Safety and tolerability of a single dose T0001 in Chinese healthy adult volunteers: a first-in-human ascending dose study

T0001 is the first mutant of etanercept with a higher affinity to tumor necrosis factor α (TNF-α) than etanercept. In order to investigate the safety and tolerability of T0001, a study was carried out in healthy Chinese subjects. A first-in-human, dose escalation study was conducted in healthy Chinese subjects. Fifty-six subjects were divided into six dose cohorts (10 mg, 20 mg, 35 mg, 50 mg, 65 mg and 75 mg) to receive a single subcutaneous injection of T0001. Safety and tolerability assessment were based on the records of vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms and adverse events (AEs). All subjects were in good compliance and none withdraw due to AEs. No serious AEs occurred. A total of twenty-three AEs in sixteen subjects were recorded, and eighteen of these AEs were believed to be related to T0001. The most frequently reported AEs were injection site reactions and white blood cell count increase. All these AEs were of mild to moderate intensity and most of them recovered spontaneously within 14 days. In this study, no dose-limiting toxicity was observed, and the maximum tolerated dose was identified as 75 mg. T0001 was considered safe and generally well tolerated at doses up to 75 mg in healthy Chinese volunteers

Detection of seizure activity in the paralyzed neonate using continuous monitoring.

In experimental animals neurologic damage may occur during seizure activity whether the seizure is accompanied by motor activity and hypoxemia or whether the animal is paralyzed and normoxemic. These findings suggest that it may be important to detect seizure activity in the paralyzed neonate. Nine infants who were mechanically ventilated and paralyzed with pancuronium had their condition diagnosed as seizure activity. Vital signs were continuously monitored and six infants had either oxygen saturation or transcutaneous oxygen measured during seizure activity. For the group as a whole, rhythmic fluctuations in vital signs, cardiac rhythm, and oxygenation occurred every four minutes (range one to seven minutes) and lasted two minutes (range one to four minutes). In seven patients whose seizures were not accompanied by cardiac arrhythmias the following mean increases were noted: systolic arterial blood pressure, 15 mm Hg (range 7 to 36 mm Hg); heart rate, ten beats per minute (-11 to 30/min); oxygen saturation, 12% (range 4% to 20%); and transcutaneous oxygen, 31 mm Hg (range 14 to 45 mm Hg). Seizures in the two patients with cardiac arrhythmias were accompanied by a decrease in systolic arterial blood pressure of 27 mm Hg (range 15 to 40 mm Hg) and in oxygen saturation of 24% (range 20% to 28%). The presence of rhythmic fluctuation in vital signs and oxygenation should alert the physician to the possibility of seizure activity in the paralyzed neonate.

Pharmacokinetics of pancuronium in patients undergoing coronary artery surgery with and without low dose dopamine.

Pancuronium is frequently used in coronary artery surgery, but its pharmacokinetics in these patients are still unknown. It is possible that dopamine, administered to prevent renal impairment induced by the surgery, might promote the elimination of pancuronium. Therefore, the pharmacokinetics of a bolus dose of pancuronium were studied in 2 groups of coronary artery surgery patients, with and without dopamine 2 micrograms/kg/min, administered during and after cardiopulmonary bypass. Dopamine in the administered dose did not influence the systemic haemodynamics. The pharmacokinetic variables in both groups did not differ from those found in an earlier study in healthy normothermic patients. Total renal clearance was not influenced by dopamine, due to post-bypass rebound hyperperfusion in the control group. Pancuronium was shown to be subject to considerable tubular reabsorption, and its elimination was found to be increased during hypothermia. Dopamine increases pancuronium elimination by an increase in glomerular filtration rate. The dopamine-induced decrease in tubular solute reabsorption did not enhance the elimination of pancuronium.

Succinylcholine-induced hyperkalemia following prolonged pharmacologic neuromuscular blockade.

While being treated for the acute respiratory distress syndrome, a 27-year-old woman developed profound hyperkalemia and cardiac arrest following the administration of succinylcholine chloride (SCh). She had none of the risk factors previously described for development of severe hyperkalemia following SCh administrations; however, she had been intermittently treated with nondepolarizing neuromuscular blocking drugs throughout the course of her illness. We suggest that immobilization of critically ill patients with pharmacologic neuromuscular blockade may predispose them to severe hyperkalemia and cardiac arrest following administration of SCh. SCh should be used with great caution in such patients.

Monitoring of anaesthesia in neurophysiological experiments.

Cortical activity can be substantially changed by the type of anaesthetic used, and by its dose level. For easy monitoring of depth of anaesthesia we describe the changes in electroencephalogram and electrocardiogram accompanying changes in depth of anaesthesia in the cat. Anaesthesia was induced by the volatile anaesthetic isoflurane. The high-frequency components (around 30 Hz) in the electroencephalogram disappear in deep anaesthesia. The electrocardiogram also shows substantial changes in contamination due to muscle fasciculations with anaesthesia level. Fasciculations appear as noise in the electrocardiogram. The amplitude of the electrical muscle activity contaminating the ECG can be easily used for the maintainance of a constant level of anaesthesia during a neurophysiological experiment.

