Idiosyncratic adverse drug reactions (IDR) induce severe medical complications or even death in patients. Alert structure in drugs can be metabolized as reactive metabolite (RM) in the bodies, which is one of the major factors to induce IDR. Structure modification and avoidance of alert structure in the drug candidates is an efficient method for reducing toxicity risks in drug design. This review briefly summarized the recent development of the methodologies for structure optimization strategy to reduce the toxicity risks of drug candidates. These methods include blocking metabolic site, altering metabolic pathway, reducing activity, bioisosterism, and prodrug.
Binding Sites ; Cytochrome P-450 Enzyme System ; metabolism ; Drug Design ; Drug Discovery ; methods ; Drug Recalls ; Drug-Related Side Effects and Adverse Reactions ; prevention & control ; Humans ; Structure-Activity Relationship

Objective To compare the effects of biphasic square waveform (BSW) with low or high energy on external defibrillation.Method Adult swine model of closed chest ventricular fibrillation induced by electricity was established.Eighteen swine,weighing (30?3.3) kg were randomly divided into three groups:50-50-50 J group (n=6),30-50-75 J group (n=6),120-150-200 J (n=6).After three minutes of ventricular fibrillation without treatment,the pigs in the three groups were defibrillated accordance to the above sequences. Results 30 J BSW didn't succed to external defibrillate.The first defibrillation successful rate of 50 J and 120 J BSW was 5/6.The total defibrillation successful rate of every group was 100%.All pigs quickly had spontaneous circulation after defibrillation and survived more than 24 hours.ST-T change of low-energy was less than that of high-energy.After resuscitation,myocardial function decreased,but there had not significant differences between groups.Conclusions In the study,30J BSW could not reach successful defibrillation,and 50 J and 120 J BSW had similar defibrillation efficacy.The ideal energy of BSW external defibrillation was 50 J.

AIMTo investigate the differences of membrane capacitance, membrane current, current density and I-V curves between smooth muscle cells isolated from RHR and NTR pulmonary arteries.

METHODSUnder antiseptic conditions, the left renal artery was exposed through a retroperitoneal flank incision and carefully dissected free of the left renal vein. A silver clip with an internal diameter of 0.2-0.3 mm was placed around the left renal artery, resulting in partial occlusion of renal perfusion. SBP was observed by tail blood pressure. Whole cell recordings were made from smooth muscle cells freshly isolated from pulmonary arteries derived from RHR or NTR.

RESULTSThe average membrane capacitance was (3.43 +/- 1.16) pF, decreased by 31.1%; membrane current was (0.54 +/- 0.26) nA, decreased by 68.2%; current density was (180 +/- 90) pA/pF, decreased by 48.6%; membrane potential was (-26.96 +/- 7.23) mV, decreased by 2.5%, all compared with that of NTR respectively. Iptakalim hydrochloride at the concentration of 0.1-100 micromol/L can significantly increased NTR potassium currents. Iptakalim hydrochloride 1-100 micromol/L can significantly increased RHR potassium currents.

CONCLUSIONMembrane capacitance, membrane current, membrane potential were decreased, I-V curves were shift downward, compared with that of NTR. Iptakalim hydrochloride might significantly increase NTR and RHR potassium currents.

Animals ; Hypertension, Renal ; metabolism ; physiopathology ; Male ; Membrane Potentials ; Muscle, Smooth, Vascular ; cytology ; metabolism ; physiology ; Myocytes, Smooth Muscle ; metabolism ; physiology ; Potassium Channels ; metabolism ; physiology ; Pulmonary Artery ; cytology ; metabolism ; physiology ; Rats ; Rats, Wistar

OBJECTIVETo observe the preventive effect different compatibilities of Ramulus Cinnamomi (RC) and peony in Guizhi Decoction (GD) on diabetic cardiac autonomic neuropathy (DCAN).

METHODSTotally 60 male rats were randomly divided into 5 groups, i.e., the blank control DM group, the model group, the methycobal group, the 1:1 (RC/peony) Guishao group, the 2:1 Guishao group, and the 1:2 Guishao group, 10 in each group. Rats were pretreated with corresponding drugs for 1 week, and then induced diabetes by intraperitoneal injection of STZ. Drugs were administrated by gastrogavage for 4 more weeks after STZ-injection. Enzyme-linked immunosorbent assay (ELISA) was employed to detect levels of tyrosine hydroxylase (TH), choline acetyltransferase (CHAT), nerve growth factor. (NGF), and ciliary neurotrophic factor (CNTF) in myocardial homogenates.

