The safety and tolerability of alkaloids from Alstonia scholaris leaves in healthy Chinese volunteers: a single-centre, randomized, double-blind, placebo-controlled phase I clinical trial.

CONTEXT: Capsule of alkaloids from the leaf of Alstonia scholaris (L.) R.Br. (Apocynaceae) (CALAS) is a new investigational botanical drug (No. 2011L01436) for bronchitis, post-infectious cough and asthma. OBJECTIVE: To observe the clinical safety and tolerability of CALAS. MATERIALS AND METHODS: Subjects were assigned to eight cohorts, and each received randomly CALAS or placebo in one of single ascending dose (SAD) of 8, 40, 120, 240, 360, 480, or in one of multiple ascending dose (MAD) of 40 or 120 mg, three times daily for 7 days. Each cohort contained two placebo subjects. RESULTS: Sixty-two enrolled volunteers completed the study and no serious adverse events and clinically significant changes in vital signs, electrocardiography, and upper abdominal Doppler ultrasonography were observed. The ratios of treatment-emergent adverse events (TEAEs) were reported in 11/46 (23.91%) of CALAS groups and 3/16 (18.75%) of the placebo group (p > 0.05), respectively, based on the results of SAD and MAD. All TEAEs were mild, transient, and disappeared without any intervention. The TEAEs possibly related to CALAS treatment were as followings: hiccups (4/46: 8%), dry mouth and nausea (3/46: 6%), increased sleep (2/46: 4%), abdominal distension (1/46: 2%), bilirubin elevated (1/46: 2%). DISCUSSION AND CONCLUSIONS: CALAS is safe and well-tolerated with no unexpected or clinically relevant safety concerns up to a single dose of 360 mg and three times daily for 7 days up to 120 mg in healthy Chinese volunteers, supporting further Phase II studies.

[Pharmacokinetics of Phosphate Retagliptin Tabletin in Patients with Renal Dysfunction].

OBJECTIVE: To compared the differences in pharmacokinetics of phosphate retagliptin tablets in patients with varying degrees of renal dysfunction. METHODS: A total of 32 patients were categorized into five groups according to their renal function: normal,mild dysfunction, moderate dysfunction,severe dysfunction,and end stage renal dysfunction (ESRD). All of the patients took a single dose of 50 mg phosphate retagliptin tablet. Their plasma and urinary concentrations of phosphate retagliptin (SP2086) and phosphate retagliptin acid (SP2086 acid) were determined using LC-MS/MS methods. The plasma pharmacokinetic parameters were calculated using WinNolin 6.1 software. RESULTS: Peak concentrations (Cmax) of SP2086 reached at (1.07±0.35) h in the patients with mild renal dysfunction,(1.50±0.89) h in the patients with moderate renal dysfunction,(1.67±2.16) h in the patients with severe renal dysfunction,(2.42±2.15) h in the patients with ESRD,and (1.75±1.21) h in the normal participants,with a clearance (CL/F) of (23.50±6.01) ,(12.90±4.34) ,(6.70±1.55) ,(3.10±0.48) ,and (30.50±10.70) L/h,respectively. With the increasing damages in renal function presented an incease in Cmax,time to reach Cmax (Tmax),and area under curve (AUC), a decrease in CL/F, of SP2086 and SP2086 acid. The 0-96 hurine cumulative excretion percentage (Ae%) of SP2086 ranged from 0.441% to 4.530%. The Ae% of SP2086 acid reached (71.7±14.3) % in the patients with mild renal dysfunction, (59.5±22.7) % in the patients with moderate renal dysfunction, (63.3±13.9) % in the patients with severe renal dysfunction, (34.1±20.0) % in the patient with ESRD,and (74.2±14.6) % in the normal participants, with a renal clearance (CL/R) of (220.0±51.2),(105.0±64.5),(54.5±7.6),(13.5±7.8),and (289.0±73.7) mL/min,respectively. Compared with the participants with normal renal function,the AUCs of SP2086 and SP2086 acid were 1.44 times and 2.32 times higher in the patients with moderate renal dysfunction,2.20 times and 4.39 times higher in the patients with severe renal dysfunction, and 2.83 times and 9.28 times higher in the patients with ESRD. CONCLUSION: The dosage of phosphate retagliptin tablet is recommended at 100 mg/d for patients with normal renal function and those with mild renal dysfunction,at 50 mg/d for patients with moderate renal dysfunction,and at 25 mg/d for patients with severe renal dysfunction. No phosphate retagliptin tablet is recommended for patients with ESRD.

