Gene/Protein Disease Symptom Drug Enzyme Compound
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The present study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PKs), and antitumor activity of the protein kinase C-alpha antisense oligonucleotide ISIS 3521 (ISIS Pharmaceuticals, Inc., Carlsbad, CA) when administered in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Patients with refractory solid tumors received ISIS 3521 as a 21-day continuous infusion administered simultaneously with 5-FU and LV given daily for 5 days repeated every 4-5 weeks (one cycle). 5-FU and ISIS 3521 PK analysis were performed on samples taken during the first cycle in all patients. Fifteen patients received ISIS 3521 at one of three dose levels: (a) 1.0 (n = 3 patients); (b) 1.5 (n = 3 patients); and (c) 2.0 (n = 9 patients) mg/kg/day. All patients simultaneously received 5-FU (425 mg/m(2)/day) and LV (20 mg/m(2)/day) for 5 consecutive days. Grade 1-2 toxicities included alopecia, fatigue, mucositis, diarrhea, anorexia, nausea/vomiting, and tumor pain. One patient had grade 3 chest pain considered to be related to 5-FU therapy, another patient had dose-limiting grade 3 mucositis resolving in <7 days, and one patient with a history of gastritis had an acute upper gastrointestinal bleed thought to be 5-FU-induced toxicity. Five patients developed cycle 1 grade 4 neutropenia, which resolved without colony-stimulating factors before the next treatment cycle. There were no effects on prothrombin time and activated partial thromboplastin time. A clinically defined MTD was not reached. The character and severity of these toxicities do not seem to be dose related, and, as such, there was no classical dose-limiting toxicity defining the MTD. ISIS 3521 PKs in the presence of 5-FU was consistent with those reported previously. 5-FU PK parameters were also similar in the presence or absence of ISIS 3521. Six of 14 patients ( approximately 43%) across all dose cohorts had an improvement in measurable tumor response ranging from minor reduction in tumor size (4 patients) to objective partial response (>50% reduction in tumor size, 2 patients). ISIS 3521 is tolerable at its recommended single-agent dose when given with 5-FU and LV. There is no apparent PK interaction between ISIS 3521 and 5-FU and LV. Antitumor activity was observed with the combination; however, it is uncertain whether clinical activity is a result of enhanced drug interaction. Our study warrants further exploration of efficacy in a Phase II and/or Phase III clinical trial setting.
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PMID:Phase I clinical and pharmacokinetic study of protein kinase C-alpha antisense oligonucleotide ISIS 3521 administered in combination with 5-fluorouracil and leucovorin in patients with advanced cancer. 1194 11

Inherited thrombophilia is a risk factor for dural sinus thrombosis (DST). To our knowledge, this is the first description with autopsy findings of a patient with DST associated with heterozygous factor V Leiden and a short activated partial thromboplastin time (aPTT). A 51-year-old woman presented with a 3-day history of headache, nausea, right-sided weakness, and focal motor seizure; she died 3 days after admission. At autopsy, a gross examination showed hemorrhage of bilateral parietal lobes and left primary motor cortex, uncal and tonsillar herniation, and pulmonary embolus of the right upper lobe. A microscopic examination of the brain showed an organizing thrombus in the superior sagittal sinus, diffuse cerebral edema, and extensive venous congestion. Laboratory studies showed heterozygous factor V Leiden by polymerase chain reaction and a very short aPTT of 17 seconds (reference range, 22-30 seconds). The combination of a heterozygous factor V Leiden mutation and a short aPTT may have contributed to the fatal DST in this patient.
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PMID:Fatal dural sinus thrombosis associated with heterozygous factor V Leiden and a short activated partial thromboplastin time. 1452 55

Severe acute respiratory syndrome (SARS) is a highly infectious disease with a significant morbidity and case fatality. The major clinical features include persistent fever, chills/rigor, myalgia, malaise, dry cough, headache and dyspnoea. Less common symptoms include sputum production, sore throat, coryza, dizziness, nausea, vomiting and diarrhoea. Older subjects may present with decrease in general well-being, poor feeding, fall/fracture and delirium, without the typical febrile response. Common laboratory features include lymphopenia with depletion of CD4 and CD8 lymphocytes, thrombocytopenia, prolonged activated partial thromboplastin time, elevated D-Dimer, elevated alanine transminases, lactate dehydrogenase and creatinine kinase. The constellation of compatible clinical and laboratory findings, together with the rather characteristic radiological features especially on HRCT and the lack of clinical response to broad-spectrum antibiotics, should quickly arouse suspicion of SARS. The positivity rates of urine, nasophargyngeal aspirate and stool specimen have been reported to be 42%, 68% and 97%, respectively, on day 14 of illness, whereas serology for confirmation may take 28 days to reach a detection rate above 90%. Recently, quantitative measurement of blood SARS CoV RNA with real-time RT-PCR technique has been developed with a detection rate of 80% as early as day 1 of hospital admission but the detection rates drop to 75% and 42% on day 7 and day 14, respectively.
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PMID:SARS: clinical features and diagnosis. 1501 29

