The common adverse reactions caused by poly (ADP-ribose) polymerase (PARP) inhibitors include hematological toxicity, gastrointestinal toxicity and fatigue. The main prevention and treatment of hematological toxicity include: regular blood tests, referral to hematology department when routine treatment is ineffective, and being alert of myelodysplastic syndrome/acute myeloid leukemia. The key points to deal with gastrointestinal toxicity include: taking medicine at the right time, light diet, appropriate amount of drinking water, timely symptomatic treatment, prevention of expected nausea and vomiting, and so on. For fatigue, full assessment should be completed before treatment because the causes of fatigue are various; the management includes massage therapy, psychosocial interventions and drugs such as methylphenidate and Panax quinquefolius according to the severity. In addition, niraparib and fluzoparib can cause hypertension, hypertensive crisis and palpitation. Blood pressure and heart rate monitoring, timely symptomatic treatment, and multidisciplinary consultation should be taken if necessary. When cough and dyspnea occur, high resolution CT and bronchoscopy should be performed to exclude pneumonia. If necessary, PARP inhibitors should be stopped, and glucocorticoid and antimicrobial therapy should be given. Finally, more attention should be paid to drug interaction management, patient self-management and regular monitoring to minimize the risk and harm of adverse reactions of PARP inhibitors.
Humans ; Poly(ADP-ribose) Polymerase Inhibitors/adverse effects* ; Phthalazines/pharmacology* ; Poly(ADP-ribose) Polymerases ; Fatigue/drug therapy*

OBJECTIVE: To investigate the regulatory effects of Olaparib on natural killer cell activating receptor (NKG2D) ligands expression on human acute myeloid leukemia (AML) cell line HL-60, and to explore the molecular mechanism of Olaparib on HL-60 cells. METHODS: After HL-60 cells in logarithmic growth phase were treated with Olaparib at different concentrations for different times (24, 48 h), the expression of NKG2D ligand on the surface of HL-60 cells was detected by flow cytometry. Western blot was used to dectect the expression of ERK expression in HL-60 cells. The killing effect of NK cells to HL-60 cells was detected by CFSE/PI method. RESULTS: 10 μmol/L Olaparib could upregulate the expression of NKG2D ligand on the surface of HL-60 cell at 24 and 48 hours, while 5 μmol/L Olaparib could induce up-regulation of the expression of ULBP-2 and ULBP-3 at 48 hours. Western blot analysis showed that ERK phosphorylation of HL-60 cells was enhanced after treating with Olaparib. The killing effect of NK cells to HL-60 cells could be enhanced by Olaparib, however, ERK inhibitor could suppress the killing effect of NK cells to HL-60 cells. CONCLUSION Olaparib can upregulate NKG2D ligands expression on the surface of HL-60 cells and enhance the cytotoxicity of NK cell to HL-60 cells. The mechanism may be related to Olaparib promoting ERK phosphorylation expression.
Cell Line, Tumor ; Cytotoxicity, Immunologic ; HL-60 Cells ; Histocompatibility Antigens Class I ; Humans ; Ligands ; NK Cell Lectin-Like Receptor Subfamily K ; Phthalazines ; Piperazines ; Poly(ADP-ribose) Polymerase Inhibitors

ABSTRACT:

BACKGROUND: The Millennium Development Goal (MDG) for 2015 has a target MMR of 52/100,000 live births but this goal been difficult to achieve. In the Philippines, 11 mothers die everyday from pregnancy related complications, a bulk contributed by Hypertension. Public health midwives sometimes attend to these obsterical emergencies often in the absence of a physician. this led to the BEmONC program, which addresses the rising morbidities from far-flung areas where resources are scarce, and helps train midwives in essential obsterical emergency care. The midwives are our allies in providing the best standard of care every mother and child rightfully deserves. Only thru periodic evaluation can we help strengthen BEmONC program, making it crucial to evaluate the midwives' knowledge and management practices in hypertension to help identify the setbacks that have impeded our progress in achieving the MDG.