[Pharmacokinetics Study of Phentolamine Mesylate Injection in Healthy Volunteers].

OBJECTIVE: To study the pharmacokinetic profile of phentolamine mesylate injection in healthy Chinese volunteers. METHODS: A total of 16 healthy volunteers were randomly divided into two groups, each receiving anterior teeth submucosal infiltration anesthesia and inferior alveolar nerve block anesthesia, respectively. The participants were injected with 0.9 mL, 1.8 mL, and 3.6 mL of 2% lidocaine HCl with 1∶100 000 epinephrine over three periods sequentially, followed by corresponding sequential injection of 0.2 mg, 0.4 mg, 0.8 mg of phentolamine mesylate at the same sites 30 min later.Blood samples were drawn from 5 min before injection to 15 h post the injection of phentolamine mesylate (16 time points). Adverse events were closely observed all the time. Plasma phentolamine mesylate was detected using UPLC-MS/MS with isotope as internal standard. WinNolin 6.1 software was used to calculate the pharmacokinetic parameters. RESULTS: Time to peak concerntration (Tmax) ranged from 12 to 13 min. Half-time of elimination (t1/2) ranged from 3.84 to 4.07 h, with a clearance (CL) of 190 L/h. Peak concentration (Cmax), area under concentration-time curves from 0 to t hour and from 0 to infinite time (AUC0-t and AUC0-∞) increased proportionally in the dose range of 0.2 mg to 0.8 mg. The results of confidence interval analysis showed nearly linear dynamic characteristics for the injection of phentolamine mesylate. All participants experienced mild adverse events, including pain at the injection point, dizziness, and palpitations. These adverse events disappeared without treatments. CONCLUSIONS: Phentolamine mesylate injection is effective for reversing oral local anesthetic effects.

[Bioequivalence of Ubenimex Capsules in Healthy Volunteers].

OBJECTIVE: To evaluate bioequivalence of two specifications of ubenimex capsules in comparison with the Japanese branded product (R). METHODS: The study adopted a 3-way crossover design in twenty-four healthy male volunteers, whose plasma concentrations of ubenimex were determined by UPLC-MS/MS after administration a single oral dose of 30 mg of domestic ubenimex T1 (10 mg/capsule), T2 (30 mg/capsule) and branded ubenimex R (30 mg/capsule) sequentially. The bioequivalence was evaluated using WinNonlin6. 1 statistical analysis software. RESULTS: One volunteer was excluded because of failure to follow medication instructions. The main pharmacokinetic parameters of ubenimex of T1, T2 and R were as follows: C(max) (2 646.73 ± 454.09) ng/mL, (2 675.91 ± 474.32) ng/mL and (2 432.79 ± 544.32) ng/mL, respectively; T(max) (0.68 ± 0.23) h, (0.76 ± 0.19) h and (0.77 ± 0.26) h, respectively; AUC(0-t) (3 925.23 ± 478.34)(ng x h)/mL, (3 804.62 ± 448.84)(ng x h)/mL and (3 789.30 ± 443.15)(ng x h)/mL, respectively; AUC(0-∞)(3 938.31 ± 479.54)(ng x h)/mL, (3 817.26 ± 450.90) (ng x h)/mL and (3 800.90 ± 444.77) (ng x h)/mL, respectively; CL/F (7.72 ± 0.92) L/h, (7.97 ± 0.98) L/h and (7.99 ± 0.90) L/h, respectively; Vd (26.08 ± 9.20 )L, (25.65 ± 10.22) L and (26.03 ± 10.05) L, respectively. The relative bioavailability F(0-t) and F(0-∞) of T1 and T2 against the branded preparation R were (103.90 ± 9.19)% and (100.77± 9.36)%, and (103.93 ± 9.20)% and (100.79 ± 9.33)%, respectively. CONCLUSION: Both ubenimex capsules T1 and T2 are bioequivalent to the Japanese branded products.

