Lung cancer is a malignant tumor with high incidence rate and mortality rate in China and even the whole world, of which non-small cell lung cancer accounts for about 80%. Anaplastic lymphoma kinase (ALK) gene mutation accounts for about 5%. Alectinib, ALK-tyrosine kinase inhibitor (ALK-TKI), has great performance in clinical. The early detection and treatment of adverse drug reactions can greatly improve clinical benefits. This paper reports a patient of ALK positive non-small cell lung cancer was admited to Baotou Central Hospital in April 2020. The diagnosis and treatment was retrospectively analyzed, and the literature was reviewed.
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Anaplastic Lymphoma Kinase/genetics* ; Antineoplastic Agents/therapeutic use* ; Carbazoles/therapeutic use* ; Carcinoma, Non-Small-Cell Lung/secondary* ; Humans ; Lung Neoplasms/pathology* ; Mutation ; Piperidines/therapeutic use* ; Pleural Neoplasms/secondary* ; Protein Kinase Inhibitors/therapeutic use* ; Retrospective Studies ; Tomography, X-Ray Computed

Pharmaceutical research has focused on the discovery and development of anticancer drugs. Clinical application of chemotherapy drugs is limited due to their severe side effects. In this regard, new naturally occurring anticancer drugs have gained increasing attention because of their potential effectiveness and safety. Fruits and vegetables are promising sources of anticancer remedy. Clausena (family Rutaceae) is a genus of flowering plants and includes several kinds of edible fruits and vegetables. Phytochemical and pharmacological studies show that carbazole alkaloids and coumarins from Clausena plants exhibit anticancer activity. This review summarizes research progresses made in the anticancer properties of plants belonging to Clausena; in particular, compounds with direct cytotoxicity, cell cycle arrest, apoptosis induction, and immune potentiation effects are discussed. This review reveals the potential use of plants from Clausena in preventing and treating cancer and provides a basis for development of relevant therapeutic agents.
Alkaloids ; chemistry ; pharmacology ; therapeutic use ; Antineoplastic Agents ; chemistry ; pharmacology ; therapeutic use ; Apoptosis ; drug effects ; Carbazoles ; chemistry ; pharmacology ; therapeutic use ; Cell Cycle Checkpoints ; drug effects ; Clausena ; chemistry ; Coumarins ; chemistry ; pharmacology ; therapeutic use ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; therapeutic use ; Humans ; Plants, Medicinal ; chemistry

OBJECTIVETo assess the association of T190C polymorphism of β3 adrenergic receptor gene (β3-AR) with chronic heart failure (CHF), and to evaluate the effect of this polymorphism on clinical response to β-AR blockade among patients with CHF.

METHODSThree hundred and thirty patients with stable CHF receiving basic therapy for heart failure were included. Before initiation and 5 months after the maximal tolerated dose of carvedilol was reached, all indices including heart rate (HR), blood pressure (BP), left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), brain natriuretic peptide (BNP) level, 6 min walk distance were measured and compared with the indices of those with a T190C genotype. Distribution of the T190C polymorphisms in the control group and CHF group was compared.

RESULTSThe frequencies of T190C genotypes of the β3-AR gene have fit with the Hardy-Weinberg equilibrium. No significant difference was found between the frequencies of T190C alleles and genotypes between the two groups (P > 0.05). Compared with CC-homozygotes, TT-homozygous patients showed substantially greater improvement in LVEF and BNP (all P < 0.01).

CONCLUSIONNo difference has been detected in the prevalence of the three genotypes between healthy and CHF subjects. The T190C variation of the β3-AR gene was not associated with increased risk for CHF. CHF patients with a T allele have greater response to carvedilol than those carrying a C allele in ethnic Han Chinese.

Adult ; Carbazoles ; therapeutic use ; Chronic Disease ; Female ; Heart Failure ; drug therapy ; genetics ; physiopathology ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Propanolamines ; therapeutic use ; Receptors, Adrenergic, beta-3 ; genetics ; Ventricular Function, Left

OBJECTIVETo investigate the effect of low-dose carvedilol combined with candesartan in the prevention of acute and chronic cardiotoxicity of anthracycline drugs in adjuvant chemotherapy of breast cancer.