GENERAL OBJECTIVE: To access the knowledge and management practices of midwives in the management of hypertension in pregnancy in accourdance to the BEmONC protocol.

STUDY DESIGN: Descriptive Study

STUDY SETTING: The 69 public health centers of Cebu City

STUDY POPULATION: Public Health Midwives

METHODOLOGY:This is descriptive study where a survey questionnaire was used and convenience sampling was done. Chi square and Fischer exact tests were employed to compare proportions. Descriptive statistics was used to summarize the data in proportion.

RESULT: More than 70% of the midwives were knowledgeable regarding expected competencies, where BEmONC-trained midwives were 5-14x more likely to identity appropriate function. However, Only a dismal 22-36% will actually administer Magnesium Sulfate, which shows that knowledge is not translated into practice. Also, more than 70% were knowledgeable on the risk factors and danger signs of hypertension in pregnancy. It also showed that the midwives agreed to give antihypertensive medications- where Methyldopa was commonly given. Among those who agreed too give Methyldopa, majority were BEmONC-trained. A number also agreed to give hydralazine and diazepam in the setting of sever preeclampsia and eclampsia, where more non-BEmONC midwives agreed. Alarmlingly, only less than 50% will refer to a physician in the management og gestational hypertension and mild preeclampsia, and only 50%-60% agreed to facilitate hospital transport in the setting of severe preeclampsia and eclampsia.

CONCLUSION: The BEmONC manual must be updated to keep up with current guidelines and ensure the conversation of knowledge into practice. The BEmONCcoverage of training must also be expanded so that all practicing midwives know the protocol. However, the DOH must further strengthen their role in the active surveillance of public health midwives and review the retention of their skills and regular practice of knowledge. Midwives must also be certified proficient, not merely trained. The must also be consulted to explore their problems in the implementation of current guidelines so we can better understand their situation as to why knowledge is not put into practice. By identifying deficiencies, we can improve and address setbacks that have impeded our progress towards achieving the Millennium Development Goal.

Human ; Knowledge ; Methyldopa ; Antihypertensive Agents ; Eclampsia ; Hypertension, Pregnancy-induced ; Magnesium Sulfate ; Midwifery ; Pre-eclampsia ; Live Birth ; Diazepam ; Hydralazine ; Obstetrics

OBJECTIVE: To explore the relevance between nasal symptoms and laryngopharyngeal reflux disease in patients with allergic rhinitis. METHOD: Thirty patients of laryngopharyngeal reflux disease were diagnosed in ENT outpatient department in our hospital. All patients have symptoms of sneeze, nasal discharge as chief complaint and they responded no effect for other normal treatment for nasal-sinusitis at least three months. Orally before meals, a dose of 5 mg Mosapride citrate each time, three times a day for 7 days. Orally before meals, a dose of 20 mg Esomeprazole each time, two times a. day for 2-3 months. Nasal spray, one spray of azelastine hydrochloride once, two times a day for 2 month. RESULT: Laryngopharyngeal reflux symptom scores at four time points (the first visit, post treatment 15 days, 45 days, 75 days) were analyzed by repeated measures analysis of variance. There is a significant difference in four time points. CONCLUSION Laryngopharyngeal reflux disease has a strong association with allergic rhinitis. Patients who has allergic rhinitis nasal symptoms as chief complaint must be exclude, the laryngopharyngeal reflux disease first.
Benzamides ; therapeutic use ; Esomeprazole ; therapeutic use ; Humans ; Laryngopharyngeal Reflux ; complications ; drug therapy ; Morpholines ; therapeutic use ; Phthalazines ; therapeutic use ; Pilot Projects ; Rhinitis, Allergic ; drug therapy ; etiology