Severe cardiovascular changes associated with pancuronium after cardiopulmonary resuscitation and after brain injury.

Severe hypertension, tachycardia or ECG changes have been reported following i.v. administration of pancuronium to patients with pheochromocytoma or bronchial asthma. These cardiovascular changes were explained by an interaction between autonomic effects of pancuronium and elevated serum catecholamines or aminophylline. We noted similar cardiovascular changes associated with i.v. administration of pancuronium in two patients after successful cardiopulmonary resuscitation and in two with midbrain hemorrhage and epidural hematoma. In these patients, pancuronium produced no abnormal cardiovascular changes when given during elective surgery or before the occurrence of midbrain hemorrhage. Thus, ischemic brain damage may play a role in producing the severe cardiovascular changes associated with pancuronium.

The neuromuscular and autonomic blocking activities of pancuronium, Org NC 45, and other pancuronium analogues, in the cat.

Twenty-six mono- or bis-quaternary salts of 3,17-dioxy-2 beta, 16 beta-dipiperidino-5 alpha-androstanes (including pancuronium) and one 17-desoxy congener were tested for neuromuscular blocking and autonomic blocking activities in the chloralose-anaesthetized cat. The 17 beta-acetoxy series, all the members of which contain an acetylcholine-like fragment in the steroidal D-ring, was most selective for effecting neuromuscular blockade. The salient member of this series is 3 alpha, 17 beta-diacetoxy-2 beta, 16 beta-dipiperidino-5 alpha-androstane 16 beta-N-monomethobromide (Org NC 45) which is highly selective in blocking neuromuscular transmission in that a dose approximately sixty times greater than the neuromuscular blocking dose was required to block responses to vagal stimulation. In contrast, in doses sufficient to produce neuromuscular block, pancuronium simultaneously blocked responses to vagal stimulation. Moreover, pancuronium and Org NC 45 exhibited the same order of neuromuscular blocking activity and therefore the latter potentially represents a useful addition to the armamentarium of neuromuscular blocking agents currently in clinical use.

Anaesthetic management of baboons undergoing heterotopic porcine cardiac xenotransplantation.

A detailed anaesthetic technique for baboons (Papio anubis) undergoing heterotopic abdominal cardiac xenotransplantation is described. Twenty-two baboons served as transplant recipients. Donors were either crossbred farm pigs (Sus scrofa) (n = 4) or transgenic pigs (Sus scroefa) (n = 18) expressing human complement regulatory proteins on the endothelium. Intra-operative management was complicated by the physiological consequences of infrarenal. abdominal aortic cross-clamping, in addition to the immunological sequelae related to cross-species transplantation. In choosing anaesthetics for this procedure, we considered the need for maximal cardiac stability throughout a long surgical procedure that required abdominal aortic cross-clamping to facilitate the implantation of an oversized porcine cardiac graft. Baboons received a balanced anaesthetic consisting of inhaled isoflurane in oxygen, intravenous fentanyl and intravenous pancuronium. The pharmacological techniques employed were found to be safe and reliable and were well tolerated by our recipients without any significant side-effects.

Anaesthetic management for atlanto axial subluxation.

A number of disease processes including congenital anomalies, malunited odontoid fractures, rheumatoid arthritis and tuberculosis can result in atlanto axial subluxation. The patient population presenting for surgery is therefore varied in age and general condition, ranging from fit young men to steroid dependent frail arthritic patients. The degree of instability and the spinal cord compression are also variable. Gauging these parameters has an important bearing on the anaesthetic management. We present management of six patients with atlanto axial subluxation in our institution.

[Clinical observation on artificial shexiang baoxin pill in treating 112 patients of coronary heart disease with angina pectoris].

OBJECTIVE: To test and verify the effect of artificial Shexiang Baoxin Pill (SXBXP, a heart protecting musk pill). METHODS: Two hundred and twenty-five patients of coronary heart disease (CHD) with angina pectoris were randomly and blindly assigned to the study group (112 cases) and the control group (113 cases). The two groups were well matched in age, sex, angina type, complication and grade of cardiac function. Two pills of artificial or natural SXBXP were given to each cases of the two groups for 3 times every day orally, for 2 weeks, respectively. RESULTS: Both the artificial and natural SXBXP could not only reduce significantly the frequency of angina episode and the daily consumption of nitroglycerin, they also could result in remarkable improvement of NST, sigma ST and exercise tolerance, as well as significant reduction of rate-pressure product. The total symptomatic effective rate of the two groups was 86.6% and 89.4% respectively, and the ECG effective rate, 52.7% and 57.5% respectively (P > 0.05), and the incidence of headache of the two groups was one for eoch. In addition, the onset of action of both agents was rapid, 88.5% of the study group and 78.6% of the control group were within five minutes. The sustained time of action of the two groups was also similar, i.e. 4.9 +/- 4.4 h vs 5.4 +/- 3.1 h. CONCLUSION: The clinical efficacy and side effect of artificial SXBXP were very similar to those of natural SXBXP.