RESULTSAfter 4-week modeling, body weight (BW) was obviously lower, but blood glucose (BG) was higher in STZ rats than in rats of the blank control DM group. There was no statistical difference in BW or BG among the 5 groups (P >0.05). Compared with the blank control group, TH, TH/CHAT, and NGF in left ventricle and ventricular septum increased, CHAT and CNTF increased in the model group (P < 0.05, P < 0.01). Compared with the model group, TH and TH/CHAT in left ventricle decreased (P < 0.05, P < 0.01), CNTF in left ventricle increased (P < 0.05), CHAT in left ventricle and ventricular septum increased (P < 0.05, P < 0.01) in the methycobal group. TH and TH/CHAT in left ventricle and ventricular septum decreased, CNTF in left ventricle and ventricular septum increased (P < 0.05, P < 0.01), CHAT in left ventricle and ventricular septum increased (P < 0.01), NGF in ventricular septum decreased (P < 0.01) in the 1:1 Guishao group. TH/CHAT in left ventricle decreased (P < 0.01), CHAT and CNTF in left ventricle and ventricular septum increased (P < 0.05, P < 0.01) in the 1:2 Guishao group. Compared with the methycobal group, CHAT in left ventricle decreased, TH and TH/CHAT in left ventricle increased in the 2:1 Guishao group (P < 0.05, P < 0.01). TH and TH/CHAT in ventricular septum decreased (P < 0.05), CHAT and CNTF in left ventricle and ventricular septum increased (P < 0.05, P < 0.01) in the 1:1 Guishao group. Compared with the 1:2 Guishao group and the 2:1 Guishao group, CHAT in left ventricle increased, TH/CHAT in left ventricle decreased, TH and TH/CHAT in ventricular septum decreased, CHAT in ventricular septum increased, CNTF in left ventricle and ventricular septum also increased in the 1:1 Guishao group (all P < 0.01).

CONCLUSIONSSTZ model rats had autonomic neural injury, manifested as lowered vagal nerve activity and hyperactive sympathetic nerves. GD could effectively suppress hyperactive cardiac sympathetic nerves and protect the vagus. Besides, GD (1:1) showed the optimal effect in regulating the balance of cardiac autonomic nerves and could be used in early prevention of DCAN.

Animals ; Blood Glucose ; Choline O-Acetyltransferase ; Diabetic Neuropathies ; drug therapy ; Drugs, Chinese Herbal ; therapeutic use ; Heart ; Heart Ventricles ; Male ; Myocardium ; Nerve Growth Factor ; Paeonia ; Rats ; Tyrosine 3-Monooxygenase

Objective To investigate the expression of caspase-10 in differentiated thyroid carcinoma and association with its development and metastasis. Methods Thyroid samples from 37 patients in a period from January 2006 to December 2007, with differentiated thyroid carcinoma were retrospectively analyzed for caspase-10 by immunohistocbemistry(streptavidin-perosidase, S-P), compared to control group of 46 cases with nodtdar goiter. The relationship between the expression of caspase-10 and the clinical pathologic characteristics of thyroid carcinoma were also explored simultaneously. Results caspase-10 were observed as brown or yellow particles located in the cytoplasm or cell membrane of nodular goiter but there were no significant evidence for its positive expression in thyroid carcinoma, caspase-10 expression was markedly down-regulated in differentiated thyroid carcinoma(29.73%,11/37) compared with benign nodules(71.74%,33/46, χ2=14.528, P<0.01). The positive expression in 18 cases with lymph node metastasis(11.11%,2/18) was significantly lower than those in 19 patients without lymph node metastasis(47.37%,9/19; χ2=4.210, P<0.01). There was no significant correlation(P> 0.05) between the expression of caspase-10 and the clinical pathologic characteristics including male, age, TNM stage and pathologic type. Conclusion Down-regulation of caspase-10 may play a critical role in carcinogenesis and development of differentiated thyroid carcinoma.

OBJECTIVEIschemic postconditioning effectively minimizes the ischemic/reperfusion injury, and the large series of case reports on its protective effects in cardiac surgery are limited. A randomized trial was conducted to investigate the effect of ischemic postconditioning on cardiopulmonary protection in children undergoing cardiac surgery for tetralogy of Fallot.

