Gene/Protein Disease Symptom Drug Enzyme Compound
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This study's objectives were to determine the maximum tolerated dose (MTD) of 9-aminocamptothecin (9-AC), given as a prolonged continuous infusion (CI) for 7-21 days, when formulated in dimethylacetamide/polyethylene glycol 400 (DMA) and then later as a colloidal dispersion (CD), and to determine the steady-state pharmacokinetics of 9-AC. Patients with solid tumors refractory to standard therapy were enrolled on this study. Total dose/cycle of 9-AC/DMA was initially escalated by duration (7-21 days), while keeping the dose rate constant at 6.2 microg/m/h (1.04-3.12 mg/m/4-week cycle). Then, the dose rate was escalated from 6.2 to 21.1 microg/m/h (3.12-10.6 mg/m/4-week cycle) while keeping the infusion duration constant at 21 days. CD formulation was escalated from 14.1 to 25 microg/m/h (7.11-12.60 mg/m/4-week cycle) while keeping the infusion duration constant at 21 days and then escalated from 28.1 to 37.5 microg/m/h (9.44-12.60 mg/m/3-week cycle) while keeping the infusion duration constant at 14 days. Sixty-two patients were evaluable for toxicity; 61 received prior chemotherapy (median 3 regimens/patient). No consistent dose-limiting toxicity (DLT) was encountered with the DMA formulation until dose level 10.60 mg/m/cycle, when two patients experienced DLTs. With the 21-day CD formulation, the MTD was 12.60 mg/m/cycle with three DLTs out of five patients. When 9-AC was given on the 14-day schedule, DLT was seen at 9.44, 11.20 and 12.60 mg/m/cycle, with consistent DLT at the two highest dose levels. All DLTs for both formulations were grade 4 hematologic toxicities (neutropenia and/or thrombocytopenia), while non-hematologic toxicities were relatively mild (including gastrointestinal toxicities and fatigue). One patient with ovarian cancer had a complete response and three had partial responses (PRs). One patient each with non-Hodgkin's lymphoma and cancer of unknown primary had a PR. Pharmacokinetic studies of both formulations of 9-AC revealed a linear relationship between increasing plasma 9-AC lactone concentration and dose. The median plasma 9-AC lactone concentration for 9-AC/CD was approximately twice that achieved by 9-AC/DMA for the same dose level. Both 9-AC formulations, given as a 21-day CI, were well tolerated with dose-limiting myelosupression at the MTD. This dose intensity exceeds that of other 9-AC phase I/II schedules. The recommended phase II dose (RPTD) is 9.42 mg/m/4-week cycle, given as a 21-day infusion. The 14-day schedule of 9-AC/CD was equally myelosuppressive with the RPTD of 9.44 mg/m/3-week cycle, although two heavily pre-treated patients (one with pelvic radiotherapy) could not tolerate this dose. Objective responses were observed in six out of 57 heavily pre-treated patients, most of which had ovarian cancer.
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PMID:Phase I trial of continuous infusion 9-aminocamptothecin in patients with advanced solid tumors: 21-day infusion is an active well-tolerated regimen. 1670 15

The purpose of this study was to determine whether volitional hyperventilation at 20 L x min(-1) above normal exercise values affected exercise duration while performing ramp exercise to exhaustion. Nine healthy subjects performed a ramp exercise test to exhaustion. On a subsequent test they hyperventilated, with the aid of visual and audio feedback, at 20 L x min(-1) greater than their initial test. Ramp exercise time to exhaustion was substantially reduced from 771.6 +/- 85.2 s to 726.6 +/- 86.6 s (p < 0.002) with the additional hyperventilation. Subjects underwent 2 more ramp exercise tests and performed a 5 s maximum voluntary ventilation or a forced vital capacity test at work rates corresponding to rest, below lactate threshold (LT), above LT, immediately after exercise, and 3 min recovery. Generally, the flow rates were not affected by exercise below LT and were enhanced during above-LT exercise, exhaustion, and recovery. This indicated a change in pulmonary function that is dependent on exercise intensity. In spite of this increased ability to generate high flow rates, exercise performance was diminished when respiratory muscle work was increased volitionally by 20 L x min(-1), indicating a strong coupling between respiratory muscle work and fatigue during ramp exercise in normal subjects.
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PMID:Volitional hyperventilation during ramp exercise to exhaustion. 1677 Mar 47

