Pharmacokinetics of EDP-420 after Multiple Oral Doses in Healthy Adult Volunteers and in a Bioequivalence Study

EDP-420 (also known as EP-013420, or S-013420) is a first-in-class bridged bicyclolide currently in clinical development for the treatment of respiratory tract infections (RTI) and has previously shown favorable pharmacokinetic (PK) and safety profiles after the administration of single oral doses of a suspension to healthy volunteers. Here we report its PK profile after the administration of multiple oral doses of a suspension to healthy adults. Bioequivalence between suspension and capsule formulations, as well as the effect of food, is also reported. The most important PK features of EDP-420 observed in these clinical studies are its long half-life of 17 to 18 h and its high systemic exposure, which support once-daily dosing and treatment durations potentially shorter than those of most other macrolide antibiotics. EDP-420 is readily absorbed following oral administration in both suspension and capsule formulations. In the multiple-oral-dose study, steady state was achieved on day 1 by using a loading dose of 400 mg/day, followed by 2 days of 200 mg/day. A high-fat meal had no effect on the bioavailability of EDP-420 administered in a capsule formulation. EDP-420 was well tolerated, with no serious or severe adverse events reported, and no subject was discontinued from the study due to an adverse event. Based on its human PK and safety profiles, together with its in vitro/in vivo activities against common respiratory pathogens, EDP-420 warrants further development, including trials for clinical efficacy in the treatment of RTI.Macrolides are currently used as a first-line treatment for respiratory tract infections (RTIs), including community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute sinusitis, pharyngitis/tonsillitis, and otitis media (5, 37). The extensive clinical usage of macrolides has resulted in the rapid emergence of macrolide resistance, particularly among streptococci, staphylococci, and enterococci (1, 13, 38). Thus, there is an urgent need to develop new antibiotics with activity against a broad spectrum of pathogens (especially resistant strains) commonly encountered in community-acquired RTIs. The design of EDP-420 (formerly known as EP-013420, or S-013420) was undertaken in response to this unmet medical need.EDP-420 represents a novel structural class of bridged bicyclolide antibacterial agents (36) (the structure is shown in Fig. ​Fig.1).1). It exhibits potent in vitro activities against RTI pathogens, including multidrug-resistant streptococci and the atypical pathogens (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila) (4, 10, 19, 24, 27-32, 34, 39). In vivo, EDP-420 has also demonstrated efficacy against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Mycobacterium avium in mouse protection tests, against S. pneumoniae and Haemophilus influenzae in a rat lung infection model, and against penicillin- and quinolone-resistant pneumococci in a rabbit meningitis model (2-4, 22, 23, 25, 32-34). The nonclinical pharmacokinetics (PK) of EDP-420 across multiple species displayed a long half-life as well as extensive distribution and uptake into respiratory tissue and fluids (14-17, 32, 33). Moreover, EDP-420 has previously shown favorable PK and safety profiles in healthy volunteers after single oral doses given as a suspension (18). Here, the PK of EDP-420 after multiple oral suspension doses in healthy adult volunteers is reported. In addition, since a capsule formulation was developed for use in phase II clinical trials, a separate clinical study was conducted to compare the PK and safety/tolerability of two formulations (i.e., capsule versus suspension) of EDP-420 in healthy adult volunteers. The potential effects of food on the oral bioavailability and systemic exposure of EDP-420 capsules were also investigated.Open in a separate windowFIG. 1.Structures of EDP-420 (top) and its gastric acidic degradant, EDP-420 9-keto (bottom).(The results of this study were presented in part at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 2007.)     

Safety and Pharmacokinetics of Multiple 750-Milligram Doses of Intravenous Levofloxacin in Healthy Volunteers

The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation.     