[Pharmacokinetics study of injected doripenemin healthy volunteers].

OBJECTIVE: To study the pharmacokinetics of injected doripenem in Chinese healthy volunteers, in order to optimize dosages for patients. METHODS: Twelve healthy volunteers were recruited in the threecross Latin square designed study. Participants received intravenous infusions of 0.25, 0.5 and 1.0 g doripenem sequentially in three periods at a random order. Plasma and urine doripenem were measured by HPLC-UV, using an internal standard method with meropenem for plasma samples and an external standard method for urine samples, respectively. Phoenix WinNonlin 6.1 pharmacokinetic software was used to calculate non-compartment pharmacokinetics parameters. SPSS 19.0 software was used for statistical analysis. RESULTS: A single dose infusion of 0.25, 0.5 and 1.0 g doripenemin 60 min produced the following respective parameters: Cmax (11.81 +/- 1.52), (22.80 +/- 3.80) and (47.26 +/- 8.38) microg/mL, Tmax (60.42 +/- 1.44), (58.33 +/- 5.77) and (60.00 +/- 0) min, t(1/2) (63.48 +/- 10.51), (69.12 +/- 16.72) and (69.30 +/- 11.71) min, AUC(0-1), (1100.86 +/- 150.04), (2111.50 +/- 359.58) and (4359.50 +/- 789.38) microg/(mL x min). Linear Regression and Confidence Interval analyses suggested a linear kinetic characteristic. Doripenem was mainly excreted through kidneys, with 24 h cumulative urine excretion rates ranging from 70% to 75% for the three doses of infusions. It was safe to administer doripenem through infusion in healthy volunteers. Adverse reactions occurred in 19.44% cases of infusions, although all were mild reactions. Tinnitus happened in two cases (8.33%) of infusions, which required close observations. CONCLUSION: Doripenem infusion possesses a linear kinetics. There is no need to adjust the regimenpatients.

[Glycemic excursions in people with normal glucose tolerance in Chengdu].

OBJECTIVE: To investigate the characteristics of glycemic excursions in people with normal glucose tolerance (NGT) in Chengdu. METHODS: A total of 50 non-obese people with normal glucose tolerance (NGT, 23-68 years old), normal blood pressures and lipid profiles participated in the study. The fluctuations of glucose levels in the participants were measured by a continuous glucose monitoring system (CGMS) for three days 72 h. The 48 h mean blood glucose (MBG), mean amplitude of glycemic excursions (MAGE), Largest amplitude of glycemic excursions (LAGE), Postprandial peak glucose (PPG), Postprandial glucose excursion (PPGE), Mean of postprandial glucose excursion (MPPGE), and absolute means of daily differences (MODD) were measured. RESULTS: The number of glucose values detected by CGMS amounted to 861+/-7 with a mean absolute difference (MAD) of 11.3%+/-10.6%. The CGMS values were significantly correlated with the capillary glucose measurements (n=1076, r=0.761, P<0.005). The participants had a MBG of (5.9+/-1.2) mmol/L, a MAGE of (1.7+/-0.7) mmol/L, a LAGE of (4.4+/-1.9) mmol/L, a daily glycemic peak (PPG) of (8.7+/-1.7) mmol/L, a nadir level of (4.3+/-0.7) mmol/L, a MPPGE of (2.3+/-1.6) mmol/L, and a MODD of (0.75+/-0.79) mmol/L. The post-breakfast Postprandial glycemic excursions (PPGE) were lower than those of post-lunch and post-dinner (P=0.01 and P=0.05). The postprandial glucose excursions in the 60-70 year-old participants were the highest (P<0.022). In 95% (77%-100%) of the daytime, the glycose levels fluctuated between 4.1 and 8.8 mmol/L, and 78% of the participants (n=39) had hyperglycemia (BG>7.8 mmol/L) and 10% (n=5) had asymtomatic hypoglycemia (BG<2.8 mmol/L). CONCLUSION: CGMS tests may be important for detecting asymptomatic hyperglycemia and hypoglycemia. The NGT people in Chengdu have exhibited abnormal blood glucose values in CGMS, revealing problems in people with normal range of blood glucose.