The aim of the 18 months follow up study was to assess the frequency of anemia during IFN/RBV therapy in patients with chronic hepatitis C; to manage anemia either with recombinant human erythropoietin (rHuEPO)--epoetin alpha or with RBV dose reduction and to compare the rate of SVR in patients with RBV dose reduction and with administration of epoetin alpha. Study enrolled 61 patients with chronic active hepatitis C aged 33-61 years. All patients had HCV genotype 1b. Out of them 41 were male and 20 female. Anemia (Hb <10 or >2 g/dL Hgb drop from baseline) developed in 41 patients out of 61 (67,21%) during the therapy. These 41 patients were randomized into two groups: 21 patients who received 40 000 IU epoetin alpha weekly (I group) and 20 patients in whom for managing anemia we used standard of care (SOC) or RBV dose reductions from 1000/1200 to 800/600 mg (II group). In all 21 patients of the I group the Hb level normalized without reduction of RBV dose. In this group of patients SVR at 6 months after completion of full course of treatment was achieved in 17 (66%) patients. Improvement of quality of life (QOL) was observed in all 21 patients. Out of 20 patients of II group with standard of care (SOC) 5 patients developed symptomatic anemia with fatigue and dyspnoea; RBV was stopped temporarily. In 15 patients RBV dose was reduced from 1200 mg to 600 mg for correction of anemia. In this group of patients SVR at 6 months after treatment completion was achieved in 7 (25%) patients. Lower RBV doses yield a lower treatment response in patients with HCV genotype 1. In anemic HCV-infected patients on RBV/PEG-IFN therapy, EPO maintains RBV dose and significantly improves anemia and QOL. EPO has the potential to improve adherence rate, which may in turn improve SVR.
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PMID:Ifn/Rbv treatment induced anemia and its correction with epoetin alpha in patients with hepatitis C. 1698 Jul 47

A 21-year old man, complaining of headaches and fatigue, with a negative past medical history and a normal clinical examination, underwent a hormonal investigation which revealed hyper-prolactinemia and intact pituitary-gonadal axis. Drug-induced hyperprolactinemia was excluded. Pituitary magnetic resonance imaging indicated a microadenoma in the right part of the gland, with a diameter of 1.5mm. No medical treatment was given as the patient had no symptoms relevant to prolactin excess. The PEG precipitation test was carried out and showed 7% recovery, which was diagnostic of the macroprolactinemia. Relatively few cases of macroprolactinemia have been published in the literature, although the condition is regarded as a fairly common cause of hyperprolactinemia. Macroprolactinemic men represent 10% of published cases.
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PMID:Macroprolactinemia in a young man and review of the literature. 1700 13

The effects of prior moderate- and prior heavy-intensity exercise on the subsequent metabolic response to incremental exercise were examined. Healthy, young adult subjects (n = 8) performed three randomized plantar-flexion exercise tests: 1) an incremental exercise test (approximately 0.6 W/min) to volitional fatigue (Ramp); 2) Ramp preceded by 6 min of moderate-intensity, constant-load exercise below the intracellular pH threshold (pHT; Mod-Ramp); and 3) Ramp preceded by 6 min of heavy-intensity, constant-load exercise above pHT (Hvy-Ramp); the constant-load and incremental exercise periods were separated by 6 min of rest. (31)P-magnetic resonance spectroscopy was used to continuously monitor intracellular pH, phosphocreatine concentration ([PCr]), and inorganic phosphate concentration ([P(i)]). No differences in exercise performance or the metabolic response to exercise were observed between Ramp and Mod-Ramp. However, compared with Ramp, a 14% (SD 10) increase (P < 0.01) in peak power output (PPO) was observed in Hvy-Ramp. The improved exercise performance in Hvy-Ramp was accompanied by a delayed (P = 0.01) onset of intracellular acidosis [Hvy-Ramp 60.4% PPO (SD 11.7) vs. Ramp 45.8% PPO (SD 9.4)] and a delayed (P < 0.01) onset of rapid increases in [P(i)]/[PCr] [Hvy-Ramp 61.5% PPO (SD 12.0) vs. Ramp 45.1% PPO (SD 9.1)]. In conclusion, prior heavy-intensity exercise delayed the onset of intracellular acidosis and enhanced exercise performance during a subsequent incremental exercise test.
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PMID:Prior exercise delays the onset of acidosis during incremental exercise. 1730 6