Parecoxib (Dynastat) is a parenteral cyclooxygenase-2 inhibitor available in Europe. Clinical trials have reported a benefit in reducing pain following oral, orthopedic, gynecologic and cardiac surgeries. The overall efficacy was dose-related and similar to ketorolac (Toradol). Several trials reported an opioid-sparing effect with parecoxib. No trials have reported significantly fewer opioid-related gastrointestinal side effects (e.g., nausea, vomiting, constipation and intestinal ileus) when opioids were administered with parecoxib versus placebo. Gastroduodenal ulcers, gastric ulcers and duodenal ulcers or erosions were less common with parecoxib than ketorolac. Parecoxib does not affect platelet aggregation, interfere with the antiplatelet affect of aspirin, affect prothrombin and partial thromboplastin time or platelet counts when administered with heparin.
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PMID:Parecoxib: a shift in pain management? 1585 57

A 37-year-old male with history of alcohol abuse presented to us with nausea, vomiting, and abdominal pain with ascites. He was diagnosed with alcoholic liver disease with coagulopathy and pancreatitis. During hospitalization, the patient developed intra-abdominal hemorrhage. He was treated with platelets, packed red blood cells and fresh frozen plasma without any improvement. Following this he was treated with activated recombinant factor VII (90 microg/kg), which resulted in normalization of the prothrombin time and the activated partial thromboplastin time and stabilization of hematocrit within a few hours. We review the current literature on the approved and off-label use of activated recombinant factor VII.
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PMID:Successful management of intra-abdominal hemorrhage in the presence of severe alcoholic liver disease with activated recombinant factor VII (rFVIIa; NovoSeven): a case report and review of the literature on approved and off-label use of rFVIIa. 1728 41

Crimean-Congo hemorrhagic fever is a tick-borne viral disease reported from more than 30 countries in Africa, Asia, South-East Europe, and the Middle East. The majority of human cases are workers in livestock industry, agriculture, slaughterhouses, and veterinary practice. Nosocomial transmission is also well described. Clinical manifestations are nonspecific and symptoms typically include high fever, headache, malaise, arthralgia, myalgia, nausea, abdominal pain, and nonbloody diarrhea. Patients may show signs of progressive hemorrhagic diathesis. Laboratory abnormalities may include anemia, leukopenia, thrombocytopenia, increased AST/ALT levels, and prolonged prothrombin, bleeding, and activated partial thromboplastin times. Diagnostic methods include antibody detection by enzyme-linked immunosorbent assay, virus isolation, antigen detection, and polymerase chain reaction. The mainstay of treatment of Crimean-Congo hemorrhagic fever is supportive, with careful maintenance of fluid and electrolyte balance, circulatory volume, and blood pressure. The Crimean-Congo hemorrhagic fever virus is susceptible to ribavirin in vitro. There is no controlled study evaluating oral versus intravenous ribavirin in treating Crimean-Congo hemorrhagic fever patients, but few studies have evaluated oral ribavirin. This article reviews the epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, prevention, and prognosis of Crimean-Congo hemorrhagic fever with a special focus on oral ribavirin as a choice of medical treatment.
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PMID:Crimean-Congo hemorrhagic fever. 1736 25

HELLP syndrome is a multi-organ disorder unique to pregnancy. It is characterized by hemolysis, elevated liver enzymes, and low platelets in patients with pre-eclampsia or eclampsia. In King Abdulaziz Oncology Center, Jeddah, seven patients with HELLP syndrome were admitted over a period of four years (1991-94). Retrospective analysis of data was done to study the clinical profile of HELLP syndrome. The incidence of HELLP syndrome in our institution was 1 per 2285 deliveries. One patient was Saudi and six were non-Saudis. The age range was 23 to 44 years, with a mean of 29 years. All patients were multipara. The disorder occurred between 24 to 33 weeks of gestational age, the average being 29 weeks. The most commonly encountered clinical feature was right upper quadrant/epigastric pain. Other features included nausea/vomiting, jaundice, hepatic encephalopathy, azotemia, hypotension and grand mal convulsions. All patients had severe pre-eclampsia pr eclampsia. Indirect hyperbilirubinemia was in the range of 2 to 8 mg/dL and elevated transaminases up to 229 U/L (n<40 U/L) were noted. Various degrees of peripheral thrombocytopenia (<150x10(9)/L) were present in seven patients. Four patients had elevated prothrombin and partial thromboplastin time with postive fibrinogen degradation products. Laboratory abnormalities returned to normal within 10 days following delivery. Four patients were delivered by cesarean section and three had vaginal deliveries. We had two maternal deaths (mortality 34%). One died of multi-organ failure and the other with adult respiratory distress syndrome. There was one stillbirth and the second baby died soon after birth due to prematurity (infant perinatal mortality 34%). We conclude that HELLP syndrome is rare among pregnant women in our institution. It should always be suspected in women with pre-eclampsia or eclampsia when they present with upper abdominal pain. Multipara seem to be more afflicted. Subclinical disseminated intravascular coagulation was detected in 55% of the patients. A majority of our patients presented late to the hospital.
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PMID:HELLP syndrome: Clinical profile of seven patients. 1737 23