METHODSForty patients were randomly divided into two groups: the experimental group with chemotherapy plus low-dose carvedilol combined with candesartan (20 cases) and control group with chemotherapy alone (20 cases). The same chemotherapy was given to the two groups. All the 40 patients had no contraindication for carvedilol and candesartan. Patients of the experimental group received low-dose carvedilol from 2.5 mg orally twice a day at first cycle to 5 mg twice a day gradually if no side reactions, and candesartan 2.5 mg orally once a day. Electrocardiogram, ultrasonic cardiogram, arrhythmia, troponin and non-hematologic toxicity were recorded and compared after the second, forth and sixth cycle of chemotherapy. Each cycle included 21 days.

RESULTSLVEF was decreased along with the prolongation of chemotherapy in the experimental group and control group. LVEDD and LVESD showed no significant changes in the experimental group, but gradually increased in the control group. After four and six cycles of chemotherapy, LVEF were (57.00 ± 5.13)% and (45.95 ± 3.68)%, respectively, in the control group, significantly lower than that of (67.00 ± 5.13)% and (57.50 ± 2.57)%, respectively, in the experimental group (P < 0.05). After six cycles of chemotherapy, LVEDD and LVESD were (50.00 ± 10.48) mm and (35.01 ± 2.99) mm, respectively, in the control group, significantly higher than those before chemotherapy (P < 0.05) and experimental group (P < 0.001). The rate of ST segment and T wave abnormalities was 80.0% in the control group after six cycles of chemotherapy, significantly higher than that of 25.0% after four cycles of chemotherapy (P = 0.001) and 10.0% after two cycles of chemotherapy (P < 0.001). The reduction of QRS voltage, arrhythmia and abnormal troponin were 55.0%, 45.0% and 45.0%, respectively, in the control group, significantly higher than those in the experimental group (20.0%, P < 0.05), (10.0%, P = 0.010) and (10.0%, P < 0.05), respectively. The rate of abnormal expression of troponin was 45.0% in the control group, significantly higher than the 10.0% in the experimental group (P < 0.05).

CONCLUSIONSThe use of low-dose carvedilol combined with candesartan can reduce the acute and chronic cardiotoxicity of anthracycline drugs, and with tolerable toxicities. This may provide a new approach to prevent cardiotoxicity of anthracycline drugs in adjuvant chemotherapy of breast cancer.

Adrenergic beta-Antagonists ; administration & dosage ; pharmacology ; Adult ; Aged ; Angiotensin II Type 1 Receptor Blockers ; administration & dosage ; pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Arrhythmias, Cardiac ; chemically induced ; Benzimidazoles ; administration & dosage ; pharmacology ; Breast Neoplasms ; drug therapy ; surgery ; Carbazoles ; administration & dosage ; pharmacology ; Chemotherapy, Adjuvant ; Cyclophosphamide ; adverse effects ; therapeutic use ; Electrocardiography ; drug effects ; Epirubicin ; adverse effects ; therapeutic use ; Female ; Fluorouracil ; adverse effects ; therapeutic use ; Humans ; Mastectomy, Radical ; Middle Aged ; Propanolamines ; administration & dosage ; pharmacology ; Stroke Volume ; drug effects ; Tetrazoles ; administration & dosage ; pharmacology ; Troponin ; metabolism