Curcumin, a yellow pigment present in the Indian spice turmeric (associated with curry powder), has been linked with suppression of inflammation; angiogenesis; tumorigenesis; diabetes; diseases of the cardiovascular, pulmonary, and neurological systems, of skin, and of liver; loss of bone and muscle; depression; chronic fatigue; and neuropathic pain. The utility of curcumin is limited by its color, lack of water solubility, and relatively low in vivo bioavailability. Because of the multiple therapeutic activities attributed to curcumin, however, there is an intense search for a "super curcumin" without these problems. Multiple approaches are being sought to overcome these limitations. These include discovery of natural curcumin analogues from turmeric; discovery of natural curcumin analogues made by Mother Nature; synthesis of "man-made" curcumin analogues; reformulation of curcumin with various oils and with inhibitors of metabolism (e.g., piperine); development of liposomal and nanoparticle formulations of curcumin; conjugation of curcumin prodrugs; and linking curcumin with polyethylene glycol. Curcumin is a homodimer of feruloylmethane containing a methoxy group and a hydroxyl group, a heptadiene with two Michael acceptors, and an alpha,beta-diketone. Structural homologues involving modification of all these groups are being considered. This review focuses on the status of all these approaches in generating a "super curcumin.".
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PMID:Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. 1877 80

The purpose of the Patients Concerns Inventory (PCI) is to identify the concerns that patients would like to discuss during their consultation. The PCI covers a range of issues including hearing, intimacy, fatigue, financial/benefits, PEG tube, relationships, regret, support for family, and wound healing. It also lists MDT members that patients would like to see or be referred on to. The PCI is completed using a touch-screen computer (TST) immediately before consultation. Responses are networked into the consultation room. A 28 weeks pilot for one consultant ran from August 2007 with 123 (of maximum 150) patients. The median time to complete the TST was 8min. Patients most frequently selected fear of recurrence (37%), dental health/teeth (27%), chewing (24%), pain in head/neck (20%), fatigue/tiredness (19%), saliva (18%) and swallowing (18%). The two MDT members they wished to see were dentist (19%) and speech/language therapist (10%). The vast majority felt the PCI made a difference (quite a bit/very much) to their consultation as it made it 'a bit more personal', 'reminds them of the points they want discussed', 'allows the consultation to get straight to the point'. Although the PCI can raise many issues it did not noticeably prolong the consultation (median 8min with PCI, 7min without PCI). The Patients Concerns Inventory (PCI) helps focus the consultation onto patient needs and promotes multidisciplinary care. Following this very successful pilot the PCI is being rolled out to other consultants in the H & N clinic.
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PMID:The development of a Patients Concerns Inventory (PCI) to help reveal patients concerns in the head and neck clinic. 1902 35

