Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based upon in vitro and in vivo synergistic activity of Type I and Type II interferons (IFNs) in preclinical in vitro and in vivo studies, we initiated a phase I trial evaluating the doses, safety, and pharmacokinetics of combinations of recombinant DNA-produced human IFN-beta ser and IFN-gamma in 27 patients with cancer. Twenty-four patients were treated with a 2-hour infusion of IFN-gamma, followed by a 10-minute iv injection of IFN-beta ser, three times a week. Patients were entered on fixed dose levels of 1 X 10(6), 3 X 10(6), 10 X 10(6), 30 X 10(6), and 100 X 10(6) units of each IFN. In addition, three patients were treated at the highest dose level with a 10-minute iv infusion of IFN-gamma and a 10-minute iv infusion of IFN-beta ser. The maximally tolerated dose when administered by this schedule for greater than or equal to 4 weeks was 30 X 10(6) units of each IFN. Dose-limiting side effects at doses of 100 X 10(6) units of each IFN consisted of fatigue, nausea, vomiting, anorexia, paralytic ileus, and neutropenia. The most common side effects at the three highest dose levels were fever, rigors often requiring parenteral meperidine, and constitutional symptoms. Reversible elevations in SGOT and LDH were also noted. Serum IFN levels were dose related, with peak titers occurring immediately after IFN administration. One patient with a nodular mixed lymphoma had a partial response which has been sustained for over 1 year. We conclude that combinations of IFN-beta ser and IFN-gamma can be safely administered on a chronic basis without enhanced or cumulative toxic effects.
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PMID:Phase I trial of combinations of recombinant interferons beta(ser) and gamma in patients with advanced malignancy. 311 70

2B1 is a bispecific murine monoclonal antibody (BsMAb) with specificity for the c-erbB-2 and Fc gamma RIII extracellular domains. This BsMAb promotes the targeted lysis of malignant cells overexpressing the c-erbB-2 gene product of the HER2/neu proto-oncogene by human natural killer cells and mononuclear phagocytes expressing the Fc gamma RIII A isoform. In a Phase I clinical trial of 2B1, 15 patients with c-erbB-2-overexpressing tumors were treated with 1 h i.v. infusions of 2B1 on days 1, 4, 5, 6, 7, and 8 of a single course of treatment. Three patients were treated with daily doses of 1.0 mg/m2, while six patients each were treated with 2.5 mg/m2 and 5.0 mg/m2, respectively. The principal non-dose-limiting transient toxicities were fevers, rigors, nausea, vomiting, and leukopenia. Thrombocytopenia was dose limiting at the 5.0 mg/m2 dose level in two patients who had received extensive prior myelosuppressive chemotherapy. Murine antibody was detectable in serum following 2B1 administration, and its bispecific binding properties were retained. The pharmacokinetics of this murine antibody were variable and best described by nonlinear kinetics with an average t 1/2 of 20 h. Murine antibody bound extensively to all neutrophils and to a proportion of monocytes and lymphocytes. The initial 2B1 treatment induced more than 100-fold increases in circulating levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 8 and lesser rises in granulocyte-monocyte colony-stimulating factor and IFN-gamma. Brisk human anti-mouse antibody responses were induced in 14 of 15 patients. Several minor clinical responses were observed, with reductions in the thickness of chest wall disease in one patient with disseminated breast cancer. Resolution of pleural effusions and ascites, respectively, were noted in two patients with metastatic colon cancer, and one of two liver metastases resolved in a patient with metastatic colon cancer. Treatment with 2B1 BsMAb has potent immunological consequences. The maximum tolerated dose and Phase II daily dose for patients with extensive prior myelosuppressive chemotherapy was 2.5 mg/m2. Continued dose escalation is required to identify the maximally tolerated dose for patients who have been less heavily pretreated.
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PMID:Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. 755 34

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.
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PMID:Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. 981 99

Seventeen patients stung by Tityus serrulatus scorpion were classified as mild (pain at the site of the sting, n = 6), moderate (local pain and one of the following manifestations: vomiting, psychomotor agitation, prostration, sweating, tachypnea, tachycardia and mild arterial hypertension, n = 10) and severe cases (equal moderate cases plus cardiac failure, pulmonary edema and shock, n = 1). Venous blood was sampled for biochemical and hematological analysis and for IL-1alpha, IL-6, IL-10, TNF-alpha, IFN-gamma and GM-CSF ELISAs at the time of hospital admission, 6 h (moderate and severe cases), and 12, 18, 36 and 72 h (severe case) later. Ten age-matched healthy volunteers were used as control. Increased serum levels of IL-1alpha was noticed in all patients, high levels of IL-6, IFN-gamma and GM-CSF were observed only in a patient with severe envenomation. Our data suggest that a systemic inflammatory response-like syndrome is triggered during severe envenomation caused by T. serrulatus sting and that release of cytokines may be involved in this response.
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PMID:Serum levels of cytokines in patients envenomed by Tityus serrulatus scorpion sting. 1040 Feb 99