Sildenafil increases the cyclic guanosine monophosphate (cGMP) by inhibition of a phosphodiesterase 5, thereby leading to an antinociceptive effect. The increased cGMP may exert the effect on an L-type calcium channel through the activation of protein kinase G (PKG). The purpose of this study was to examine the possible involvement of a PKG-L-type calcium channel on the effect of sildenafil at the spinal level. Catheters were inserted into the intrathecal space of male SD rats. Pain was induced by applying 50 microliter of a 5% formalin solution to the hindpaw. The sildenafil-induced effect was examined after an intrathecal pretreatment of a PKG inhibitor (KT 5823), or a L-type calcium channel activator (FPL 64176). Intrathecal sildenafil produced an antinociceptive effect during phase 1 (0~10 min interval) and phase 2 (10~60 min interval) in the formalin test. Intrathecal KT 5823 and FPL 64176 attenuated the antinociceptive effect of sildenafil during both phases. Sildenafil is effective against both acute pain and the facilitated pain state at the spinal level. In addition, the inhibition of an L-type calcium channel by activation of the PKG may contribute to the antinocieptive mechanism of sildenafil in the spinal cord.
Animals ; Calcium Channel Agonists/pharmacology ; Calcium Channels, L-Type/*physiology ; Carbazoles/pharmacology ; Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors/*physiology ; Dose-Response Relationship, Drug ; Male ; Pain/drug therapy/*physiopathology ; Pain Measurement ; Piperazines/*pharmacology/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Purines/pharmacology/therapeutic use ; Pyrroles/pharmacology ; Rats ; Rats, Sprague-Dawley ; Sulfones/*pharmacology/therapeutic use

OBJECTIVETo investigate the effect of prostaglandin D2 receptor antagonists on the airway inflammation in rats with asthma.

METHODSForty male SD rats were randomly divided into four groups: Group A (normal control), Group B (asthma group), Group C (CRTH2 antagonist BAYu3405 treatment group), Group D (DP1 antagonist BWA868C treatment group). Asthma was induced by ovalbumin (OVA) challenge. The rats in each group were sacrificed 24 h after the last challenge of OVA.DP1/CRTH2 receptors on eosinophils (EOS) were measured by radiological binding assay (RBA). The left lungs were used for histological examinations and bronchoalveolar lavage fluid (BALF) was collected from the right lungs. The total cell numbers, EOS absolute count and differential cell counts in BALF were performed. Serum concentrations of IL-4, 5 and IFN-gamma were measured by ELISA.

RESULTSRats in BAYu3405 treatment group showed profoundly decreased infiltrates of EOS and lymphocytes in the wall of bronchus when compared with those of asthma group and BWA868C treatment group. Serum concentrations of IFN-gamma in rats of BAYu3405 treatment group increased, but IL-4 and IL-5 decreased significantly when compared with those in rats of asthma group and BWA868C treatment group (P<0.01), and BALF EOS count was decreased significantly (P<0.01). Peripheral blood EOS count was higher than that in rats of normal control group, but was not significantly different from that in rats of asthma group and BWA868C treatment group. The combining capacity of CRTH2 and DP total combining capacity on EOS in asthma group, BAYu3405 treatment group and BWA868C treatment group were significantly higher than those in Group A (P<0.01). There was no significant difference in DP1 among all the groups (P>0.05).

CONCLUSIONCRTH2, but not DP1 antagonist can effectively ameliorate airway inflammation in rats with asthma.

Animals ; Asthma ; chemically induced ; drug therapy ; pathology ; Bronchi ; immunology ; pathology ; Carbazoles ; pharmacology ; therapeutic use ; Inflammation ; drug therapy ; Male ; Ovalbumin ; Prostaglandin D2 ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Immunologic ; antagonists & inhibitors ; Receptors, Prostaglandin ; antagonists & inhibitors ; Sulfonamides ; pharmacology ; therapeutic use

OBJECTIVETo examine serum B-type natriuretic peptide (BNP) levels and BNP expression of protein and mRNA in the right ventricular myocardium in juvenile rats with right heart failure (RHF) and the effects of beta-adrenergic receptor blocker carvedilol on serum and myocardial BNP levels in order to investigate the role of BNP in the diagnosis and treatment of RHF.