Mattis痴呆程度量表在血管性痴呆和Alzheimer病中的应用

目的：探讨Mattis痴呆程度量表评价血管性痴呆和Alzheimer病的作用。方法：应用Mattis痴呆程度量表对30例正常老年人，20例血管性痴呆病人和15例Alzheimer病人进行了测试。结果：血管性痴呆患者和Alzheimer病患者在启动和保存能力、概念形成能力和记忆力方面均有显著障碍（P＜0．05）。MDRS的注意力分测验、空间结构分测验在三组间未发现有统计学意义的改变。对早期血管性痴呆和Alzheimer病痴呆的区别上，MDRS的启动和保存分测验，记忆分测验的得分差异较大，尤以记忆障碍的改变突出。结论：对痴呆的评价中记忆功能的评价意义较大。     

Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (C_max) values were generally attained within 2 h postdose. The mean values of C_max and area under the concentration-time curve from 0 to 24 h (AUC_0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean C_max and AUC_0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These C_max and AUC_0–24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (V_ss/F), half-life (t_1/2), and renal clearance (CL_R) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, V_ss/F, t_1/2, and CL_R following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.     

阿尔茨海默病、血管性痴呆及轻度认知损害患者载脂蛋白E基因多态性分析

目的探讨载脂蛋白E（ApoE）基因多态性与阿尔茨海默病（AD）、血管性痴呆（VD）和轻度认知损害（MCI）的关系。方法收集AD、VD及MCI患者外周血检测ApoE基因型,进行χ²检验。结果所有患者中ε3/ε3基因型所占比例最大,未检测到ε2/ε2及ε4/ε4基因型。AD组ε3/ε4基因型（P=0.001）及ε4基因（P=0.013）高于MCI组。VD组ε4基因高于MCI组（P=0.044）。结论ApoE ε4基因与AD的关系最为密切,是AD的危险因素。但其与VD和MCI的关系尚需进一步研究。     

Pharmacokinetics of EDP-420 after Ascending Single Oral Doses in Healthy Adult Volunteers

