 percent) and bicitopenia ( 9,3 percent)(AU)

Reacciones adversas del imatinib como droga de segunda línea en pacientes con leucemia mieloide crónica / Adverse reactions to imatinib as second-line drug in patients with chronic myeloid leukemia

El imatinib es un inhibidor sintético de la tirosina cinasa usado en el tratamiento de la leucemia mieloide crónica (LMC) y considerado como la droga de primera línea para el tratamiento de la enfermedad. Los efectos adversos más comunes son: náuseas, dolores musculoesqueléticos, diarrea, erupción cutánea, fatiga y mielosupresión, a expensas, fundamentalmente, de la línea granulopoyética. Se realizó un estudio en 43 pacientes adultos (23 femeninos y 20 masculinos) con LMC Ph+ en fase crónica, atendidos en el Instituto de Hematología e Inmunología y en otros servicios de hematología del país. Todos los casos presentaron resistencia o intolerancia al tratamiento con interferón alfa recombinante (INFα) y recibieron terapia con imatinib (400mg/día) en el período comprendido entre abril del 2003 hasta julio del 2008. El 48,8 por ciento de los pacientes no tuvieron reacciones adversas. Dentro de los efectos adversos no hematológicos, los más frecuentes fueron: 23,3 por ciento dolores óseos, musculares o ambos; 23,3 por ciento edemas; 20,9 por ciento hipopigmentación de la piel; y 11,6 por ciento nódulos subcutáneos. Dentro de las reacciones hematológicas, en el 14 por ciento se diagnosticó la anemia hemolítica inmune por droga; en el 11,6 por ciento la trombocitopenia inmune por droga; y en el 9,3 por ciento bicitopenia

Imatinib is a synthetic inhibitor of kinase-tyrosine used in the treatment of chronic myeloid leukemia (CML) and also is considered as the first-line drug for the treatment of this entity. The commonest side effects include: nausea, musculoskeletal pains, diarrhea, cutaneous eruption, fatigue and myelosuppression mainly at the expense of granulopoiesis line. A study was conducted in 43 adult patients (23 females and 20 males) presenting with CML pH+ in chronic phase, seen in the Hematology and Immunology Institute and in other Hematology services in our country. All cases showed resistance and intolerance to treatment with recombinant Alfa-Interferon (INFα) and Imatinib therapy (400 mg/day) from April, 2003 to July, 2008. The 48,8 percent of patients have not adverse reactions. The more frequent non-hematologic side effects include bone, muscular or both pain (23 percent), edema (23,3 percent); skin hypopigmentation (20,9 percent), and subcutaneous nodules (11,6 percent). In hematological reactions are included the drug-hemolytic anemia (14 percent) drug-immune anemia, drug immune thrombocytopenia (11,6 percent) and bicitopenia ( 9,3 percent)

Subacute toxicity of colistin methanesulfonate in rats: comparison of various intravenous dosage regimens.

The relative nephro- and neurotoxicity of colistin methanesulfonate (CMS) was investigated with rats during 7 days of intravenous administration in regimens mimicking twice- and once-daily dosing of a clinically relevant dose for humans. Histological examination revealed more-severe renal lesions with the regimen corresponding to once-daily dosing, indicating that the potential for renal toxicity may be greater with extended-interval dosing.