A 37-year-old woman with congenital afibrinogenemia presented with chronic subdural hematoma (CSDH) manifesting as severe headache, nausea, and somnolence after a minor head trauma. Brain computed tomography scans showed a right subdural hematoma associated with midline shift. Laboratory studies showed prolongation of prothrombin time, activated partial thromboplastin time, and undetectably low level of fibrinogen. Until the present episode, she had received plasma-derived fibrinogen concentrate around menstruation and pregnancy. She had also suffered from spinal cord infarction due to vertebral artery occlusion. Burr-hole evacuation and drainage of CSDH was successfully performed using fibrinogen concentrate. The development of CSDH with afibrinogenemia is very rare. Although the past repeated administrations of fibrinogen concentrate were suspected to generate CSDH, paradoxical thrombotic complications caused by upregulation of prothrombin activation, thrombin generation, and growth factors released from platelets might be related to the development of CSDH with congenital afibrinogenemia.
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PMID:Chronic subdural hematoma in a patient with congenital afibrinogenemia successfully treated with fibrinogen replacement. 2212 82

Crimean-Congo hemorrhagic fever (CCHF), is a fatal viral infection transmitted to humans through a tick bite or exposure to blood or tissues of viremic hosts. The clinical presentation is characterized by sudden onset high fever, headache, myalgia, abdominal pain and nausea-vomiting followed by gastrointestinal, urinary, respiratory tract and brain hemorrhage. Laboratory findings include leucopenia, thrombocytopenia, elevated liver enzymes, prolonged prothrombin time and activated partial thromboplastin time. We report a case of CCHF who was treated with a combination of DFPP and ribavirin therapy. As a result of this multimodal treatment, patient's clinical symptoms and laboratory findings improved gradually.
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PMID:Double filtration plasmapheresis for a case of Crimean-Congo hemorrhagic fever. 2361 28

Nasal-type extranodal natural killer (NK)/T-cell lymphoma (ENKL) is a highly invasive cancer with a poor prognosis. More effective and safer treatment regimens for ENKL are needed. Pegaspargase (PEG-Asp) has a similar mechanism of action to L-asparaginase (L-Asp), but presents lower antigenicity. The aim of the present research was to evaluate the safety profile and the latent efficacy of a PEG-Asp-based treatment regimen in patients with ENKL. Data collected from 20 patients with histologically confirmed ENKL, admitted to the Third Affiliated Hospital of Sun Yat-Sen University from January 2009 to August 2013, were included in the study. All patients received 2500 IU/m2/IM PEG-Asp on day 1 of every 21-day treatment cycle. Patients received combination chemotherapy with CHOP (n=5), EPOCH (n=7), GEMOX (n=7) or CHOP with bleomycin (n=1). After 2-5 treatment cycles (median, 4 cycles) of PEG-Asp-based chemotherapy, five patients (25%) showed a complete response (CR), and the overall response rate (ORR) was 60%. Grade 3/4 neutropenia occurred in fourteen patients (70%). Grade 3 alanine aminotransferase (ALT) elevation was observed in two. Grade 1-2 non-hematological toxicity consisted of activated partial thromboplastin time (APTT) elongation (n=9), hypofibrinogenemia (n=6), hypoproteinemia (n=17), hyperglycemia (n=3), and nausea (n=6). No allergic reactions were detected. No treatment related death was reported. Our results suggested that PEG-Asp-based chemotherapy presented an acceptable tolerance and a potential short-term outcome in patients with nasal-type ENKL.
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PMID:Efficacy and tolerance of pegaspargase-based chemotherapy in patients with nasal-type extranodal NK/T-cell lymphoma: a pilot study. 2512 11


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