Rotavirus is the most common cause of severe gastroenteritis in young children, but the pathogenesis and immunity of this disease are not completely understood. To examine the host response to acute infection, we collected paired serum specimens from 30 children with rotavirus diarrhea and measured the levels of nine cytokines (interleukin-1beta [IL-1beta], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, gamma interferon [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) using a microsphere-based Luminex Flowmetrix system. Patients with acute rotavirus infection had elevated median levels of seven cytokines in serum, and of these, the levels of three (IL-6, IL-10, and IFN-gamma) were significantly (P < 0.05) higher than those in serum from control children without diarrhea. Patients with fever had significantly (P < 0.05) higher levels of IL-6 in serum than control children, and those with fever and more episodes of diarrhea had significantly (P < 0.05) higher levels of TNF-alpha than those without fever and with fewer episodes of diarrhea. We further demonstrated a negative association (P < 0.05) between the levels of IL-2 and the number of stools on the day on which the first blood sample was collected. Finally, patients with vomiting had significantly (P < 0.05) lower levels of IFN-gamma than those without vomiting. Our pilot study provides evidence that the types and magnitudes of cytokine responses to rotavirus infection in children influence or reflect the clinical outcome of disease. These findings suggest that certain cytokines may play an important role in the pathogenesis of and the protection against rotavirus disease in children and, consequently, may provide directions and insights that could prove critical to the prevention or treatment of this important disease.
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PMID:Cytokines as mediators for or effectors against rotavirus disease in children. 1460 58

IFN-gamma (interferon-gamma) has several applications in the treatment of IFN-gamma-related skin disorders. While systemic delivery - the major route used to administer IFN-gamma - results in significant side effects and toxicity, including fever, fatigue, nausea, vomiting and neurotoxicity, transdermal delivery has a very low transduction efficiency. In order to improve the efficiency of transdermal IFN-gamma delivery, we introduced a Pen (penetratin) peptide, a 16-amino-acid-long polypeptide corresponding to the third helix of the DNA-binding domain (homoeodomain) of Antennapedia (a Drosophila transcription factor). The human IFN-gamma gene was then fused with a gene fragment that encodes the Pen of Antennapedia in a bacterial expression vector, producing a genetic in-frame Pen-IFN-gamma. The expressed and purified Pen-IFN-gamma was then found to have a much more efficient transduction profile than native IFN-gamma. In addition, compared with native IFN-gamma, Pen-IFN-gamma exhibited similar activities when added exogenously to a culture medium: (i) induction of IRF-1 gene expression, and (ii) NF-kappaB (nuclear factor kappaB) luciferase reporter activation. These results indicate that the transdermal delivery system using Pen may be an excellent way to replenish IFN-gamma in the various disorders related to this cytokine.
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PMID:Transdermal delivery of interferon-gamma (IFN-gamma) mediated by penetratin, a cell-permeable peptide. 1580 34

YM-393059, (+/-)-N-(4,6-dimethylpyrimidin-2-yl)-4-[2-(4-methoxy-3-methylphenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl]benzenesulfonamide difumarate, is a novel phosphodiesterase (PDE) inhibitor that inhibited the PDE7A isoenzyme with a high potency (IC50=14 nM) and PDE4 with a moderate potency (IC50=630 nM). In a cell-based assay, YM-393059 was found to inhibit anti-CD3 antibody, Staphylococcal enterotoxin B, and phytohaemagglutinin-induced interleukin (IL)-2 production in mouse splenocytes with IC50 values ranging from 0.48 to 1.1 microM. It also inhibited anti-CD3 antibody-induced interferon (IFN)-gamma and IL-4 production in splenocytes with IC50 values of 1.8 and 2.8 microM, respectively. YM-393059's inhibition of anti-CD3 antibody-stimulated cytokine (IL-2, IFN-gamma, and IL-4) production was 20- to 31-fold weaker than that of YM976, a selective PDE4 inhibitor. However, orally administered YM-393059 and YM976 inhibited anti-CD3 antibody-induced IL-2 production equipotently in mice. In addition, YM-393059 inhibited lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo more potently than IL-2 (ED50 values of 2.1 mg/kg and 74 mg/kg). In contrast to YM976, YM-393059 did not shorten the duration of alpha2-adrenoceptor agonist-induced sleep in mice, which is a model for the assessment of the typical side effects caused by PDE4 inhibitors, nausea and emesis. YM-393059 is a novel and attractive compound for the treatment of a wide variety of T-cell-mediated diseases.
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PMID:The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo. 1678 Aug 33

The present study was conducted to study the impact of the virulence factors invC and sseD of the two type III secretion systems of Salmonella enterica serovar Typhimurium (S. Typhimurium) on the pathogenesis of the porcine S. Typhimurium DT104 infection. For this purpose, two S. Typhimurium mutant strains with a disrupted invC gene of the Salmonella pathogenicity island 1 or with a disrupted sseD gene of the Salmonella pathogenicity island 2 have been studied in experimental infection of pigs. Twenty-two 7-week-old male hybrid pigs were either infected with one of the mutants or the wild-type S. Typhimurium DT104 strain. Each group was examined for clinical signs, Salmonella shedding rate and the specific antibody response. Survival and replication were evaluated by qualitative and quantitative determination of the colonization rate. The humoral and cellular immune responses were examined using isotype-specific ELISA and quantitative real-time PCR of IL-2, IL-4, IL-10, IL-12 and IFN-gamma. The results proved that both mutants had a lower virulence (with marked differences between both mutants) than the wild-type and that both virulence factors have importance in porcine salmonellosis. Only pigs infected with the wild-type S. Typhimurium DT104 exhibited typical clinical symptoms of salmonellosis like anorexia, vomiting, disturbed demeanour, fever and diarrhoea. Deletion of the invC gene resulted in a significantly reduced colonization rate. Interestingly, the mRNA expression of both type-1 and type-2 cytokines were significantly decreased in pigs infected with either the invC-mutant and the sseD-mutant strain.
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PMID:Impact of Salmonella Typhimurium DT104 virulence factors invC and sseD on the onset, clinical course, colonization patterns and immune response of porcine salmonellosis. 1752 77