EDP-420 (EP-013420, S-013420) is a first-in-class bicyclolide (bridged bicyclic macrolide) currently in clinical development for the treatment of respiratory tract infections. It has good preclinical pharmacokinetic properties across multiple species and potent in vitro and in vivo activity against respiratory tract infection pathogens, including Haemophilus influenzae, atypical organisms (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila), and multidrug-resistant streptococci. The safety, tolerability, and pharmacokinetics of an orally administered EDP-420 suspension in 40 healthy adult subjects were assessed in a randomized, double-blind, placebo-controlled, ascending single-dose study. Eligible subjects were sequentially randomized into one of five study groups (i.e., 100-, 200-, 400-, 800-, or 1,200-mg dosing groups) consisting of eight subjects (six active and two placebo) each. EDP-420 was well tolerated. There were no serious adverse events reported, nor were there any dose-limiting clinical or laboratory adverse events reported. EDP-420 was rapidly absorbed after a single oral dose. The mean plasma terminal half-life ranged from 15.6 to 20.1 h with low clearance. At the 400-mg dose, the area under the curve was 14.4 μg·h/ml, which well exceeded the required area under the concentration-time curve to cover common respiratory tract infection pathogens based on preclinical pharmacokinetic/pharmacodynamic modeling. The long half-life and high systemic exposure of EDP-420 support once-daily dosing and may allow for shorter treatment durations compared to other macrolide antibiotics. Based on its human pharmacokinetic profiles, taken together with its in vitro/in vivo activity against common respiratory pathogens, EDP-420 warrants efficacy trials for the treatment of respiratory tract infections.Macrolide antibiotics have been used effectively and safely as first-line treatments for respiratory tract infections (RTI) for more than 50 years (34). However, the incidence of worldwide resistance to antibiotics (including macrolide antibiotics) is increasing. For example, Streptococcus pneumoniae is the most commonly implicated bacterium in RTI, being responsible for 45% of the cases of community-acquired pneumonia and 34% of acute sinusitis (1, 2). Fully 31% of S. pneumoniae infections in the United States have yielded organisms resistant to the macrolide antibiotic erythromycin, and nearly one-third are resistant to penicillin. S. pneumoniae resistance is more common in Asia, where 80% of S. pneumoniae infections are erythromycin resistant, and 53% are penicillin resistant (11, 35, 38). Thus, there is an urgent need to develop new antibiotics with activity against a broad spectrum of pathogens (especially resistant strains) commonly encountered in community-acquired RTI (1, 11, 35, 38).EDP-420 (formerly EP-013420 and S-013420) is a novel bridged bicyclic macrolide antibiotic (the structure is shown in Fig. ​Fig.1)1) currently in clinical development for the treatment of RTI. It was designed specifically to combat atypical and respiratory tract pathogens that have acquired resistance to macrolide antibiotics. EDP-420 has a unique 6,11-O-bridging moiety, with replacement of the cladinose sugar by a 3-keto group (33). RNA footprinting suggests that EDP-420 binds near the entrance to the peptide exit tunnel of the 50S ribosomal subunit from E. coli and forms interactions with both domain V and domain II of 23S rRNA (36). The additional binding motif to the 50S ribosomal subunit (i.e., a second binding site along the 23S rRNA hairpin loop 35 of domain II) provided by the 6,11-O-bridging moiety should help overcome macrolide, lincosamide, and streptogramin B resistance, resulting in an improved structure-activity relationship.Open in a separate windowFIG. 1.Structure of EDP-420.EDP-420 exhibits potent in vitro activities against RTI pathogens, including multidrug-resistant streptococci and atypical organisms (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila) (21, 28, 31). For example, MIC₉₀ (i.e., the MIC required to inhibit the growth of 90% of organisms) for EDP-420 against 115 strains and 100 clinical isolates of S. pneumoniae, including macrolide-resistant strains carrying mefA and/or ermB genes, was 0.25 μg/ml, which is comparable to that of telithromycin (MIC₉₀ = 0.125 μg/ml) and significantly better than that of clarithromycin, azithromycin, and erythromycin (MIC₉₀ > 64 μg/ml) (37). The antibacterial activity of EDP-420 against S. pyogenes carrying constitutive type ermB was 32 times more potent than that of telithromycin (27). EDP-420 is potent against methicillin-susceptible Staphylococcus aureus, including strains with inducible type ermA/C (27). The MIC₉₀ of EDP-420 against Legionella spp. was 0.031 μg/ml, which is comparable to that of levofloxacin and significantly more active than erythromycin and azithromycin (9, 24). In one study, 80% of S. pneumoniae strains (10 strains, including an erythromycin-resistant strain) and all of the Haemophilus influenzae strains (10 strains) tested showed minimum bactericidal concentration/MIC ratios of <4, and EDP-420 killed more than 99.9% of viable cells of S. pneumoniae and of H. influenzae at 2× the MIC within 4 h (21). The postantibiotic effects of EDP-420 on two strains of H. influenzae, SR24159 and SR1280, lasted 4.3 and 2.2 h, which exceed and were comparable to the corresponding values for clarithromycin (2.0 and 0.2 h) and telithromycin (4.3 and 2.3 h), respectively (21). The growth of H. influenzae in the infected epithelial layers was still inhibited 12 h after the removal of EDP-420; however, bacterial growth resumed almost immediately after the removal of clarithromycin, telithromycin, and levofloxacin (26). EDP-420 showed potent intracellular activity and persistent effects against L. pneumophila both in the alveolar epithelial cells and in the bone marrow macrophages (25).In vivo, EDP-420 also demonstrated efficacy against S. pneumoniae, S. pyogenes, S. aureus, and Mycobacterium avium in mouse protection tests; against S. pneumoniae and H. influenzae in a rat lung infection model; and against penicillin- and quinolone-resistant pneumococci in a rabbit meningitis model (3-6, 17, 19, 20, 22, 28, 30, 31). The oral mean effective doses of EDP-420 sufficient to protect 50% of the mice (ED₅₀) from lethal infection were 2.93, 3.27, 3.12, and 2.12 mg/kg against S. pneumoniae SR16605, S. pneumoniae SR20946 (ermB), S. pneumoniae SR26113 (ermB), and S. pyogenes C-203, respectively, while telithromycin required higher doses of 3.07, 16.5, 3.65, and 4.24, respectively (31). The in vivo efficacy of EDP-420 against rat lung infection caused by H. influenzae SR11925 and SR1280 was comparable to that of telithromycin (31). EDP-420 nonclinical pharmacokinetics (PK) across multiple species displayed a long half-life, as well as extensive distribution and uptake into respiratory tissue and fluids (12-15, 28, 30). The preclinical safety results and good PK properties, along with the in vivo antimicrobial profiles and results of the efficacy studies in animals, supported the decision to begin phase 1 testing in healthy adult volunteers.(This study was presented in part at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, in September 2007.)     