Severe insulin allergy after percutaneous transluminal coronary angioplasty.

BACKGROUND: Insulin therapy is essential for type 1 and inadequately controlled type 2 diabetic patients. Insulin allergies have become less common since the introduction of highly purified human recombinant insulin. There are rare reports of severe insulin allergic reactions after percutaneous transluminal coronary angioplasty (PTCA) in patients with type 2 diabetes who had no previous allergic reactions. To better understand the causes and presentation of this rare acute reaction, we present the following observed case. CASE SUMMARY: A 63-year-old Chinese man (height, 172 cm; weight, 68.5 kg) with a 17-year history of type 2 diabetes and hypertension was first admitted to the West China Hospital, Sichuan University, Sichuan, People's Republic of China, for uncontrolled type 2 diabetes. He used regular human insulin, neutral protamine Hagedorn insulin, or premixed insulin without any allergic reactions. Four months later, PTCA was performed because of an acute myocardial infarction. The patient was administered 50 mg of protamine after active abdominal bleeding due to a right external iliac artery rupture. Three months later, recurrent raised, pruritic erythema occurred at the insulin injection site immediately after injection. Four weeks later, he experienced an attack of generalized urticaria at multiple previous injection sites (abdomen, upper arms, thighs) after injecting premixed insulin. It was accompanied by dizziness and palpitations. During the following 3 months, the symptoms recurred 3 times; one time, the patient reported losing consciousness for 2 to 3 minutes. The results of a skin prick test found that he was allergic to human recombinant insulin and insulin lispro. The allergy was resolved by changing his treatment regimen from insulin to oral hypoglycemic agents. A Naranjo score of 10 suggested a definite relationship (score >or=9) between the adverse drug reaction and the insulin administration. CONCLUSIONS: We present a definite case of allergy associated with insulin and insulin lispro administration. The patient had not experienced anaphylactic reactions prior to PTCA and protamine administration.

[The preliminary application of autologous platelet-rich gel used to treat refractory diabetic dermal ulcer].

OBJECTIVE: To assess the effectiveness and security of autologous platelet-rich gel (APG) in the treatment of refractory diabetic dermal ulcers. METHODS: Thirteen diabetic patients with refractory skin lesions were enrolled for this study, and APG was produced by platelet (PLT)-rich plasma (PRP) with thrombin and calcium gluconate. APG treatment consisted of wound dressed with APG, followed by topical washing and cleaning. The APG was then covered with Vaseline gauze and left for 48 to 72 hours, after which the wounds were treated conventionally until the next PLT-gel treatment. The clinical endpoints of the study were the healing rate. RESULTS: A total of 13 patients entered the pilot study. There were no drop-outs in the study. 69.2% ulcers were cured, and especially the ulcer areas were reduced significantly in the first 3 weeks; no adverse reactions were observed. CONCLUSION: Topical therapy with APG may be considered as an effective adjuvant method to treating refractory diabetic dermal ulcer.