METHODSFifty-one four-week-old Sprague-Dawley rats were randomly assigned to 5 groups: RHF 1, RHF 2, carvedilol-treated RHF, control 1 and control 2. RHF was developed 4 weeks after an intraperitoneal injection of monocrotaline in the RHF 1, RHF 2 and carvedilol-treated RHF groups. The rats in the RHF 1 and the control 1 groups were sacrificed after the RHF event for observing pathological changes in the myocardium. After the RHF event, the carvedilol-treated group was given intragastric administration of carvedilol (3.5 mg/kg/d) for 2 weeks. The RHF 2 and the control 2 groups were given distilled water of equal dose instead. The rats were sacrificed 2 weeks after carvedilol or distilled water administration. Serum BNP levels were measured using ELISA. BNP protein and mRNA expression in the right ventricular myocardium were measured by immunohistochemistry and RT-PCR, respectively. Haemodynamics and some physiological indexes were measured.

RESULTSSerum BNP levels and BNP protein and mRNA expression in the right ventricular myocardium were significantly higher in the RHF 1 group than those in the control 1 group (p<0.01). Serum BNP levels and BNP protein and mRNA expression in the right ventricular myocardium increased more significantly in the RHF 2 group. There was a positive correlation between serum BNP levels and myocardial BNP protein expression in the RHF group (r=0.698, p<0.01). Serum BNP levels and BNP protein and mRNA expression in the carvedilol-treated RHF group were significantly reduced when compared with the RHF 2 group (p<0.05). Carvedilol treatment also resulted in improved hemodynamics and relieved right ventricular hypertrophy.

CONCLUSIONSBNP may serve an index for the diagnosis of RHF and the evaluation of severity in children with RHF. Carvedilol shows protections against RHF caused by pressure load.

Adrenergic beta-Antagonists ; pharmacology ; Animals ; Carbazoles ; pharmacology ; therapeutic use ; Heart Failure ; blood ; drug therapy ; pathology ; physiopathology ; Natriuretic Peptide, Brain ; blood ; genetics ; Propanolamines ; pharmacology ; therapeutic use ; RNA, Messenger ; analysis ; Random Allocation ; Rats ; Rats, Sprague-Dawley

Carbazoles ; therapeutic use ; Child, Preschool ; Heart Failure ; complications ; drug therapy ; Humans ; Male ; Propanolamines ; therapeutic use ; Takayasu Arteritis ; complications ; drug therapy ; Vasodilator Agents ; therapeutic use

BACKGROUNDThe loss of cardiac myocytes is one of the mechanisms involved in acute myocardial infarction (AMI)-related heart failure. Autophagy is a common biological process in eukaryote cells. The relationship between cardiac myocyte loss and autophagy after AMI is still unclear. Carvedilol, a non-selective alpha1- and beta-receptor blocker, also suppresses cardiac myocyte necrosis and apoptosis induced by ischemia. However, the association between the therapeutic effects of carvedilol and autophagy is still not well understood. The aim of the present study was to establish a rat model of AMI and observe changes in autophagy in different zones of the myocardium and the effects of carvedilol on autophagy in AMI rats.

METHODSThe animals were randomly assigned to a sham group, an AMI group, a chloroquine intervention group and a carvedilol group. The AMI rat model was established by ligating the left anterior descending coronary artery. The hearts were harvested at 40 minutes, 2 hours, 24 hours and 2 weeks after ligation in the AMI group, at 40 minutes in the chloroquine intervention group and at 2 weeks in other groups. Presence of autophagic vacuoles (AV) in the myocytes was observed by electron microscopy. The expression of autophagy-, anti-apoptotic- and apoptotic-related proteins, MAPLC-3, Beclin-1, Bcl-xl and Bax, were detected by immunohistochemical staining and Western blotting.