Pharmacokinetics,Pharmacodynamics, and Tolerability of GS-9851, a Nucleotide Analog Polymerase Inhibitor,following Multiple Ascending Doses in Patients with Chronic Hepatitis C Infection

We conducted this double-blind, parallel-group, placebo-controlled, randomized, multiple-ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-9851 (formerly PSI-7851) in treatment-naïve patients infected with hepatitis C virus (HCV) genotype 1. Thirty-two patients received active doses up to 400 mg of GS-9851 once daily for 3 days. GS-9851 and the metabolite GS-566500 (formerly PSI-352707) were rapidly cleared from the plasma, with half-life (t_1/2) values of approximately 1 h for GS-9851 and 3 h for GS-566500. Accumulation (21%) was observed only for GS-331007 (formerly PSI-6206) after multiple dosing. GS-331007 was the primary drug-related moiety in the plasma and urine. Increases in the GS-9851, GS-566500, and GS-331007 maximum concentrations in plasma (C_max) and area under the concentration-time curve (AUC) were less than dose proportional, particularly at the highest doses. The decline in plasma HCV RNA levels was dose dependent, and a mean maximal change from the baseline of −1.95 log₁₀ IU/ml was obtained for 400 mg GS-9851, compared with −0.090 log₁₀ IU/ml for the placebo. Most patients had a decrease in HCV RNA of ≥1.0 log₁₀ IU/ml after 3 days'' dosing with 400 mg GS-9851. No virologic resistance was observed. GS-9851 was generally well tolerated, with no notable differences in adverse event frequency across doses. The pharmacokinetic profile observed in this study was similar to that seen in a single-ascending-dose study in healthy subjects.     

Pharmacokinetics,Safety, and Tolerability of Faldaprevir in Patients with Renal Impairment

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC_0–∞) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number {"type":"clinical-trial","attrs":{"text":"NCT01957657","term_id":"NCT01957657"}}NCT01957657.)     

Safety,Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers

Neuropathic pain affects ~ 6.9–10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, and pharmacokinetics of a voltage‐dependent and use‐dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo‐controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7‐day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (C_max), area under the concentration‐time curve from predose to 24 hours postdose (AUC_0–24), time to C_max (T_max), and terminal half‐life (t 1/2), among others, were assessed. Drug‐related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug‐related AE. SAD results showed that C_max and AUC increased with dose, T_max was 1–2 hours, and t _1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady‐state was achieved from day 5 onward. These data indicate that oral vixotrigine is well‐tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Neuropathic pain is a common condition; available treatments are of limited effectiveness and have multiple drug interactions and tolerability issues.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ These 2 phase I studies investigated the safety, tolerability, and pharmacokinetics (PKs) of vixotrigine administered as a single dose or in multiple doses in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ This study describes the safety, PKs, and tolerability of a voltage‐dependent and use‐dependent sodium channel blocker being developed for neuropathic pain conditions.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ These results support the further clinical development of vixotrigine, inform on dosing for clinical trials in individuals with neuropathic pain, and test the potential benefit of voltage‐dependent and state‐dependent sodium channel blockade in the treatment of neuropathic pain.

