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The concentrations of mitoxantrone in urine were not altered by pre-incubation with a β-glucuronidase or sulfatase pristiq 100mg with visa, suggesting that the drug is not excreted renally as either the glucuronide or sulfate conjugate (Smyth et al order pristiq 100 mg with amex. This metabolite has been identified in the urine of patients given mitoxantrone (Blanz et al. After two further courses of 6 mg/m2 mitoxantrone, her breast milk contained 120 ng/mL mito- xantrone 3–4 h after dosing and 18 ng/mL by five days, and the concentration remained at this level for 28 days. This finding indicates that the drug is slowly released from a deep tissue compartment (Azuno et al. The drug was not developed for oral use, and in a review mito- xantrone was described as being poorly absorbed when administered orally [species not mentioned] (Batra et al. In rats, dogs and monkeys, the disappearance of intravenously administered [14C]- mitoxantrone from plasma was rapid, followed by a slow terminal elimination phase (James et al. Extensive tissue binding was indicated, with 50, 25 and 30% of the dose still retained 10 days after intravenous administration in rats, dogs and monkeys, respectively. In beagle dogs, tri- exponential elimination from plasma was reported, with a very rapid initial distribution phase with a half-time of 6. Extensive tissue retention was again reported, the higher concentrations 24 h after dosing being found in the liver, kidney and spleen. Two metabolites were detected, accounting for 30% of the radiolabel in plasma and 50% in urine, but were not identified (Lu et al. A rapid distribution and a slow elimination phase were also observed in mice, with retention in body tissues, particularly liver and kidney (Rentsch et al. A naphthoquinoxaline metabolite of mitoxantrone has been reported in rats and pigs, resulting from the oxidation of the phenylenediamine substructure (Blanz et al. In general, mitoxantrone is believed to be active in mammalian cells in vitro in the absence of exogenous metabolic activation; however, inhibition of cyto- chrome P450 mixed-function oxidase by metyrapone in HepG2 hepatoxic cells and rat hepatocytes blocked the cytotoxic activity of mitoxantrone, suggesting that conversion to reactive species might be important (Duthie & Grant, 1989; Mewes et al. Leukopenia is the main dose-limiting effect, the lowest leukocyte counts typically being found 10–14 days after a single dose, with recovery by day 21. In a large European trial, seven of 264 patients experienced cardiac abnormalities (3%). Risk factors that may be predictive of the cardiotoxicity of this drug are previous anthracycline therapy, mediastinal radiotherapy and a history of cardiovascular disease (Crossley, 1983). The number of cardiotoxic events increases with cumulative doses of mitoxantrone > 120 mg/m2 in patients who have previously been treated with anthra- cyclines, and > 160 mg/m2 in patients who were not previously treated. The cumulative dose at which a patient has a 50% probability of having to discontinue treatment because of cardiotoxicity was estimated to be 182 mg/m2, representing approximately 13 courses of treatment. Other toxic effects seen with standard doses of mitoxantrone (12–14 mg/m2) include nausea and vomiting (in approximately 50% of patients), diarrhoea (15%), stomatitis and mucositis (20%) and alopecia (50%), although these effects are usually mild and transient (Crossley, 1983). As the drug is an intense blue colour, discolouration of urine and skin is not uncommon. With higher doses (40–90 mg/m2 or 12 mg/m2 on days 1–3), the toxic effects are typically more severe, and hepatotoxicity has been reported (Feldman et al. After intraperitoneal dosing, peritonitis is the dose-limiting toxic effect (Alberts et al. Many of the studies of the toxicity of mitoxantrone have focused on its cardiac effects, particularly in comparison with doxorubicin, another anthracycline known to be toxic to the heart. At doses > 2 mg/kg bw, mito- xantrone induced cardiovascular and renal toxicity in rabbits (Hulhoven et al. Two cats died of complications that may have been attributable to mitoxantrone: one of cardiomyopathy and the other of pulmonary oedema (Ogilvie et al. She had received no other treatment and had not taken hormones or oral contraceptives. Measurement of lutein- izing hormone, follicle-stimulating hormone and oestradiol in her blood showed that their concentrations were in the menopausal range (Shenkenberg & Von Hoff, 1986). Three weeks later, she received mitoxantrone at 12 mg/m2 for three days in combination with cytarabine. The pregnancy continued, with normal fetal growth, for 60 days when she had complete remission. It should be noted, however, that this trans- location occurs in nearly all cases of de-novo acute promyelocytic leukaemia. The therapy for the primary leukaemia included induction with cytarabine and mitoxantrone, two consolidations with cyta- rabine, daunorubicin and etoposide and then cytarabine and amsacrine followed by maintanence therapy with 6-mercaptopurine and cytarabine. Pedersen-Bjergaard and Philip (1991) reported a balanced translocation involving chromosome band 21q22 in a case of acute myeloid leukaemia that followed mito- xantrone-containing therapy. These strand breakage effects could be enhanced in T-47D human breast cancer cells by prior stimulation with oestrogen. Mitoxantrone was highly effective in causing chromosomal aberrations in cultured Chinese hamster cells and in human peripheral blood lymphocytes in tissue culture.