RESULTSAVs were not observed in necrotic regions of the myocardium 40 minutes after ligation of the coronary artery. A large number of AVs were found in the region bordering the infarction. Compared with the infarction region and the normal region, the formation of AV was significantly increased in the region bordering the infarction (P < 0.05). The expression of autophagy- and anti-apoptotic-related proteins was significantly increased in the region bordering the infarction. Meanwhile, the expression of apoptotic-related proteins was significantly increased in the infarction region. In the chloroquine intervention group, a large number of initiated AVs (AVis) were found in the necrotic myocardial region. At 2 weeks after AMI, AVs were frequently observed in myocardial cells in the AMI group, the carvedilol group and the sham group, and the number of AVs was significantly increased in the carvedilol group compared with both the AMI group and the sham group (P < 0.05). The expression of autophagy- and anti-apoptotic-related proteins was significantly increased in the carvedilol group compared with that in the AMI group, and the positive expression located in the infarction region and the region bordering the infarction.

CONCLUSIONSAMI induces the formation of AV in the myocardium. The expression of anti-apoptosis-related proteins increases in response to upregulation of autophagy. Carvedilol increases the formation of AVs and upregulates autophagy and anti-apoptosis of the cardiac myocytes after AMI.

Adrenergic beta-Antagonists ; pharmacology ; Animals ; Apoptosis ; Apoptosis Regulatory Proteins ; analysis ; Autophagy ; drug effects ; Beclin-1 ; Carbazoles ; pharmacology ; therapeutic use ; Immunohistochemistry ; Male ; Microscopy, Electron, Transmission ; Myocardial Infarction ; drug therapy ; pathology ; Myocardium ; ultrastructure ; Propanolamines ; pharmacology ; therapeutic use ; Rats ; Rats, Wistar ; Vacuoles ; drug effects

OBJECTIVETo study the effects of carvedilol combined with perindopril on Ca(2+) pump activity and the density of Ca(2+)-release channel ryanodine receptor (RyR2) in the myocardial sarcoplasmic reticulum (SR) in rats with chronic heart failure caused by myocardial infarction.

METHODSRat models of chronic heart failure established by left coronary artery ligation were divided into different groups and treated with carvedilol (6 mg.kg(-1).d(-1)), perindopril (4 mg.kg(-1).d(-1)), terazosin (2 mg.kg(-1).d(-1)), or the combination of carvedilol (6 mg.kg(-1).d(-1)) and perindopril (4 mg.kg(-1).d(-1)) for 9 weeks. Another 12 rats with sham operation served as the sham-operated group. The hemodynamic parameters, activity of SR Ca(2+) pump, and RyR2 density were determined.

RESULTSCompared with shame-operated group, the rats with chronic heart failure showed significantly increased left ventricular end-diastolic pressure (LVEDP) (P<0.01) and decreased +dP/dtmax, -dp/dtmax, activity of SR Ca(2+) pump and density of RyR2 (P<0.01). Both monotherapies with carvedilol and perindopril attenuated the increment of LVEDP, and significantly increased +dp/dtmax, -dp/dtmax, activity of SR Ca(2+) pump and density of RyR2 (P<0.01). Combined treatment even further enhanced the therapeutic effects, whereas terazosin produced no obvious effect. The activity of SR Ca(2+) pump was strongly correlated to +dp/dtmax and -dp/dtmax (r=0.596 and 0.684, respectively, P<0.01).

CONCLUSIONProlonged treatment with beta-blocker carvedilol in combination with ACE inhibitor perindopril may improve the hemodynamic parameters, enhance Ca(2+) pump activity and increase the density of RyR2 of myocardial SR more effectively than either monotherapy in preventing and treating chronic heart failure following myocardial infarction.

Animals ; Calcium ; metabolism ; Carbazoles ; pharmacology ; therapeutic use ; Drug Therapy, Combination ; Heart Failure ; drug therapy ; etiology ; metabolism ; Male ; Myocardial Infarction ; complications ; metabolism ; Perindopril ; pharmacology ; therapeutic use ; Propanolamines ; pharmacology ; therapeutic use ; Rats ; Rats, Wistar ; Ryanodine Receptor Calcium Release Channel ; drug effects ; Sarcoplasmic Reticulum ; drug effects ; metabolism