Neuropathic pain can arise from a lesion or disease of the somatosensory system, including peripheral fibers (Aβ, Aδ, and C fibers) and central neurons. ¹ The signs and symptoms of neuropathic pain include allodynia, spontaneous paroxysmal pain, hyperalgesia, and, on occasion, causalgia or incessant burning pain. ² The estimated prevalence of neuropathic pain in the general population is 6.9–10%. ³ Substantial impairment of quality of life is caused due to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. ¹ Voltage‐gated sodium channels (Navs) are complex transmembrane proteins responsible for the initiation and propagation of action potentials in neurons. ⁴ Gain‐of‐function changes produced by missense substitutions in the genes encoding Nav1.7–1.9 have been implicated in human pain syndromes through genetic studies. ^{5 , 6} Loss‐of‐function autosomal recessive mutations in the gene encoding the α‐subunit of Nav1.7 result in congenital insensitivity to pain. ^{5 , 7} Sodium channel subtype Nav1.7 is expressed in peripheral sensory neurons innervating skin, viscera, and dorsal root and trigeminal ganglia in the orofacial region, together with sympathetic neurons and olfactory epithelia. ⁸ Nav1.8 is a tetrodotoxin‐resistant subtype, expressed in nociceptive sensory neurons. ⁸ Nav1.9, the most recently identified Nav subtype, is a marker of primary nociceptors, also expressed in the enteric nervous system. ⁸ Carbamazepine, which is known to target Nav channels, is used to treat neuropathic pain, in particular trigeminal neuralgia (TN), ^{2 , 9} although use is limited due to poor tolerability, need for titration, and potential pharmacological interactions. ⁹ Thus, there is a need for effective and well‐tolerated treatments for neuropathic pain.Vixotrigine is a voltage‐dependent and use‐dependent Nav channel blocker ¹⁰ currently under investigation for neuropathic pain conditions, including painful small fiber neuropathy and TN. ^{11 , 12} Several preclinical studies of vixotrigine have been completed to date. In rats, oral vixotrigine administered at 0.1–5 mg/kg produced a dose‐related reversal of Freund’s complete adjuvant‐induced hypersensitivity to pain as measured by weight bearing. In this study, the minimum effective dose resulting in 50% of the maximum response was 1 mg/kg (Biogen, data on file). Following a single oral dose of ¹⁴C‐labeled vixotrigine in Sprague‐Dawley rats at a target level of 30 mg freebase/kg, drug‐related material was eliminated via urine (mean 58.1% of the dose) and feces (mean 35.9% of the dose). Elimination was rapid, with a mean of 92.9% of the dose recovered by 24 hours postdose (Biogen, data on file).Here, we report the findings of 2 clinical studies designed to investigate the safety, tolerability, and pharmacokinetics (PKs) of vixotrigine in healthy volunteers, following either single escalating doses or repeat dosing. In addition, the effect of food on vixotrigine PK parameters was investigated in the repeat dosing study.     

Safety, Pharmacokinetics, and Antiretroviral Activity of Multiple Doses of Ibalizumab (formerly TNX-355), an Anti-CD4 Monoclonal Antibody, in Human Immunodeficiency Virus Type 1-Infected Adults

Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log₁₀) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4⁺ T-cell receptors was correlated with serum ibalizumab concentrations. There was no evidence of CD4⁺ T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.     

Safety and Pharmacokinetics of the Antiorthopoxvirus Compound ST-246 following Repeat Oral Dosing in Healthy Adult Subjects