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View Online 422 Chapter 15 the nucleus to initiate the transcription of genes involved in the promotion of cell growth 100 mg pristiq overnight delivery, proliferation pristiq 50mg amex, differentiation and survival, as well as cytokine and growth factor expression. The pathway is normally activated by growth factor and cytokine receptor stimulation and participates in cytokine signalling and haematopoiesis. Symptoms include fatigue, night sweats, fever, itching (pruritus), abdominal discomfort, pain under le ribs, early satiety, weight loss and bone/muscle pain,29,32 and it negatively impacts patient QoL. Splenomegaly is associated with abdominal discomfort and pain and leads to poor nutritional status, cachexia and low cholesterol. Patients with 0 risk factors have low-risk disease; the addition of one risk factor changes the classication to intermediate-1 risk; the presence of two risk factors changes the classica- tion to intermediate-2 risk; and high-risk patients have three or more risk factors. Treatments included hydroxyurea, corticosteroids, thalidomide, lenalidomide, ana- grelide, epoetin alfa and danazol. Additional treatment options for splenomegaly are splenic irradiation and splenectomy, but they are associated with cytopenias, and splenectomy carries risks of perioperative complications and mortality. Selection of ruxolitinib as a development candidate was based on in vitro and in vivo pharmacology data, its pharmacokinetic prole and toxicology data, described in part below. It exists as a white to off-white to light pink powder, and it is soluble in aqueous buffers ranging from pH 1 to 8. Ruxolitinib tablets contain ruxolitinib phosphate, along with microcrystalline cellulose, lactose monohydrate, magnesium stearate, colloidal silicon dioxide, sodium starch glycolate, povidone and hydrox- ypropyl cellulose. Testing against 26 additional kinases showed no inhibition by ruxolitinib when used at Figure 15. View Online The Discovery and Development of Ruxolitinib for the Treatment of Myelobrosis 427 Table 15. No myelosuppressive or immunosuppressive effects were seen in ruxolitinib- treated mice. Rapid and almost complete (96%) absorption was observed, and maximum serum concentra- tions (C ) were reached in 1–2 hours. Excretion is primarily renal, as 74% of a single 25 mg radio- labelled dose administered to healthy subjects was recovered in urine, and 22% was recovered in faeces. Patients with enlarged spleens at study entry were evaluated over a 3 month period to determine the proportion achieving a $50% reduction in palpable spleno- megaly. Overall, spleen size reductions were rapid and durable, occurring in most patients within the rst 1–2 months and lasting for approximately 2 years. Patients with reductions in spleen size reported reductions in abdominal discomfort. Heat maps were constructed to show the differences in plasma levels of each of these factors for individual patients at baseline versus healthy controls and also for individual patients at day 28 versus baseline (Figure 15. Levels of erythropoietin and leptin, which were below normal at baseline, increased aer ruxolitinib treatment. Non-haematological toxicities occurred at an incidence of <10% and were of low grade. The main haema- tological toxicities were new-onset anaemia in patients who were transfusion- independent at baseline (23%) and dose-limiting grade 3 or 4 thrombocy- topenia (20%). Aer an initial decrease in mean haemoglobin levels over the rst three to four cycles of therapy, levels stabilised or improved from the nadir with subsequent therapy. Green indicates markers present at lower levels at baseline and markers that decreased with ruxolitinib treatment. Red indicates markers present at higher levels at baseline and markers that increased with ruxolitinib treatment. As of September 2013, the long-term extension phases of both trials remain ongoing. Aer 24 weeks of treatment, signicantly more patients achieved a $35% reduction in spleen volume from baseline with ruxolitinib (41. Almost all patients who received ruxolitinib had reductions in spleen volume at week 24; in contrast, most patients who received placebo had increases or no change in spleen volume. While almost all patients who received ruxolitinib experienced some decrease in spleen volume, the majority of patients in the placebo group experienced increases in spleen volume over the 24 week period (Figure 15. Of the ruxolitinib-treated patients with a $35% reduc- tion in spleen volume, 67% maintained this reduction for at least 48 weeks. Most symptom improvements with ruxolitinib occurred within the rst 4 weeks of treatment and were maintained through week 24. At week 24, patients who received ruxolitinib treatment showed decreases in these pro-inammatory cytokines, while patients who received placebo had minimal changes. Plasma levels of leptin and erythropoietin increased by week 24 in rux- olitinib-treated patients and showed no or minimal change in patients who received placebo. These events generally occurred early in the course of therapy and were managed with red blood cell transfusions and dose adjustments/treatment View Online The Discovery and Development of Ruxolitinib for the Treatment of Myelobrosis 433 interruptions, respectively. Non-haematological events generally occurred at similar frequencies in both treatment groups. Ecchymosis, dizziness and headache occurred more frequently in the ruxolitinib group and were mainly grade 1 or 2. Secondary end points included the proportion of patients who achieved a $35% spleen volume reduction from baseline at week 24, duration of reduction of spleen volume $ 35%, and time to reduction in spleen volume $ 35%.