[Cardiac arrhythmia and myocardial contraction in opium and ephedrone addiction]. / Narusheniia ritma serdtsa i sokratimost' miokarda pri opiinoi i éfedronovoi narkomanii.

Sixty-two patients with opium and ephedrone abuse were studied. They underwent 24-hour Holter monitoring, resting ECG and echocardiography, 18 of them having volumetric loading with polyglucine, 400.0 ml, i.v. Sinus tachycardia was detected in 67.4%, ventricular extrasystole in 4.7%, supraventricular extrasystole with infrequent paroxysms of supraventricular tachycardia in 11.6%. Despite the fact that signs of heart failure were absent and myocardial contractility was normal at rest, echocardiography along with volume loading allow one to reveal in patients some abnormal contractile alterations in the left ventricle. These include its increased volumes, decreased ejection fraction and circulatory shortening rate of myocardial fibers, which suggests that the compensatory potentials of the myocardium are reduced in drug abuse.

[Pumpan in the treatment of ischemic heart disease associated with arterial hypertension]. / Pumpan pri lechenii ishemicheskoi bolezni serdtsa v sochetanii s arterial'noi gipertoniei.

AIM: To study effectiveness of natural combined medicine pumpan in patients with ischemic heart disease (IHD) including cases with concomitant arterial hypertension (AH). MATERIAL AND METHODS: 35 patients with different forms of IHD (myocardial infarction, stable and unstable angina pectoris of functional class III-IV) received conventional treatment combined with pumpan given for 7-11 weeks. Changes in clinical condition, biochemical blood indices, ECG, echo-CG, 24-h arterial pressure monitoring data were investigated. RESULTS: The addition of pumpan to the standard therapy reduced frequency of anginal attacks, improved intracardiac hemodynamics, psychic and adaptive indices. CONCLUSION: Pumpan is a good adjuvant to conventional treatment of various IHD forms including combination of IHD with AH. Pumpan enables reduction in the required doses of beta-blockers, ACE inhibitors, nitrates, sedatives. It also provides hypocoagulatory and hypocholesterolemic effect.

[Effect of a compound preparation pumpan on exercise tolerance and clinical course of ischemic heart disease]. / Vliianie kompleksnogo preparata "Pumpan" na perenosimost' fizicheskikh nagruzok i klinicheskoe techenie ishemicheskoi bolezni serdtsa.

AIM: To study effects of the drug pumpan on exercise tolerance and myocardial ischemia induced by exercise in patients with ischemic heart disease of functional class II-III. MATERIAL AND METHODS: The study included 30 patients with various forms of ischemic heart disease (myocardial infarction, coronary artery bypass grafting) having stable effort angina of functional class II-III. RESULTS: The addition of a compound drug pumpan to a standard antianginal therapy reduced the number of anginal attacks and ST depression at bicycle exercise test. CONCLUSION: Pumpan is an adjuvant medication in conduction of antianginal therapy in ischemic heart disease patients with stable angina of effort of functional class II-III.

Acquired long QT syndrome and elective anesthesia in children.

We present the case of a child who had had a previous episode of torsades de pointes (TdP) and who was scheduled for elective surgery under general anesthesia. The pathophysiology of this condition and the anesthesia concerns are discussed. An 8-year-old male with a history of osteogenic sarcoma had undergone an uneventful limb salvage procedure 2 years earlier. During a subsequent admission to the hospital, he had had a cardiopulmonary arrest with complete recovery. Telemetry electrocardiogram (ECG) rhythm recordings obtained during the event showed TdP that degenerated into ventricular fibrillation, which then terminated spontaneously. On a subsequent ECG, the QTc interval was 694 ms. The prolonged QT interval was attributed to homeopathic use of cesium chloride supplements and the QT interval normalized after cesium was stopped. He presented for an elective procedure and, with an anesthetic plan that emphasized medications without known effect on the QT interval, had an uneventful perioperative course. The optimal anesthesia plan for patients with prolonged QT or those suspected to be at risk for prolongation of the QT interval has not been well described. Available evidence suggests that using total intravenous anesthesia with propofol may be the safest and was used uneventfully in this case. Additionally, this case emphasizes the need to inquire about the use of supplements and naturopathic medications, even in children, that may have life-threatening side effects or interactions with anesthetic agents.