ST-246, a novel compound that inhibits egress of orthopoxvirus from infected cells, is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, placebo-controlled, escalating multiple-dose study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral dose of 250, 400, or 800 mg for 21 days to nonfasting healthy human volunteers. ST-246 appeared to be well tolerated, with no serious adverse events (AEs). Headache, for which one subject in the 800-mg group discontinued the study, was the most commonly reported AE in all treatment groups. The multiple-dose pharmacokinetics of ST-246 was well characterized. The day 21 mean elimination half-lives were calculated at 18.8, 19.8, and 20.7 h for each of the 250-, 400-, and 800-mg/day dose groups, respectively. Steady state was reached by day 6 (within 3 to 5 half-lives), saturable absorption was observed at the 800-mg dose level, and the fraction of parent drug excreted in the urine was very low. Based on these results, administration of 400 mg/day ST-246 can be expected to provide plasma concentrations above the efficacious concentration demonstrated in nonhuman primate models in earlier studies.Human orthopoxviruses cause a spectrum of diseases ranging from severe disseminated lesional disease characteristic of the most common type of variola virus infection (variola major) to localized lesional infection caused by vaccinia virus. Of the several species of orthopoxvirus known to infect humans, variola virus, the etiological agent of smallpox, causes far more serious infections than the other species of poxviruses (3). While variola virus no longer exists in the environment, other orthopoxviruses continue to circulate and cause disease. Monkeypox virus, which is endemic in some areas of the Democratic Republic of the Congo, causes a zoonotic disease that is characterized by a generalized infection resembling a milder version of smallpox (7). Vaccinia-like viruses have been isolated from patients in Brazil presenting with localized lesions of the hands and arms (10), and cowpox virus infections are increasing in certain parts of Europe (11). These viruses are believed to be maintained in the population through rodent reservoirs, and zoonotic disease is thought to arise from contact with infected animals or through an intermediate species such as cattle or domestic pets (7, 11). Disease severity in all cases is influenced by the status of the host immune system, with individuals who suffer from certain skin disorders or who are immunocompromised developing the most severe infections (2, 3).There are currently no U.S. Food and Drug Administration-approved therapies other than early vaccination that can alter the outcome of disease or potentially prevent disease in a population that has been exposed to pathogenic orthopoxviruses (4, 6). Because vaccination has a lag period for antibody formation and carries the risk of certain severe side effects, and because it is not universally available to all who might potentially need it, there is clearly a need for a safe, small-molecule, oral medication that is highly active against variola virus and possibly other zoonotic poxviruses, such as monkeypox, cowpox, and vaccinia-like viruses.ST-246 is a low-molecular-weight compound {Tecovirimat; 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benzamide} that was discovered through a deliberate effort to develop orally available antiviral drugs for use in biodefense (1, 12). ST-246 is chemically unrelated to any substance currently approved for human use for human or veterinary applications. In a number of animal studies, oral administration of ST-246 not only protected nonhuman primates from variola and monkeypox viruses but also protected mice from lethal infection with vaccinia virus, cowpox virus, and ectromelia virus (8, 12) and squirrels from severe monkeypox disease (9), implying that ST-246 could also be used to control vaccination complications and to prevent or treat zoonotic poxvirus disease.Safety pharmacology studies of mice and nonhuman primates demonstrated that ST-246 was well tolerated after a 28-day multiple-dose administration with a no-observable-effect level (NOEL) of 2,000 mg/kg and 300 mg/kg for mice and nonhuman primates, respectively. A phase I clinical study was conducted to determine the safety, tolerability, and clinical pharmacokinetics (PK) of ST-246 administered orally as a single dose of 500, 1,000, or 2,000 mg (fasting) or 1,000 mg (nonfasting) to healthy human volunteers (5). The study concluded that ST-246 at these dose levels was safe and well tolerated. The pharmacokinetics in plasma showed dose proportionality over 500- and 1,000-mg dose levels but not over 1,000- and 2,000-mg dose levels. At the 1,000-mg dose level, nonfasting subjects had greater apparent maximum concentration of drug in serum (C_max), time to maximum concentration of drug in serum (T_max), and area under the curve from zero hour to infinity (AUC_0-∞) than fasting subjects (5).Based on these results, and given the variability in exposure levels in both monkeys and humans in the nonfasting and fasting states, it has been predicted that doses of 400 mg and 800 mg for humans who are nonfasting will encompass plasma drug exposure levels comparable to those that provide protective efficacy in the nonhuman primate model of orthopoxvirus disease. The purpose of this study was to determine the safety, tolerability, and clinical pharmacokinetics of ST-246 when administered orally as a single dose of 250, 400, or 800 mg every day for 21 days to nonfasting healthy human volunteers.     