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One point needs further investigation: whether or not a pretest with one set of questions will pick out individuals who are susceptible to detection with a different set of questions buy pristiq 100mg cheap. In the experiments mentioned the same questions were used for both pretest and test quality 100 mg pristiq. Some experimental results (14) lead to the general proposition that if some overt response is required there are greater autonomic and muscular reactions to a stimulus. With larger responses one would expect differentiation between truth and falsehood to be easier. However, "explanatory" answers should probably be avoided for purposes of instrumental detection. Inasmuch as the overt response required does seem to influence the physiologic records, responses of uncontrolled length would tend to confuse the interpretation. Relationship of Operator and Subject The possibility of an interviewer and subject having effects upon one another has been brought out in several studies in a psychiatric situation (15, 27). Although no study has been made of such interaction in a police-type interrogation, the occurrence seems quite likely. In any such interview the manner of the operator while asking a question is probably subject to unconscious variation. Actually presentation of a set of questions on "flash cards" or in a "memory drum" device may be indicated. Plans for Interrogation Lie detection experiments have generally dealt with just one plan of questioning: the presentation of a series of supposedly neutral questions with certain critical ones imbedded in it at unannounced places. Responses to the two sorts of questions are evaluated as -155- though they were independent. Field workers, on the other hand, have developed a variety of ingenious plans (20, 26) which seem sometimes to be more effective. A radically different plan is to let S know when a critical question or group of questions is coming. This procedure is accomplished by going through a question series in the same order often enough so that S knows what to expect. A series of responses is then evaluated as a whole: deception being taken as indicated, on the later repetitions, when responses become progressively larger as the critical questions are approached and die out rapidly thereafter. In some variables there is, further, the possibility of observing a mounting base level as questions near the climax. For a situation other than lie detection, experiments (16, 32) have demonstrated the progressive increase in reaction to stimuli as a noxious question is approached. Conditioned responses are said to be formed to the preceding stimuli on the earlier runs through the series. As a method of detecting deception there is much to be said for this organized schedule of questions. Whereas the unexpected question will produce a brief response, with unidentifiable anticipation probably enlarging responses to neutral stimuli and confusing the issue, the organized schedule permits a detection based on a number of readings, in fact, on the pattern of responses in a whole series. Whatever general scheme of questioning is used, there must be some regard to the adaptative process already described. Size of response to a question in nearly all variables is going to be affected by its position in a series. Current practice evidently recognizes the fact by avoiding the first position for critical questions. A position at the end of a series would be almost as unfavorable, since, other things being equal, the response to a stimulus in that position will be the smallest. Question series of one form or another need to be so planned that the adaptation trend can be discounted in the interpretation. Apparently the successful operator will learn to decide on the meaning -156- of his results by some rules of thumb which he has difficulty putting into words even to himself. To exactly what set of cues he is responding it is difficult to say, for apparently no one has made an analysis of the exact difference between records which are judged positive and those which are judged negative or inconclusive. For the experimenter the problem is different, since he is obliged to say exactly how he has arrived at an answer. His procedure, therefore, will usually be, as in the Indiana studies, to settle upon some rather obvious aspect of response that can be definitely measured, and then find out how well he can do at detection with this information about each response. Naturally, he is discarding a good deal of information while he does this, information about other features of the response which might be supplementary or superior to that which he is using. It may well be that the duration of the response also has a meaning (beyond its correlation with amplitude). The field operator might allow for this feature intuitively along with other characteristics such as latency, doubleness or singleness of response, rate of rise, etc.

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