Patients with renal disease are at increased risk of acquiring hepatitis C virus (HCV) infection because of their frequent exposure to blood from transfusions or exposure to HCV-contaminated medical equipment during hemodialysis. The prevalence of anti-HCV antibodies among hemodialysis patients varies between 5-10% in the developed world, and 10-70% in developing countries. Acute hepatitis C is often mild and associated with few, if any symptoms. The major complication of acute HCV infection is chronic hepatitis, which occurs in up to 80% of the cases, the long-term outcome being cirrhosis, portal hypertension, hepatic failure, and hepatocellular carcinoma. Interferon alpha (IFN-alpha) has shown activity against HCV. Twenty four to 48 week course of therapy with interferon could lead to a sustained loss of HCV RNA, normalization of alanine aminotrasferase (ALT) levels, and resolution of the liver disease. Sustained viral response was achieved in approximately half of the treated patients. Therapy with interferon was associated with a number of adverse events such as: "flu-like" symptoms, neurological, gastrointestinal symptoms, anemia, fatigue, thrombocytopenia, leucopenia. A major advance in therapy came with the addition of ribavirin to interferon therapy. Peginterferon-alpha-2a (40KD) is a new 'pegylated' subcutaneous formulation of interferon-alpha-2a, that was developed to improve the pharmacokinetic profile and therapeutic efficacy of interferon-alpha-2a. In our study, fourteen hemodialysis patients with chronic hepatitis C received 135 microg PEG-IFN alpha-2a subcutaneously, once a week, after dialysis session for a period of 48 weeks. In the intention-to-treat analysis, sustained viral response was present in 36% of the patients (five out of fourteen patients) at the end of the follow up period. The biochemical response with normalization of serum ALT levels during the treatment was observed in all treated patients (83 +/- 20.1 U/L at base line vs. 23.4 +/- 4.6 U/L after the 48 weeks; p < 0.01). At present, therapy for hepatitis C should be considered in hemodialysis patients with significant liver disease, minimal other co morbidities, and a reasonable likelihood of prolonged survival or if renal transplantation is planned.
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PMID:New approaches in the therapy of hepatitis C in dialysis patients. 1925 44

Hepatitis C virus is a worldwide public health problem and carries an increased economic burden that affects individuals, employers, insurers and health systems. Estimates suggest that by the year 2008, the yearly costs of hepatitis C virus will exceed US$1 billion. The authors conducted a literature search to identify studies on pharmacoeconomics and outcomes research for hepatitis C virus. According to the literature, the new standard for disease management is interferon-alpha, chemically linked with polyethylene glycol (pegylated interferon-alpha) as a monotherapy, or in combination with ribavirin. The authors reviewed a number of articles providing original research on outcomes related to pegylated therapies. Clinical outcomes and end points included sustained and early virologic response, disease progression, liver complications and mortality; economic outcomes included direct medical costs related to in- and outpatient costs, screening and diagnostics. Studies that consider health-related quality of life and fatigue were also identified. While most of the studies adopted Markov modeling to predict the likely outcomes and the effects of therapy, it is also important to consider indirect costs, such as productivity loss related to absenteeism. Future research on the use of pegylated interferons, weight-adjusted dosing of ribavirin, and the treatment of relapsers and nonresponders should provide valuable data that can be incorporated into cost-effectiveness studies.
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PMID:Review of cost-effectiveness studies of pegylated therapies for hepatitis C. 1980 3

In search of strategies to operate photochromic compounds in aqueous environments, we synthesized two oxazines with a pendant oligo(ethylene glycol) chain each and a co-polymer with multiple oxazine and oligo(ethylene glycol) tails appended to a common macromolecular backbone. The hydrophilic character of the oligo(ethylene glycol) chains imposes solubility in water on two of the three systems. Their laser excitation in water opens the oxazine ring in less than 6 ns to generate zwitterionic isomers able to absorb in the visible region of the electromagnetic spectrum. The photogenerated species revert spontaneously back to the original forms with first-order kinetics. The transition from organic solvents to aqueous environments, however, causes a five-fold decrease in the quantum yield of the photoinduced ring-opening process and elongates the lifetime of the photogenerated isomer from the nanosecond to the microsecond domain. These hydrophilic and photochromic switches can be interconverted hundreds of times between their two states with no sign of degradation in water. As a result, our structural design for the realization of water-soluble photochromic compounds can lead to the development of viable strategies to modulate the structures and functions of biomolecules with microsecond switching times and excellent fatigue resistances under the influence of optical stimulation.
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PMID:Hydrophilic and photochromic switches based on the opening and closing of [1,3]oxazine rings. 2012 86


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