METHODSOne hundred and five-children with tetralogy of Fallot undergoing surgery were randomly assigned to control (n=58) and ischemic postconditioning groups (n=47). Ischemic postconditioning was performed by intermittent aortic clamping after reperfusion. After surgery, the duration of intensive care unit (ICU) stay, capacity of blood transfusion, hemodynamics, inotropic scores, respiratory function, and release of blood lactate were assayed.

RESULTSThere was a significant decrease in the ICU stay in the postconditioned group compared with the control group (37+/-21 hrs vs 54+/-26 hrs; P<0.05 ). The capacity of blood transfusion (308+/-230 mL vs 526+/-515 mL; P<0.05) and the inotropic scores (5.9+/-5.0 vs 10.3+/-7.7; P<0.05) in the postconditioned group were significantly reduced compared with those in the control group. Blood lactate contents in the postconditioned group was significantly lower that those in the control group 1, 3, 6, 9, 12 and 20 hrs after surgery. The postconditioned group showed more improved hemodynamics and respiratory function than the control group.

CONCLUSIONSIschemic postconditioning may provide clinical benefits with respects to myocardial and pulmonary protections in children undergoing repair for tetralogy of Fallot.

Adolescent ; Cardiac Surgical Procedures ; methods ; Cardiopulmonary Bypass ; Child ; Child, Preschool ; Female ; Hemodynamics ; Humans ; Infant ; Lactic Acid ; metabolism ; Male ; Myocardial Reperfusion Injury ; prevention & control ; Postoperative Complications ; prevention & control ; Respiration ; Tetralogy of Fallot ; physiopathology ; surgery

OBJECTIVETo observe the preventive effect of different compatibilities of Ramulus Cinnamomi (RC) and Radix Paeomiae alba (RPA) in Guizhi Decoction (GZD) on neurotransmitters and their rate-limiting enzymes, and neurotrophic factors of cardiac sympathetic denervation model rats induced by 6-hydroxydopamine (6-OHDA).

METHODSTotally 54 male Wistar rats were randomly divided into 6 groups, i.e., the blank control group, the model group, the methycobal group, the 2:1 (RC/RPA) Guishao group, the 1:2 Guishao group, and the 1:1 Guishao group, 9 in each group. Sympathetic denervation was induced by intraperitoneal injection of 6-OHDA for three successive days. Rats in the methycobal group and GZD groups were administered with corresponding decoction by gastrogavage 1 week before modeling (methycobal at the daily dose 0.15 mg/kg; GZD at the daily dose of 4.0, 5.5, 5.5 g crude drugs/kg for GZD 1:1, 1:2, and 2:1 groups). All medication lasted for 10 successive days. Levels of norepinephrine (NE), tyrosine hydroxylase (TH), choline acetyl-transferase (ChAT), nerve growth factor (NGF), growth associated protein43 (GAP-43) and ciliary neurotrophic factor (CNTF) in myocar- dial homogenates of right atrium and ventricular septum were detected by ELISA.

RESULTSCompared with the blank control group, levels of NE, TH, TH/ChAT ratio, and GAP-43 in myocardial homogenates of right atrium and ventricular septum decreased in the model group, and level of NGF increased (P < 0.01, P < 0.05). Compared with the model group, levels of NE and GAP-43 increased in the right atrium and interventricular septum; NGF level of the ventricular septum decreased in the methycobal group and each GZD groups. TH and TH/ChAT ratio in the right atrium increased in the 2:1 Guishao group and the 1:2 Guishao group (P < 0.01, P < 0.05); NGF levels in the right atrium and interventricular septum decreased only in the 1:1 Guishao group (P < 0.01, P< 0.05). Compared with the methycobal group, levels of NE, TH, and GAP-43 in the right atrium and interventricular septum increased, and NGF levels in the right atrium and interventricular septum decreased in the 1:1 Guishao group (P < 0.05). Compared with the methycobal group, levels of NE and GAP-43 in interventricular septum increased in the 2:1 Guishao group (P < 0.05).

CONCLUSIONGZD (with the proportion between RC and RPA 2:1 and 1:1) could improve contents of neurotransmitters and their rate-limiting enzymes, as well as neurotrophic factors in cardiac sympathetic denervation model rats induced by 6-OHDA, alleviate cardiac sympathetic denervation induced by 6-OHDA, and maintain the balance of sympathetic-vagal nerve system.