OBJECTIVE: To determine if greater efficacy could be achieved with the intranasal antihistamine azelastine and the intranasal corticosteroid fluticasone propionate used concurrently in the treatment of nasal obstruction of persistent non-allergic rhinitis. METHOD: A total of 162 persistent non-allergic rhinitis cases with moderate to severe nasal obstruction were randomized to treatment with the following: the combination therapy or nasal corticosteroids monotherapy. Efficacy was assessed by change from baseline in nasal obstruction score at week 2 and week 6 visits. The perceptions of global treatment satisfaction(convenience, side effects, cost and effectiveness) in both groups were analyzed. RESULT: In both groups, the nasal obstruction score assessment descended significantly at week 2 and week 6 visits versus at baseline (all P < 0.01). At week 2 and week 6 visits, the nasal obstruction score in the combination therapy groups were significantly improved than that in nasal corticosteroids monotherapy groups (all P < 0.01). The perceptions of global treatment satisfaction in the combination therapy groups were significantly better (P < 0.05). CONCLUSION Azelastine nasal spray and intranasal corticosteroid in combination may provide a substantial therapeutic benefit for patients with persistent non-allergic rhinitis, especially nasal obstruction. The combination therapy was well tolerated and safety.
Administration, Intranasal ; Adrenal Cortex Hormones ; therapeutic use ; Drug Therapy, Combination ; Histamine H1 Antagonists ; therapeutic use ; Humans ; Nasal Obstruction ; Phthalazines ; therapeutic use ; Rhinitis ; drug therapy

A series of phthalazine ketone compounds were synthesized and the structures were confirmed by H NMR and HR-MS spectrum. All target compounds were obtained through 7 steps, including selective reduction, nitration, bromination, ring enlargement, reduction, Knoevenagel and acylated reaction. The compounds were evaluated for their immunosuppressive effects of T-cell proliferation and inhibitory activity of IMPDH type II in vitro, as well as their structure-activity relationship were assessed. Several compounds exhibited strong immunosuppressive properties, especially compounds 7f and 7h, with IC50 values of 0.093 micromol x L(-1) and 0.14 micromol x L(-1) respectively, which were superior to mycophenolic acid. The information obtained from the studies may be useful for further research on the immunosuppressive agents.
Animals ; Cell Proliferation ; drug effects ; Female ; IMP Dehydrogenase ; metabolism ; Immunosuppressive Agents ; chemical synthesis ; chemistry ; pharmacology ; Inhibitory Concentration 50 ; Mice ; Mice, Inbred BALB C ; Phthalazines ; chemical synthesis ; chemistry ; pharmacology ; Spleen ; cytology ; Structure-Activity Relationship ; T-Lymphocytes ; drug effects

The poly(ADP-ribose) polymerases (PARPs) is an important group of enzymes in DNA repair pathways, especially the base excision repair (BER) for DNA single-strand breaks (SSBs) repair. Inhibition of PARP in DNA repair-defective tumors (like those with BRAC1/2 mutations) can lead to cell death and genomic instability, what is so called "synthetic lethality". Currently, PARP inhibitors combined with cytotoxic chemotherapeutic agents in the treatment of BRCA-1/2 deficient cancers are in the clinical development. In this review, we will be focused on the development of combination application of PARP inhibitors with other anticancer agents in clinical trials.
Animals ; Antineoplastic Agents ; therapeutic use ; Benzimidazoles ; therapeutic use ; Breast Neoplasms ; drug therapy ; genetics ; DNA Repair ; Drug Therapy, Combination ; Enzyme Inhibitors ; therapeutic use ; Female ; Humans ; Indoles ; therapeutic use ; Melanoma ; drug therapy ; Mutation ; Ovarian Neoplasms ; drug therapy ; genetics ; Phthalazines ; therapeutic use ; Piperazines ; therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors

The advent of targeted therapies, combined with an unsustainable rate of failure in oncology drug development, has resulted in a number of new approaches to clinical trials. Early clinical trials are no exception, with efforts to improve the eventual success rate of late stage trials through evolving phase I trial methodologies, the addition of extensive pharmacodynamic studies, and early adoption of patient selection strategies. Unfortunately, some of these new approaches have met with mixed results. Furthermore, no clear metrics are available to determine whether these designs are more successful than previous strategies. This review examines the evolution of phase I trials and draws upon several examples of strategies that have been successful as well as those that have not, and outlines a pragmatic approach to phase I trials as our understanding of the molecular biology of individual malignancies emerges.
Antineoplastic Agents ; administration & dosage ; pharmacokinetics ; therapeutic use ; Clinical Trials, Phase I as Topic ; Drug Delivery Systems ; methods ; Humans ; Maximum Tolerated Dose ; Molecular Targeted Therapy ; methods ; Neoplasms ; diagnostic imaging ; drug therapy ; Phthalazines ; pharmacokinetics ; Positron-Emission Tomography ; Protein Kinase Inhibitors ; pharmacokinetics ; Pyridines ; pharmacokinetics ; Quinazolines ; administration & dosage ; pharmacokinetics ; therapeutic use

PARP is an important protein in DNA repair pathways especially the base excision repair (BER). BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting poly(ADP-ribose) polymerase (PARP), SSBs accumulate and become double stand breaks (DSBs). The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Over the last few years, excitement over this class of agents has escalated due to reported activity as single agent in BRCA1- or BRCA2-associated ovarian or breast cancers, and in combination with chemotherapy in triple negative breast cancer. This review covers the current results of clinical trials testing those two principles. It also evaluates future directions for the field of PARP inhibitor development.
Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Benzamides ; administration & dosage ; Benzimidazoles ; administration & dosage ; Breast Neoplasms ; drug therapy ; enzymology ; genetics ; DNA Breaks, Double-Stranded ; DNA Breaks, Single-Stranded ; DNA End-Joining Repair ; DNA Repair ; Enzyme Inhibitors ; therapeutic use ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Homologous Recombination ; Humans ; Mutation ; Ovarian Neoplasms ; drug therapy ; enzymology ; genetics ; Phthalazines ; administration & dosage ; Piperazines ; administration & dosage ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases ; metabolism

OBJECTIVETo study the effect of PKC signalling pathway and aldose reductase (AR) on the expression of fibronectin (FN) induced by transforming growth factor-β1 (TGF-β1).

METHODSHuman mesangial cells (HMCs) were cultured and transfected with pcDNA3-AR, and subject to AR gene silencing with small interfering RNA (siRNA) and then the cell was treated with recombinant human TGF-β1. The AR mRNA expression in the HMCs was examined using real time RT-PCR and protein expression of AR and FN was detected by Western blotting.

RESULTSThe cultured HMC treated with TGF-β1 showed increased expression of AR and FN, the normal HMC showed not reduced expression of FN after incubation with single inhibitors of AR.Pre-incubation of cells with inhibitors of AR and PKC, then the different groups of cells were treated with TGF-β1, and the induction effect on FN expression was suppressed (34%) in HMC. HMCs transfected with AR showed a strong protein expression of FN, which was increased by 3.6-fold after treatment with TGF-β1 (P < 0.05), and the induction effect on FN expression was suppressed by GÖ6983 (42%) in HMCs (P < 0.05). The HMC with AR gene knock-down by siRNA showed a decreased expression of AR and 90% decrease of FN protein in HMCs (P < 0.01), and TGF-β1-induced up-regulation of FN was significantly suppressed by siRNA (12%) in HMCs (P < 0.01).

CONCLUSIONSAR is capable of regulating FN expression only in the presence of TGF-β1, and this reaction is possibly accomplished through the activation of PKC signalling pathway.

Aldehyde Reductase ; antagonists & inhibitors ; biosynthesis ; genetics ; Benzothiazoles ; pharmacology ; Carbazoles ; pharmacology ; Cells, Cultured ; Fibronectins ; metabolism ; Gene Knockdown Techniques ; Humans ; Indoles ; Maleimides ; Mesangial Cells ; cytology ; metabolism ; Phthalazines ; pharmacology ; Protein Kinase C ; antagonists & inhibitors ; metabolism ; RNA, Messenger ; metabolism ; RNA, Small Interfering ; genetics ; Signal Transduction ; Transfection ; Transforming Growth Factor beta1 ; pharmacology ; Up-Regulation