长春西汀治疗血管性痴呆认知功能障碍的疗效观察

目的：探讨长春西汀对血管性痴呆（VD）患者认知功能障碍的治疗作用。方法：VD患者42例随机分为长春西汀组和对照组各21例,分别给予长春西汀和胞二磷胆碱治疗,治疗前后分别测定2组患者的瑞文测验联合型（CRT）及临床记忆量表（CMS）评分。结果：长春西汀组治疗前后有显著性差异,而对照组无明显好转。结论：长春西汀对改善VD患者的认知障碍具有显著疗效。     

Pharmacokinetics of a New Anticonvulsant (CGP 33101) in Epileptic Male Patients and Healthy Male Subjects after Single Ascending Oral Doses of 400--1200 mg

Information on the pharmacokinetic behavior of a new anticonvulsant agent (CGP 33101) was obtained after oral administration of ascending doses to male epileptic patients maintained on existing antiepileptic drug (AED) therapy, as well as to healthy male subjects. Single doses of 400, 800 and 1200 mg were administered to 12 of the 16 epileptic patients participating in the clinical trial and all 3 healthy subjects; the remaining patients received placebo doses on each dosing occasion. The study's primary objectives were to obtain single-dose add-on tolerability information, as well as preliminary pharmacokinetic data for the drug candidate. Either placebo or 400, 800 and 1200 mg of the compound, administered as 200-mg tablets, were coadministered with enzyme-inducing antiepileptic medications to the patients participating in the trial. These AEDs dilantin, tegretol, depakote, mysoline and tranxene) were administered individually or as combination therapy of two or three, with each patient being on the existing therapy for a minimum of 3 weeks prior to receiving the drug candidate (CGP 33101) as an add-on. Three healthy male subjects were included in the study to provide concurrent pharmacokinetic data at equivalent doses, as well as additional safety data in the absence of concomitant medication. Plasma concentrations of the new drug candidate were determined in samples obtained predose through 120-h postdose, with a 5-day washout period between doses. Preliminary pharmacokinetic parameters, such as peak plasma concentrations (C(max), times to peak levels (T(max)), areas under the plasma concentration-time curve (AUC) and terminal half-lives (T(1/2)), were determined in both epileptic patients and healthy subjects following all three doses. The mean T(max) values were similar for all three dose levels in both patients and subjects, indicating that the rate of absorption was comparable. Mean C(max) values increased in a dose-related manner with increasing dose in epileptic patients. The corresponding values showed a dose-proportional relationship in healthy subjects. The relationship between C(max) values and the administered dose did not change in patients or subjects when the data was corrected for dose and/or body weight. After the peak, plasma levels declined, but were still quantifiable in most patients and subjects at 36 h following all three doses. The mean AUC values increased in a dose-proportional manner with increasing dose in healthy subjects. The corresponding mean patient data appeared to increase in a dose-related manner. The relationship between AUC values and size of the administered dose did not change in either patients or subjects when the data was corrected for dose and/or body weight. The terminal elimination half-lives (T(1/2)) were apparently shorter in patients compared to the healthy subjects and were independent of the close administered.     

Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor, following Oral Administration of Single Doses to HIV-Infected Adults

We conducted a double-blind, placebo-controlled, parallel, dose-escalation trial to evaluate the pharmacokinetics and safety of single, oral doses of amprenavir (141W94; formerly VX-478), a potent inhibitor of human immunodeficiency virus (HIV) type 1 protease, administered as hard gelatin capsules in 12 HIV-infected subjects. The doses of amprenavir evaluated were 150, 300, 600, 900, and 1,200 mg. Amprenavir was rapidly absorbed, with the time to maximum concentration occurring within 1 to 2 h after dosing. On the basis of power model analysis, the increase in the maximum concentration of amprenavir in plasma (Cmax) was less than dose proportional, and the increase in the area under the concentration-time curve from time zero to infinity (AUC0-infinity) was greater than dose proportional; mean slopes (with 90% confidence intervals) were 1.25 (1.16 to 1.35) and 0.78 (0.78 to 0.86) for AUC0-infinity and Cmax, respectively. Amprenavir was eliminated slowly, with a terminal-phase half-life of 8 h. A second study was conducted to determine the bioavailability of the hard gelatin capsule relative to that of a subsequently developed soft gelatin capsule. The capsules were bioequivalent in terms of AUC0-infinity but not in terms of Cmax; geometric-least-squares means ratios (with 90% confidence intervals) were 1.03 (0.92 to 1.14) and 1.25 (1.03 to 1. 53) for AUC0-infinity and Cmax, respectively. Administration of soft gelatin capsules of amprenavir with a high-fat breakfast resulted in a 14% decrease in the mean AUC0-infinity (from 9.58 to 8.26 microg. h/ml), which is not likely to be clinically significant. The most common adverse events related to amprenavir were headache, nausea, and hypesthesia. Amprenavir appears to be safe and well tolerated over the dose range of 150 to 1200 mg. On the basis of the present single-dose studies, amprenavir is an HIV protease inhibitor with favorable absorption and clearance pharmacokinetics that are only minimally affected by administration with food.     

Safety,Pharmacokinetics, and Pharmacodynamics Study in Healthy Subjects of Oral NEO6860, a Modality Selective Transient Receptor Potential Vanilloid Subtype 1 Antagonist

Most previous transient receptor potential vanilloid subtype 1 (TRPV1) antagonist programs have been put on hold, mainly because of on-target adverse events: hyperthermia and impaired noxious heat sensation. NEO6860 is a TRPV1 antagonist, blocking capsaicin activation of the target, with little or no effect against pH or heat activation. The hypothesis is that this pharmacological profile will translate into analgesia without undesired effects on the body temperature or heat-pain threshold. This phase I, double blind, placebo controlled, ascending dose study, included 64 subjects. Pharmacodynamics (intradermal capsaicin test) was explored. The study was comprised of 6 dose levels (50, 100, 200, 400, 800, and 1,200 mg) and 2 doses of 500 mg, 12 hours apart. NEO6860 was rapidly absorbed and systemic exposure increases were less than dose proportional. Median time of maximum observed plasma concentration values ranged from 2 to 3 hours. The mean apparent plasma terminal elimination half-life was between 4 and 8 hours. No significant food-effect or gender-effect was observed. The most frequently reported events were feeling hot, headache, paresthesia, nausea, and dizziness. Single oral doses of up to 800 mg and two 500-mg doses administered 12 hours apart of NEO6860 were well tolerated in this study. Unlike other TRPV1 antagonists, no clinically significant increase in temperature or heat pain threshold/tolerance was noted despite thorough and specific monitoring of these parameters. At all doses, most subjects reported a sensation of “feeling hot,” with a rapid onset and transient. NEO6860 showed an improvement in the pharmacodynamics parameters (evoked pain and secondary hyperalgesia) at 3 and 8 hours post NEO6860 dosing.

Safety and Pharmacokinetics of the Anti-Orthopoxvirus Compound ST-246 following a Single Daily Oral Dose for 14 Days in Human Volunteers

ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (C(max)) and relative exposure for each dosing interval (AUC(τ)) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application.     

脑脊液中SS、AVP、β-EP、NSE与血管性痴呆的相关性研究

目的:探讨脑脊液(CSF)中生长抑素(SS)、精氨酸加压素(AVP)、β-内啡肽(β-EP)、神经元特异性烯醇化酶(NSE)与血管性痴呆(VD)的相关性并评定其对VD早期诊断的价值。方法:选择VD患者(VD组)60例,无痴呆脑梗死患者(CI组)70例及健康人(对照组)30例,运用简易精神状态量表(MMSE)、Hachinski缺血量表(HIS)和社会功能活动调查(FAQ)评定VD组患者认知功能;用放射免疫分析法(RIA)测定3组CSF中SS、AVP、β-EP含量,用双抗体免疫夹心法(ELISA)测定CSF中NSE含量。结果:与对照组比较,VD组CSF中SS、AVP、β-EP、NSE含量均显著降低(P<0.01),而CI组CSF中AVP、NSE显著增高(P<0.01),SS、β-EP有所下降(P>0.05);VD组CSF中SS、ANP、β-EP及NSE含量均明显低于CI组(P<0.01);VD组CSF中SS、AVP、β-EP、NSE含量随痴呆程度的加重而递减(P<0.01)。结论:CSF中SS、AVP、β-EP、NSE的含量下降与VD病情程度呈正相关。这些指标的监测有助于VD的早期诊断,亦可作为判断病情轻重的重要依据。