Animals ; Choline O-Acetyltransferase ; metabolism ; Ciliary Neurotrophic Factor ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; GAP-43 Protein ; metabolism ; Heart ; drug effects ; innervation ; Male ; Myocardium ; metabolism ; Nerve Growth Factor ; metabolism ; Norepinephrine ; metabolism ; Oxidopamine ; adverse effects ; Random Allocation ; Rats ; Rats, Wistar ; Sympathectomy ; Tyrosine 3-Monooxygenase ; metabolism

OBJECTIVETo assess the therapeutic effect, timing of administration, complication prevention and management of the double filtration plasmapheresis (DFP) in the treatment of refractory myasthenia gravis (MG).

METHODSThirty-one patients with refractory MG were treated with KM 8800 membrane plasmapheresis monitor. DFP was performed every 3 days and the exchanging liquid was composed of 50 ml of 20% albumen and 1000 ml plasma substitute. Physical examination for absolute clinical score and blood sample was collected for AchR-Ab determination early in the morning on days 0, 3, 7, 14 of DFP.

RESULTSWith a total effective rate of 91.9%, complete recovery, basic recovery, improvement, and response was achieved in 2, 4, 11, and 17 patients, respectively, whereas the other 3 failed to respond. Hypotension occurred twice in 2 cases and was corrected after symptomatic treatment.

CONCLUSIONDFP may effectively lower blood AchR-Ab level of with minimal complications, and can be valuable for treatment of refractory MG.

Adolescent ; Adult ; Autoantibodies ; blood ; Child ; Female ; Filtration ; Humans ; Male ; Middle Aged ; Myasthenia Gravis ; blood ; therapy ; Plasma Exchange ; methods ; Receptors, Cholinergic ; immunology ; Retrospective Studies ; Treatment Outcome

Acyclovir ; therapeutic use ; Anti-Inflammatory Agents ; therapeutic use ; Antiviral Agents ; therapeutic use ; Brain Stem ; pathology ; virology ; Encephalitis ; complications ; diagnosis ; drug therapy ; virology ; Herpes Zoster ; complications ; diagnosis ; drug therapy ; virology ; Herpes Zoster Oticus ; diagnosis ; drug therapy ; etiology ; virology ; Humans ; Male ; Methylprednisolone ; therapeutic use ; Middle Aged

The study was aimed to investigate the potential effect of procyanidins (PC) as a antithrombotic agent and its mechanism. 48 male SD rats were randomized into 6 groups, which include 8 rats each. Group A was normal control, group B was model control (no treatment), group C was group treated with aspirin [10mg/(kg x d)], groups D, E and F were treated with low, medial and high dose [100, 200 and 400 mg/(kg x d)] of PC respectively. In accordance with Kurz's protocols, rat's model of thrombosis of common carotid artery was contructed with FeCl(3), but for goup A 0.9% of normal saline was used for 20 minutes. The thromboxane B2 (TXB(2)), 6-Keto-PGF1alpha and GMP-140 contents in plasma were measured. The results showed that compared with the normal control group, the contents of TXB(2) and GMP-140 in plasma markedly increased in all of PC groups and aspirin group, and the contents of 6-Keto-PGF1alpha in plasma decreased. Compared with the model group, the contents of TXB(2) and GMP-140 in plasma markedly decreased in all of PC groups and aspirin group, and the contents of 6-Keto-PGF1alpha in plasma increased. Compared with the aspirin group, the contents of TXB(2) and GMP-140 in plasma reduced in all of PC groups and the contents of 6-Keto-PGF1alpha in plasma increased which was obvious in PC 400 mg/(kg x d) group. It is concluded that PC shows obvious anti-thrombosis effect, its mechanism closely correlates with inhibition of platelet activation and aggregation as well as protecting vasoendothelial cells. Antithrombosis of PC shows significant dose-dependence. The effect of the PC 400 mg/(kg x d) surpass the aspirin, but there is no significant difference between the PC 200 mg/(kg x d) and aspirin. This study provides experimental basis for clinical prevention and treatment of thrombosis.
Animals ; Biflavonoids ; pharmacology ; Carotid Artery Thrombosis ; blood ; prevention & control ; Carotid Artery, Common ; Catechin ; pharmacology ; Fibrinolytic Agents ; pharmacology ; Male ; Platelet Activation ; drug effects ; Platelet Aggregation ; drug effects ; Proanthocyanidins ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley