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12U LAKE JACKSON TIDE '99 Try-outs
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Lake Jackson Tide '99 Try-Outs
We are a first year 12U team looking for all positions. Our team wants hardworking, self-motivated girls with great attitudes. Not only should the girls be dedicated and committed but also the parents and families that support them. We believe the key to a great team is not only the players but their families - it is truly a team effort.
We will have try-outs on Wednesday, January 12 at 7:00 and Saturday January 15 at 1:00 on Field 1 at the Lake Jackson Softball complex.
Please call (979) 388-0441 or email email@example.com if you want to attend or request a private try-out. All try-outs are confidential.
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text:
Health Service
Food and
Drug Administration
Rockville, MD 20857
Date: February 20, 2002
To: Antiviral Drug Products Advisory Committee Members
and Guests
From: Pleconaril Review Team
Through: Debra Birnkrant, MD
Director, DAVDP
Re: Background Package for NDA 21-245: PicovirÔ (pleconaril)
memorandum serves as an introduction to the FDA presentation at the upcoming
March 19, 2002, meeting of the Antiviral Drug Products' Advisory Committee
(AVAC). At this meeting we will ask you to discuss the NDA for ViroPharma's
PicovirÔ (pleconaril) for the
treatment of acute picornaviral viral respiratory infection (VRI, "common
cold") in adults.
The background materials from FDA
represent the findings and opinions of the primary reviewers of each
discipline, based on their reviews of the respective submissions from
ViroPharma. It must be emphasized that this document represents the review
team's preliminary findings, and that no regulatory decision has been made on
the status of the application. Indeed,
the advice the AVAC provides will be critical in our regulatory decision making.
Pleconaril represents the
first antiviral drug to be considered for approval for treatment of the common
cold. Currently, only treatments that target individual symptoms of VRI are
approved, e.g., analgesics, antihistamines, and decongestants. Under the Food,
Drug and Cosmetics Act (FD&C Act), the FDA approves drugs based on
"substantial evidence" of safety and effectiveness. A recommendation for
approval by the committee needs to take into account the FD&C Act's
evidentiary standard and the overall risk/benefit ratio for the drug in question.
In the case of pleconaril, the risk/benefit consideration relates to the
identification of infected patients, the variability of efficacy results, the
efficacy results in smokers versus non-smokers and males versus females, and
the overall safety profile of pleconaril.
Beyond the overall examination of the safety and efficacy data for pleconaril, some critical issues for you to consider as you read the Agency information and Applicant's background materials include the study results, indication, resistance, and whether additional data would be necessary to support approval. We look forward to a very interesting meeting and thank you in advance for your time and efforts in this important meeting.
will ask you to consider the following issues during your deliberations on this
Variable Study Results
In two large phase 2 studies (843-020 and 843-032), pleconaril produced a median 0.0 to 0.5 day treatment effect in both the all randomized (ITT) patient population and those subjects the applicant determined to be picornavirus infected (PCR+, ITT-I). Low rates of PCR positivity, high rates of concomitant cold medication use, the inclusion of smokers, and a stringent endpoint which required all symptoms to have completely resolved may have contributed to the lack of a clearly demonstrated treatment effect in the phase 2 program.
Studies 843-043 and 843-044 were identically designed, multi-center, double-blind, randomized, placebo-controlled phase 3 studies. For the primary endpoint, the treatment effect for pleconaril was a median of 0.5 (study 843-043) and 1.5 days (study 843-044) compared to placebo. In both studies, the difference between pleconaril and placebo was statistically significant in the ITT-I population. In the ITT population, the difference reached statistical significance only in study 843-044.
rhinoviral infection is generally a mild, self-limited illness that typically
subsides in adults in 7 to 11 days, depending on the reference cited. The median time to resolution of VRI in
patients treated with pleconaril in the two pivotal trials ranged from 6.0 and
8.0 days, depending on how the analyses handled patients who did not have
resolution of their VRI or who prematurely discontinued; however, the overall
treatment effect was maintained.
Multiple secondary clinical endpoints were analyzed and included: time to patient assessment of no illness, time to reduction in symptom severity and resolution of individual symptoms, tissue use[1], time to return to baseline activity level, and the impact of concomitant cold symptom relief medication use.
generally places the greatest emphasis on the primary endpoint. Secondary
endpoints may be supportive but results should be interpreted with caution because
of large numbers of potential comparisons, required adjustments for p values,
and, in some cases, the small number of patients included in some analyses. In
general, most secondary endpoints showed similar trends in favor of pleconaril
as observed for the primary endpoint.
Randomization was stratified on smoking history; 30% of study patients were classified as smokers. Compared to non-smokers, smokers experienced an overall longer duration of VRI. For smokers, time to resolution of symptoms was numerically greater in the pleconaril group compared to the placebo group.
Gender analysis is required under FDA regulations. Analysis by gender demonstrated that the magnitude of the treatment effect among men was 0.4 days and in women it was approximately 1.0 day.
studies were conducted in young, healthy individuals. Phase 1 studies suggest
that no dose adjustment would likely be necessary when pleconaril is administered
to elderly (>65 years) patients.
In the pivotal studies, only 4% of patients were >65 years of
age or older which precluded an assessment of safety or efficacy in this
population. There are no data on treatment of patients with underlying cardiovascular,
pulmonary disease, patients with allergic rhinitis, or patients who are
immunocompromised or otherwise seriously ill. Pediatric VRI treatment trials
are ongoing.
applicant proposes the picornavirus-infected patients (PCR+), designated ITT-I,
as the primary population for assessing efficacy. Arguably, the all randomized
population (ITT) is also a valid population for assessing efficacy since
pleconaril will be prescribed based on presenting symptoms without a readily
available PCR assay.
of the NDA raised a number of questions about the methods employed to identify
picornavirus-infected patients. The applicant states that 65% of patients in
the two pivotal trials were infected with picornaviruses (PCR+). Infected patients were identified by an
experimental TaqMan assay. TaqMan negative samples were subsequently tested for
picornavirus using an experimental ELOSA system. All PCR+ samples were
subsequently cultured in a rhinovirus-specific culture system; 63% of PCR+
samples were culture positive. Methodological questions include:
Primer and probe selection. The probe sequence submitted by ViroPharma contains a region of eight consecutive Gs and Cs, while the primer sequences each contain three Gs and/or Cs and on one primer these are consecutive. Tighter binding by these primers may inhibit primer dissociation and could lead to variable PCR products.
Number of cycles. The TaqMan assay is run for a total of 60 cycles. The 60-cycle reaction could allow for an increase in non-specific amplification in samples that contain weakly homologous regions. Any non-specific amplification could also have an adverse effect on the sensitivity and specificity of the assay.
Determination of threshold
fluorescence level for detection of picornarvirus PCR. The threshold set by the
applicant was 0.1. Based on information
from the manufacturer of the assay (ViroMed), this threshold level may be too
low and a more appropriate threshold might be in the range of 0.4 – 0.6. Thus, incorrect threshold placement could
result in an incorrect assay definition of positivity. Also, a low threshold
value could subject individual samples to assay background that could impact
the relative quantitative results of the assay.
Additional studies to assess the performance of the TaqMan assay to identify picornavirus-infected patients are ongoing and results are expected in early March; these data will be available for discussion at the AVAC meeting. (For additional discussion about these issues, please see Appendix A).
Approximately 24% of isolates examined exhibited either
a baseline lack of susceptibility (13%) or a loss of susceptibility (10.7%) to
pleconaril against picornaviruses.
The adult VRI safety database includes information on 2,488 patients who received at least one dose of pleconaril. Of these, 1,046 patients received the proposed regimen, 400 mg TID for 5 days (15 doses), using the proposed commercial tablet formulation. Nearly 2,000 patients received placebo in VRI studies with the tablet being of the same composition without the active ingredient.
Gastrointestinal events (abdominal pain, nausea, vomiting, and diarrhea), and headache were the most common adverse events reported in the adult VRI safety database, with headache occurring slightly more frequently among patients who received pleconaril. There were no significant laboratory abnormalities identified.
Menstrual Disorders
There was a significantly higher rate of menstrual abnormalities in women treated with pleconaril while taking estrogen/progestin-based oral contraceptives (OC) compared to women taking OCs and placebo. The frequency for pleconaril/OC users was 2.4% in 5-7 day treatment trials compared to <1% for placebo/OC users. In a six-week VRI prevention study, the frequencies were 53%, 69%, and 25% among women taking OCs with pleconaril 400 mg QD, 400 mg BID, and placebo, respectively. This will be discussed in greater detail in section V, below.
In a theophylline/pleconaril interaction study, three of 15 subjects experienced tachycardia and palpitations when the two drugs were co-administered. In this study, subjects were naïve to theophylline prior to enrollment.
Patients in the clinical trials were otherwise healthy adults with no history of underlying cardiovascular or pulmonary disease. Palpitations and/or tachycardia with and without dizziness or syncope were reported by seven patients treated with pleconaril (0.3%) compared to two treated with placebo (0.1%). Four of the pleconaril-treated patients discontinued from studies due to these events.
The original pleconaril IND was filed June 23, 1993 by Sterling Winthrop and transferred to ViroPharma on July 5, 1995.
Pleconaril had been investigated as a treatment for enteroviral meningitis. Difficulty in identifying a correct dose, identifying patients with enteroviral meningitis with a PCR assay, determining an objective endpoint, and the inability to consistently demonstrate a treatment effect led to termination of development for this indication. Likewise, the applicant investigated pleconaril as a possible treatment for pediatric hand, foot, and mouth disease, but was not able to establish efficacy.
of pleconaril for treatment of acute VRI followed results of a study in which
it appeared that prophylactic administration of pleconaril reduced the severity
and duration of VRI in a coxsackie A-21 prevention study. Subsequently, the
applicant conducted multiple phase 2 studies to assess pleconaril's activity in
patients with VRI, and to prevent asthma exacerbations in patients with VRI.
NDA contains data from six clinical trials, including two pivotal studies
(843-043 and 843-044). Both pivotal studies were identical in design, and were
conducted during the same time period (September-December 2000), in a similar
geographic distribution (US and Canada). Both studies evaluated the safety and
efficacy of pleconaril versus placebo in patients presenting with symptoms
consistent with a viral upper respiratory tract infection.
studies 843-010, 843-020, and 843-032 investigated various doses (200 mg and
400 mg) and dosing schedules (BID or TID for 5 or 7 days) in patients who
presented with symptoms of a VRI. Study
843-013 attempted to evaluate pleconaril's utility in preventing acute
exacerbations in patients with a VRI and a history of asthma. A summary of the six trials included in the
NDA is presented in Table 1.
Table 1. Adult VRI Studies
No. |
Design |
Regimens |
Patients |
1o Endpoint |
843-010 |
Double-blind, randomized, |
200 mg TID 7 days |
Pleconaril |
to complete resolution of all symptoms (score of 0) for 48 hours |
843-013 |
Double-blind, randomized, |
200 mg TID 7 days |
Pleconaril |
Number and proportion of
patients with an asthma exacerbation |
843-020 |
Double-blind, randomized, |
400 mg BID 7 days |
Pleconaril: BID: 335 TID: 349 Placebo: 340 |
Time to complete
resolution of the signs and symptoms of VRI (symptom score of 0) sustained
for 48 hours |
843-032 |
Double-blind, randomized, |
400 mg TID 7 days |
Pleconaril: 436 |
Time to alleviation of all VRI symptoms sustained for 24 hours |
843-043 843-044 |
Double-blind, randomized, |
400 mg TID 5 days |
(843-043) Pleconaril: 526 Placebo: 526 (843-044) Pleconaril: 520 Placebo: 524 |
Time to resolution of rhinorrhea and alleviation (absent or mild) of other VRI symptoms without use of concomitant cold medications for 48 hours |
a review of the design and results of studies 843-010, 843-013, 843-020, and
843-032, please see Appendix B.
The applicant selected 400 mg (2 x 200 mg capsules)
TID for five days (15 doses) as adequate for the inhibition of picornaviral
replication in the treatment of VRI. For additional information on
pharmacokinetics, dose, and regimen, please see Appendix C.
B. Phase 3 Studies 843-043 and 843-044
Study Design and
Baseline Characteristics
Studies 843-043 and 843-044 were identically designed multi-center, double blind, randomized, placebo-controlled studies. Study 843-043 was conducted in 97 centers and 843-044 was conducted in 106 centers. Both studies were conducted in Canada and the U.S. between August and December 2000.
Patients with moderate to severe rhinorrhea and at least one other symptom of VRI (cough, nasal congestion, pharyngeal symptoms, malaise and myalgia) were randomized to receive either pleconaril 400 mg TID x 5 days or matching placebo (total 15 doses). The first dose of study medication was to be administered within 36 hours of first symptom onset (later revised to 24 hours based on post-hoc analysis of study 843-032).
Prior to the first dose, nasal mucus was collected for PCR analysis to detect picornaviral RNA using an experimental TaqMan assay system. TaqMan negative samples were re-tested using a modified experimental Enzyme-Linked Oligo Sorbant Assay (ELOSA). Only samples that were determined to be PCR+ by one of these techniques were sent for viral culture. Follow-up nasal mucus specimens for PCR were obtained on study days 3 and 6.
Patients underwent baseline assessment of VRI symptoms including rhinorrhea, nasal congestion, pharyngeal symptoms (sore throat), cough, myalgia and malaise using an ordinal numerical scoring system for severity. Rhinorrhea was scored as absent (not present, score=0), mild (1 tissue per hour, score=1), moderate (2-5 tissues per hour, score=2) or severe (more than 5 tissues per hour, score=3). Nasal congestion, pharyngeal symptoms, cough, malaise and myalgia were similarly scored as absent (not present), mild (noticeable), moderate (bothersome), or severe (interferes with activity) using the same ordinal numeric scoring system.
As shown in Table 2, both studies predominantly enrolled female Caucasians with a mean age of 36 years.
Table 2. Baseline
demographic characteristics of all-randomized patients
Study 843-044 |
Pleconaril (n=526) |
Placebo (n=526) |
Pleconaril (n=520) |
Placebo (n=524) |
Mean (years) Range |
36 17-77 |
36 18-77 |
36 18-82 |
37 18-86 |
Male Female |
33% 67% |
34% 66% |
30% 70% |
28% 72% |
White Black Hispanic Asian Other |
75% 11% 10% 2% 2% |
79% 10% 7% 2% 2% |
90% 4% 3% 1% 1% |
88% 5% 4% 1% 2% |
Smokers Mean (years)
Range |
29% 12 <1-48 |
29% 15 <1-50 |
28% 12 <1-60 |
27% 12 <1-50 |
Pre-study cold medication use |
28% |
29% |
32% |
30% |
Time between first symptom and first dose of study medication Mean (hours) Range |
18.4 3.2-26.5 |
18.4 2.2-25.3 |
18 1.8-39.1 |
17.8 2.4-43.2 |
Baseline symptom scorea Range |
9 4-16 |
9 4-16 |
9 4-18 |
9 4-18 |
PCR+b |
337 (64%) |
326 (62%) |
344 (66%) |
356 (68%) |
Viral culture + at baselinec |
201 (38%) |
196 (37%) |
206 (40%) |
224 (43%) |
a. Maximum score=18
b. PCR + on days 1, 3 and/or 6 by research based TaqMan or modified ELOSA.
c. Viral cultures were conducted only
on samples that were positive by either the TaqMan or ELOSA.
PCR+ patients had slightly higher severity scores for rhinorrhea, congestion, and sore throat compared to PCR- patients. Also, PCR+ patients were more likely to have used cold symptom relief medications prior to study entry.
Review of
Primary Efficacy
The applicant's primary efficacy population is all patients whose nasal mucus tested positive for picornavirus PCR during the study (infected patients, ITT-I). For completeness, analyses of efficacy in the all-randomized patient population (ITT) are also presented.
Summary of
Clinical Virology
Nasal samples were tested for picornavirus using an experimental TaqMan PCR assay. Samples that tested negative by TaqMan were re-tested using an experimental Enzyme-Linked Oligo Sorbent Assay (ELOSA) in an attempt to identify additional picornavirus-infected patients. On study days 3 and 6 nasal mucus samples were collected and tested using only the TaqMan assay (instillation of 0.5 ml of saline was used to obtain nasal mucus in patients who could not expectorate mucus). Based on these procedures, the applicant concluded that 65% of patients were picornavirus PCR+ at some time during the studies.
samples were cultured. Cultures were considered positive for rhinovirus based
on presence of plaque forming units. Cultures were not further evaluated to
confirm that the cultures were, in fact, rhinoviruses versus entero or other
In studies 843-043 and 043-044, 13% of baseline isolates
(96/744) were not inhibited by pleconaril concentrations of 10 mg/ml.
Further, during the 5-day course of treatment, reduced susceptibility to
pleconaril (defined as >10-fold decrease in susceptibility compared to
baseline pre-treatment isolate) emerged in 10.7% of virus isolates tested
(28/263 isolates).
Primary Efficacy
Endpoint and Analysis
The primary endpoint for studies 843-043 and 843-044 was the median time (days) to resolution of rhinorrhea and alleviation (absent or mild) of other symptoms of VRI without use of concomitant cold medications for 48 hours.[2]
The manner in which patients who did not reach the primary endpoint were handled impacts the analysis of efficacy. The applicant censored patients at the time immediately after their last recorded observation. The FDA analysis considered any patient who did not have resolution of their VRI or prematurely discontinued the study as treatment failures and assigned them the last possible observation as the day of healing (day 18.5). The applicant and FDA's analysis of the primary endpoint is presented in Table 3; you will note that although the treatment effect remains stable, the overall duration of illness is increased by >1 day.
Table 3. Time to
resolution (days) of rhinorrhea and alleviation (absent or mild) of other
symptoms of VRI without use of concomitant cold medications for 48 hours
Study 843-043
Diff. Placebo Pleconaril p-value |
Diff. Placebo Pleconaril p-value |
Applicant Analysis |
N w/resolution Median |
526 417 (79%) 6.9 |
526 430 (82%) 6.4 |
0.5 0.201 |
524 411 (78%) 7.1 |
520 423 (81%) 6.2 |
0.9 0.015 |
N w/resolution Median |
326 258 (79%) 7.2 |
337 282 (84%) 6.6 |
0.6 0.037 |
356 286 (80%) 7.7 |
344 290 (84%) 6.2 |
1.5 0.001 |
FDA Analysis |
Median |
526 7.5 |
526 7.0 |
0.5 0.13 |
524 80 |
520 7.0 |
1.0 0.014 |
ITT-I (n)
Median |
324 7.5 |
334 7.0 |
0.5 0.03 |
350 8.5 |
343 7.0 |
1.5 0.004 |
Efficacy Results
According to Randomization Strata
Randomization was stratified based on smoking status and pre-treatment use of symptomatic cold relief medications.
Smokers Compared to Non-Smokers
Approximately 30% of study participants had a
smoking history. At baseline, smokers reported slightly more severe cough,
otherwise there were no significant demographic differences between smokers and
non-smokers. A history of smoking clearly impacted the duration of VRI overall,
and resulted in numerically negative treatment effect for pleconaril. The FDA
analysis of the primary endpoint based on smoking status is presented in Table
Table 4. Time (days) to the primary endpoint in smokers and non-smokers
Study 843-043
Placebo Pleconaril |
Placebo Pleconaril |
ITT Smokers (n) Median |
152 8.0 |
153 7.5 |
138 7.5 |
136 8.5 |
ITT Non-smokers (n) Median |
374 7.5 |
374 6.5 |
386 8.0 |
384 6.0 |
ITT-I Smokers (n) Median |
76 8.0 |
102 9.0 |
90 8.5 |
87 9.0 |
ITT-I Non-smokers (n) Median |
224 7.5 |
219 6.5 |
249 8.5 |
240 6.5 |
Pre-Treatment Cold
Medication Users Compared to Non-Users
At study entry, patients were stratified on pre-treatment use of cold symptom relief medications. Approximately 30% of participants in both studies used at least one dose of symptom relief medication (e.g., acetaminophen, ibuprofen, dextromethorphan, pseudoephedrine, Dristan, Dimetapp, echinacea, zinc, or NyQuill,) prior to initiation of study medication. Patients with moderate/severe pharyngeal symptoms, myalgia, and malaise appeared to be more likely to have used pre-treatment cold relief medications. The analysis of the primary endpoint by use and non-use of pretreatment cold relief medications is presented in Table 5.
Table 5. Time (days) to primary endpoint in users and non-users of pre-treatment cold medications
Study 843-043
Placebo Pleconaril |
Placebo Pleconaril |
ITT users (n) Median |
138 8.0 |
138 8.5 |
163 8.0 |
162 8.5 |
ITT non-users (n) Median |
388 7.0 |
388 6.5 |
361 8.0 |
358 6.5 |
ITT-I users (n) Median |
85 9.5 |
101 8.5 |
119 9.0 |
120 8.5 |
non-users (n)
Median |
215 7.5 |
220 6.5 |
237 7.4 |
224 6.0 |
Analysis by Gender
Analysis of the primary endpoint by gender demonstrated:
Ø In men, there was a median 0.4 day treatment effect in favor of pleconaril over placebo, 5.7 versus 6.1 days (p=0.210).
Ø Women treated with pleconaril experienced a median 1.0-day faster time to resolution compared to women treated with placebo, 7.0 versus 8.0 days.
Analysis of
Secondary Endpoints
Multiple secondary clinical endpoints were analyzed and included: time to patient assessment of no illness, time to reduction in symptom severity and resolution of individual symptoms, tissue use, time to return to baseline activity level, and the impact of concomitant cold symptom relief medication use.
generally places the greatest emphasis on the primary endpoint. Secondary
endpoints may be supportive but results must be interpreted with caution
because of the large number of potential comparisons, required adjustments for
p values, and, in some cases, the small number of patients included in the
analysis. The results of a number of these analyses are presented for
Analyses of time to patient assessment of no cold are presented in Table 6.
Table 6. Time
(days) to patient assessment of "no cold"
Study 843-043 Placebo Pleconaril |
Placebo Pleconaril |
ITT (n) Median |
526 6.7 |
526 6.0 |
524 6.9 |
520 5.9 |
ITT-I (n) Median |
326 6.9 |
337 6.5 |
356 7.4 |
344 6.3 |
of time to resolution of the individual symptoms of VRI was assessed and the
results are presented in Tables 7a and 7b.
Study 843-043.
Placebo Pleconaril |
Placebo Pleconaril |
Rhinorrhea (n) |
490 6.0 |
486 6.5 |
495 6.5 |
489 5.5 |
Congestion (n) |
467 60 |
472 6.0 |
482 6.0 |
471 6.0 |
Cough (n) |
411 6.0 |
387 6.0 |
402 7.0 |
399 5.5 |
Pharyngitis (n) |
396 4.0 |
352 3.5 |
375 3.5 |
380 3.0 |
Malaise (n) |
448 4.5 |
448 4.0 |
454 4.0 |
445 4.0 |
Myalgia (n) |
366 4.0 |
328 3.0 |
337 4.0 |
344 3.5 |
Table 7b. Median time (days) to resolution (score=0) of symptoms of VRI, ITT-I
Study 843-043.
Placebo Pleconaril |
Placebo Pleconaril |
Rhinorrhea (n) |
284 7.0 |
302 6.0 |
323 7.5 |
311 6.0 |
Congestion (n) |
274 6.5 |
294 5.5 |
318 6.5 |
305 6.0 |
Cough (n) |
242 6.5 |
238 6.5 |
262 7.0 |
258 6.0 |
Pharyngitis (n) |
228 3.5 |
212 3.0 |
243 3.5 |
234 3.0 |
Malaise (n) |
261 4.5 |
276 4.0 |
307 4.0 |
287 3.5 |
Myalgia (n) |
206 3.5 |
192 3.0 |
223 3.5 |
222 3.0 |
Analysis of nights disturbed by VRI symptoms is presented in Table 8.
Study 843-043 Placebo Pleconaril |
Placebo Pleconaril |
ITT w/sleep
disturbance (n) Median |
440 3.0 |
414 2.0 |
427 3.0 |
419 2.0 |
ITT-I w/sleep
disturbance (n) Median |
282 3.0 |
276 2.0 |
300 3.0 |
289 2.0 |
There was no difference in time to return to baseline level of activity between pleconaril and placebo for the ITT or ITT-I populations, median 3.0 days.
At baseline each patient was dispensed acetaminophen and dextromethorphan and instructed to use these relief medications only if necessary. All use was to be documented in the patient diaries. Approximately 50% of study participants used symptomatic relief medications during the study, and there were no differences in the frequency or duration of use between pleconaril and placebo-treated patients.
V. Safety Summary
The adult VRI safety database includes information on 2,488 patients who received at least one dose of pleconaril; 1,046 of whom received the proposed dose of 400 mg TID for 5 days (15 doses), using the proposed commercial tablet formulation.
Gastrointestinal events (abdominal pain, nausea, vomiting, diarrhea), and headache were the most common adverse events reported in the adult VRI safety database. Of significant concern is the apparent higher rate of menstrual disorders among females treated with pleconaril and concomitant progestin and/or estrogen-based oral contraceptives (OCs). Another potential concern was the occurrence of tachycardia and palpitations that was temporally related to administration of pleconaril alone and in combination with theophylline. There were no significant changes in clinical laboratory or hematologic parameters in the phase 2 and 3 VRI trials reviewed where pleconaril was dosed for 5-7 days.
Treatment emergent adverse events (all cause and all severity) observed in the two pivotal VRI studies are presented in Table 9.
Table 9. Treatment-emergent adverse events in pivotal adult VRI studies, (%)
Event |
Pleconaril (n=1046) |
Placebo (n=1040) |
Headache |
23 |
21 |
Diarrhea |
7 |
7 |
Nausea |
6 |
4 |
Vomiting |
2 |
2 |
Abdominal pain |
2 |
4 |
Sinusitis |
3 |
2 |
Bronchitis |
3 |
3 |
Increased cough |
3 |
3 |
Pain |
3 |
2 |
Fever |
1 |
2 |
Dizziness |
2 |
1 |
Hematuria |
1 |
<1 |
Otitis media |
1 |
<1 |
Rhinitis |
2 |
3 |
Allergic reactions |
<1 |
<1 |
Rash |
<1 |
<1 |
Menstrual disorders |
2 |
1 |
Abnormal LFTs |
<1 |
1 |
Palpitations/tachycardia |
<1 |
<1 |
There were no significant differences in the frequency of adverse events between PCR+ and PCR- patients in studies 843-043 and 843-044.
Headache, primarily mild in severity, has been reported consistently by 18-20% of patients in the VRI safety database. In the two pivotal studies, the frequency of headache was similar as was the number of patients who discontinued due to headache, four pleconaril and six placebo. Although some cases of headache were quite likely due to the underlying VRI, many were reported during treatment and therefore may have been treatment related. Other etiologies for headaches have not been suggested.
Gastrointestinal-related adverse events were reported at a similar frequency across the studies in the VRI safety database as shown in Table 9. In the two pivotal studies, 17 (1.6%) and six (.05%) pleconaril and placebo-treated patients, respectively, discontinued due to GI adverse events. Review of discontinuations due to GI events demonstrated a pattern: onset of symptoms was within 1-2 days of initiation of study medication with resolution within 1-2 days of discontinuation. In general, gastrointestinal symptoms are not part of the typical constellation of symptoms reported by patients with VRI. One possibility is that the GI events are formulation related. The placebo and pleconaril formulations used in the pivotal studies contain sodium laurel sulfate (SLS).[3] Other etiologies for these gastrointestinal events have not been suggested.
Menstrual Disorders
There was a significant increase in menstrual disorders (such as epimenorrhea, intermenstrual bleeding, menstrual disorder, amenorrhea, menorrhagia, early menses, prolonged menstrual cycle, and delayed menses) among women treated with pleconaril and using progestin/estrogen-containing OCs.
Menstrual disorders were identified in 7/229 (3.1%) of women who were taking OCs during 5-7 days of treatment with pleconaril compared to 0/223 who were treated with placebo. Among women who received pleconaril but were not using OCs, the rate of menstrual disorders was 0.1%.
Additional information on menstrual disorders from a recently completed six-week prophylaxis study were submitted and reviewed. The observed results are suggestive of a dose response relationship. At least one of the menstrual disorders listed above was observed in 20 (25%), 52 (53%), and 40 (69%) women taking placebo, pleconaril 400 mg QD, or pleconaril 400 mg BID and an OC. The most common events were epimenorrhea and intermenstrual bleeding.
During week one of the prophylaxis study, the prevalence of menstrual disorders was 3%, which was the same as the prevalence in the 5-7 day treatment trials. The prevalence peaked by week three to 28%, and began to decrease by week seven.
Also, there appeared to be a potential dose response for the occurrence of epimenorrhea and intermenstrual bleeding among women receiving pleconaril and not taking OCs; however the numbers of patients in this analysis are very small.
animal studies, pleconaril was not found to be mutagenic, teratogenic, or
genotoxic, and did not negatively impact viability or normal development,
including reproductive performance of the offspring. In a 6-month toxicology study conducted in rats, mild to moderate
macroscopic uterine horn distention was observed at necropsy in low (10 mg/kg
BID) and high dose animals (50 mg/kg BID).
Corresponding microscopic uterine horn dilatation was observed in two of
two low dose animals and five of 15 high dose animals. These findings were also present in one high
dose animal at the end of the two-month recovery period. At the time the toxicology study was
reviewed, these findings were not considered sufficient to warrant a hold for a
dosing duration of five days, since no similar toxicities were noted in
one-month dog and rat studies or in six month dog studies.
A total of 13 (eight pleconaril and five placebo) pregnancies have been reported in women receiving pleconaril in 5-7 day treatment and six-week prevention studies. Of the eight pregnancies that occurred in pleconaril recipients, two occurred in women taking an OC at the time they became pregnant. One pregnancy terminated in an abortion and one pregnancy is ongoing. All the other women were using barrier methods at the time they became pregnant.
The etiology of the menstrual disorders has not yet been determined. Possible mechanisms include CYP 3A4 induction, changes in intestinal flora, interference in enterohepatic circulation, displacement of albumin binding of estrogen, changes in sex hormone binding globulin, changes in steroid receptor binding, and partial antagonism of estrogen receptors.
Two studies investigating changes in serum progesterone, luteinizing hormone and follicle-stimulating hormone are ongoing. A third study investigating the possibility of induction of the CYP 3A4 enzyme system using midazolam is also ongoing. Very preliminary data suggests that pleconaril causes induction of CYP 3A4 and decreases ethinyl estradiol exposures. Additional data from these studies will be presented at the AVAC meeting.
potential pharmacodynamic interaction between pleconaril and theophylline was
identified. During the conduct of an interaction study, four of 14 subjects
experienced palpitations, tachycardia, dizziness, and/or syncope, during the
combination dosing period. In addition, general adverse events of palpitations,
nausea, vomiting, abdominal pain, and dizziness were reported more frequently
during the theophylline/pleconaril periods. At the time of these events, no
significant changes in either theophylline or pleconaril pharmacokinetics noted
were noted.
In the adult VRI database 18 patients (eight placebo and 10 pleconaril) reported cardiac-related adverse events for which a cardiac etiology could not be ruled out. Nine patients, seven pleconaril and two placebo, complained of tachycardia and/or palpitations. Of these, six of the pleconaril patients reported tachycardia and/or palpitations within one hour of ingestion of pleconaril, four discontinued from treatment due to tachycardia and/or palpitations, one patient's event was considered serious. No patients underwent re-challenge following resolution of the events.
There were no apparent differences in heart rate or blood pressure noted in the VRI safety database.
applicant has proposed the following post-approval activities:
additional pediatric VRI studies using an endpoint of time to 50% reduction in
pleconaril's ability to prevent VRI in patients with underlying pulmonary
disease (e.g., chronic asthma and COPD)
transmission of VRI and development of resistance
VII. Issues for Discussion
below are a number of issues for you to consider during the discussion
period. Please note that these issues
may change prior to the meeting.
the applicant established efficacy of pleconaril for treatment of acute
picornavirus VRI in adults?
consider the following points as you discuss this question:
used to identify infected patients
of treatment effect across the phase 2 studies, and studies 843-043 and 843-044
of the primary efficacy population
need to institute treatment within 24 hours of onset of the first symptoms
in males versus females
in smokers versus non-smokers
If the answer to question 1 is yes, please provide your recommendations for
labeling. Please include a discussion
of the populations and sub-populations for which pleconaril should or should
not be labeled, and any recommendations for statements to clarify how
pleconaril should be used.
If the answer to question 1 is no, please discuss what additional data would be
helpful to establish pleconaril's efficacy.
the applicant demonstrated safety in adult patients with symptoms of acute VRI?
consider the following points as you discuss this question:
types and frequencies of adverse events are generally similar between
pleconaril and placebo, with headache and gastrointestinal symptoms occurring
most frequently.
frequency of menstrual disorders occurring in females using OCs while being
treated with pleconaril.
and palpitations were reported in <1% of otherwise healthy patients treated
with pleconaril, and were pronounced in a theophylline/pleconaril interaction
study. Patients with significant pulmonary and cardiovascular disease were not
included in any of the studies.
If the answer to question 2 is yes, please provide any recommendations for
labeling. Please include a discussion of the populations and sub-populations
for which pleconaril should or should not be labeled, and recommendations for
specific safety related statements that should be included in the labeling.
If the answer to question 2 is no, please discuss what additional data would be
helpful to establish pleconaril's safety.
provide comments on the applicant's proposed phase 4 studies. Please also provide suggestions for any
other study designs or patient populations that should be studied as phase 4
Additional studies to assess the performance of the TaqMan assay to identify picornavirus-infected patients are ongoing and results are expected in early March; these data will be available for discussion at the AVAC meeting and may supercede the concerns outlined below.
basis for Taqman PCR is to continuously measure PCR product accumulation using
a dual-labeled flourogenic oligonucleotide probe called a TaqMan®
probe. This probe is composed of a short (ca. 20-25 bases) oligodeoxynucleotide
labeled with two different fluorescent dyes.
On the 5' terminus is a reporter dye and on the 3' terminus is a
quenching dye. This oligonucleotide
probe sequence is homologous to an internal target sequence present in the PCR
amplicon. When the probe is intact,
energy transfer occurs between the two flourophors and the quencher quenches
emissions from the reporter. During the extension phase of PCR, the probe is
cleaved by 5' nuclease activity of Taq polymerase thereby releasing the reporter
from the oligonucleotide-quencher and producing an increase in reporter
emission intensity
The fluorescence intensity of reporter and quencher dyes is measured and the increase in normalized reporter emission intensity over the course of the amplification is calculated. The results are then plotted versus time, represented by cycle number, to produce a continuous measure of PCR amplification. To provide precise quantification of initial target in each PCR reaction, the amplification plot is examined at a point during the exponential phase of amplification. This is accomplished by assigning a fluorescence threshold above background and determining the time point at which each sample's amplification plot reaches the threshold (defined as the threshold cycle number or CT). Differences in threshold cycle number can be used to quantify the relative amount of PCR target contained within each tube.
1) As noted by Applied Biosystems, the manufacturer of the TaqMan system, the use of Primer Express® software in designing primers and probes is critical for the successful development of an assay. The assay under review did use this software for primer and probe design, however there are at least two areas of concern. As noted by the Primer Express software:
TaqMan® Probe:
runs of an identical nucleotide. This is especially true for guanine (G), where
runs of four or more Gs should be avoided
TaqMan® Primers:
five nucleotides at the 3' end should have no more than two G and/or C bases
Because of heterogeneity between rhino and enteroviruses,
and that the assay used only two primers, it is not clear how effective the
assay can be at detecting all various serotypes. In addition, as noted below there was significant variation in
the level of detection of the serotypes.
Therefore, these primer-binding characteristics have the ability to
significantly affect both the sensitivity and specificity of the assay.
Threshold Value
The threshold is the numerical value assigned for each run that reflects the average DRn (change in fluorescence) during the initial cycles of PCR (baseline). The threshold should be placed in the region of exponential amplification across all of the amplification plots. This region is depicted in the log view of the amplification plots as the portion of the plot that is linear. The threshold line should neither be placed in the plateau phase or in the initial linear phase of amplification. In the case of the ABI 5700 the threshold is manually adjusted so there may be variation in where individual investigators believe placement should be set.
It is possible
that the threshold currently set for this assay, 0.1, may be too low and a more
appropriate threshold would be in the range of 0.4 – 0.6.1. While there is a range of threshold values
that could be appropriate, incorrect threshold placement could result in an
incorrect assay definition of positivity.
A low threshold value would subject
individual samples to assay background and could impact the relative
quantitative results of the assay.
In the
clinical studies, 67% (6/9) of the assay failures were due to the negative
control crossing the threshold value.
Number of Cycles
The current assay is run for a total of 60 cycles. In general, most assays are run for a maximum of 45 cycles.
The 60-cycle reaction could allow for an
increase in non-specific amplification in samples that contain weakly
homologous regions.
non-specific amplification would also have an adverse effect on the sensitivity
and specificity of the assay.
Possible resolutions to this issue would include analyzing the reaction products by ethidium bromide-stained agarose (acrylamide) gel electrophoresis, Southern blotting/probe hybridization, or fluorescence assay. These were requested of ViroPharma but have not been received to date.
Pre-Clinical Studies
Validation Reports
1) The validation report in the original NDA submission identified the primers and probe selected for the assay using the appropriate Primer Express software and these would generate a 67-68 nucleotide (nt) fragment.
A validation report from ViroMed, who
performed the TaqMan assays for the applicant, states that the primers and
probe selected using the Primer Express software generated a 150 nt fragment;
ViroPharma will clarify the exact length of the nt fragment.
Limits (Analytical Sensitivity)
1) Detection limits vary widely between serotypes. Detection limits were expressed in genome equivalents (GE)/plaque forming units (pfu). Five human rhinovirus (HRV) serotypes representing both major (serotypes 14,16, and 89) and minor (serotypes 1A and 1B) receptor binding groups were used to establish the limit of detection.
Analytical Sensitivity |
GE (RNA) per reaction |
GE/pfu |
30 |
132 |
50 |
1055 |
14 |
1289 |
12675 |
16 |
47 |
408 |
89 |
2036 |
33,068 |
Given that particle/pfu ratios for picornaviruses are generally between
200 –10002 and since there should be no more than one genome per
virus particle (or less), these GE/pfu ratios appear to be overstated.
The analytical sensitivity varied over 60-fold, from 30 to 2,036 GE per
reaction depending on virus serotype.
There is a discrepancy between the claimed limit of detection (LOD) of
the TaqMan assay. In the ViroMed validation report the LOD is stated as 1.0
pfu/ml while in the studies submitted by ViroPharma, the listed LOD is 10
The exact quantitative nature of the TaqMan assay cannot be evaluated
as the calibrators also serve as the positive control for the assay and
therefore will only control for substantial reagent failure. When control and calibrators are the same
material, the calibrators will appear to function within the parameters of each
assay but there may be substantial inter-assay variation that will not be
When used with spiked clinical material (nasal mucus) the detection
limits of the TaqMan assay varied among the serotypes by 2000 fold.
1) Two virus culture systems were utilized in the clinical studies.
a) In one, samples of nasal mucus specimens were inoculated into WI-38 cells (human embryonic lung cells), inculbated at 33° C, and examined for cytopathic effect (cpe) over the course of 14 days.
second culture system employed Hela I-CAM cells with other conditions being
2) Only samples positive in the TaqMan assay were analyzed by cell culture, no negative specimens were tested.
cultures were not assessed for picornavirus positivity. Although cultures were deemed positive for
cpe, this was not confirmed to be due to picornavirus by pH lability,
identification of the serotypes, immunofluorescent assay, or DNA sequence
while a positive culture was suggestive of picornavirus, the applicant provided
no evidence for either the presence or absence of actual picornavirus
Study 843-032 when compared to culture, the TaqMan assay had a sensitivity of
93% (88-97%) and specificity of 75% (72-78%).
"expanded gold standard" was used to re-evaluate sensitivity and
specificity. "True positives" were
considered to be either (i) virus culture positives regardless of PCR results,
or (ii) TaqMan and ELOSA positives regardless of culture results.
is no valid measure for specificity for either assay, and neither result has
been independently confirmed.
Statistically this analysis will always favor the PCR result, since one
PCR assay is being "confirmed" by a second PCR assay.
The design and primary endpoint analysis for each of
four phase 2 studies are presented below.
Presented below are analyses of the primary endpoint for each study.
Study 843-010 was the first study to investigate the safety and
efficacy of pleconaril in the treatment of VRI. The primary endpoint was time to complete resolution of all systemic
symptoms (score of 0) for 48 hours among the all randomized (ITT) patient
population. Nasal mucus was PCR+ for picornavirus in 29% percent of
patients, too few upon which to conduct an analysis.
Table 2. Time (days) to complete resolution of
all systemic symptoms for 48 hours
Placebo |
Pleconaril 200 mg TID |
Pleconaril 400 mg TID |
ITT (n) Median p-value versus placebo |
74 10 |
73 9 0.501 |
74 10 0.504 |
Study 843-013 evaluated two doses of pleconaril (200 mg or 400 mg
TID for seven days) in the treatment of rhinovirus VRI in patients with
bronchial asthma. The purpose was to determine if treatment of VRI in patients
with asthma might reduce the morbidity and mortality associated with such
exacerbations. The low rates of asthma exacerbations and picornavirus PCR+
patients precluded any efficacy assessments.
Study 843-020 evaluated the safety and
efficacy of two doses of pleconaril (400 mg BID or TID for seven days) for
treatment of picornavirus VRI. The primary endpoint was time to reduction of a
composite symptom score to 0 (all signs and symptoms absent) for two
consecutive days (48-hours) in adult patients with acute picornavirus VRI.
Nasal mucus was PCR+ for picornavirus in 41% of patients.
Table 3. Time (days) to
resolution of all VRI symptoms sustained for 48 hours
Combined Placebo |
Pleconaril 400mg BID |
Pleconaril 400mg TID |
(n) Median p-value versus placebo |
340 8 |
335 8 0.31 |
347 8 0.011 |
(n) Median p-value versus placebo |
128 8 |
136 8 0.69 |
147 9 0.70 |
Study 843-032 evaluated the safety and
efficacy of pleconaril 400 mg TID or matching placebo TID for seven days (total
21 doses) in patients >14 years of age presenting with acute VRI. The first
dose of study medication was to be administered within 36 hours of the onset of
symptoms. The primary endpoint was time to alleviation of all VRI symptoms
sustained for 24 hours. Nasal mucus was PCR+ for picornavirus in 43% of
Table 4. Time
(days) to resolution of all VRI symptoms sustained for 24 hours
Placebo |
Pleconaril 400mg TID |
Difference p-value |
(n) Median |
439 9.0 |
436 9.0 |
0.0 0.7 |
ITT-I (n) Median |
280 9.5 |
240 9.0 |
0.5 0.11 |
The applicant conducted an extensive PK development program. Unless otherwise noted, the PK studies involved healthy volunteers between 18 and 75 years of age. Relevant findings and issues raised by pharmacokinetic studies that are applicable to the adult VRI indication include:
reaches maximal plasma concentration (Cmax) about 3.0 hours (range
2.0-5.0 hours) after oral administration.
bioavailability of pleconaril is increased by 4-6.5 fold after administration
of pleconaril with a meal high in calories, fat, and protein, as compared to
administration of pleconaril in a fasted state.
is highly bound (99.8%) to plasma proteins.
oral absorption, pleconaril displays a bi-exponential disposition profile with
a short alpha half-life (2-3 hours) and a long terminal half-life (180 hours).
The pharmacokinetics
following a single dose may not predict multiple dose pharmacokinetics, due to
the prolonged half-life after multiple doses (1010 hours after 400 mg TID for 5
days) compared to that after single dose (180 hours).
accumulation of pleconaril is modest (2-fold) after pleconaril 400 mg TID for 5
days. Steady state is not reached after 5 days of treatment with pleconaril.
balance was not achieved following 288 hours of collection of urine and feces
after a single radiolabeled oral dose of 200 mg pleconaril under fed conditions
(37.6% of administered radioactivity recovered in urine and feces).
is excreted in urine and feces as multiple inactive metabolites. The cytochrome
P450 drug metabolizing enzymes are not significantly involved in the major
biotransformation pathways of pleconaril. Therefore, co-administered drugs that
are CYP450 substrates, inhibitors or inducers are not expected to alter the
pharmacokinetic profile of pleconaril.
In vitro studies showed that pleconaril may be a
weak CYP1A2 (Ki: 8.8 μM), CYP2C9 (Ki: 6.4 μM), and CYP2C19 (Ki: 10
μM) inhibitor. The in vivo
pleconaril-theophylline drug-drug interaction study showed that pleconaril
increased theophylline AUC by 15%, but not Cmax. Palpitations, syncope and tachycardia were observed during the
theophylline and pleconaril combination treatment but not during theophylline
alone treatment. These symptoms appeared to be unrelated to theophylline AUC or
Cmax. Pleconaril had no effect on pharmacokinetics of S- or R-warfarin.
An increased incidence of menstrual disorders, including
break-through bleeding, was observed in pleconaril treated women who took oral
contraceptives, both in prophylaxis and treatment studies. The potential for pleconaril induction
of CYP450 enzymes is currently under investigation.
pharmacokinetic profile of pleconaril is not clinically significantly changed
due to age or renal impairment.
Hepatic impaired subjects have 40% lower pleconaril
exposures compared to healthy subjects after a single 400 mg pleconaril oral
liquid dose. The difference may be due to lower fat and meal consumption in
hepatic impaired subjects compared to healthy subjects during the study or
reduced albumin level in hepatic impaired subjects. Thus, the results of this study
are inconclusive.
population PK study was inconclusive due to insufficient blood samples,
inappropriately fixed parameters (using ka,
Q/F, V2/F and tlag values from Phase I studies with
different formulations of pleconaril), and poor prediction of observed
The dose
selected (400 mg TID for 5 days) may not be optimal based on the free drug
concentrations achieved in the plasma and estimated nasal tissue concentration
from a rat model, compared to non-protein adjusted MIC90 of pleconaril
for piconavirus. Also, no higher dose was studied and no exposure-response was
[1] Tissue use was measured
during the study as a surrogate for the severity of rhinorrhea.
[2] The endpoint evolved through
numerous derivations and symptom scoring systems, and represents conclusions
reached primarily from post-hoc analyses of previously completed studies. The
endpoint represents assessments of four components hypothesized to be important
in assessing treatment response in patients with VRI. Absence of rhinorrhea was chosen because it represents the
predominant symptom of VRI. Alleviation
of other symptoms to absent or mild provides outcome data on the more acute
phase of VRI. The 48-hour observation period was chosen to ensure that
sufficient time elapsed to document that the VRI had ended. Finally, absence of
concomitant cold medication would likely ensure that patients would not report
a reduced duration of VRI that could have been attributed to use of symptom
relief cold medications.
[3] SLS is a generally recognized as safe (GRAS) anionic emulsifying, detergent used as a tablet lubricant and wetting agent in cosmetics and topical pharmaceutical products. It is a moderately toxic agent with irritating effects to the eyes, skin, mucous membranes, upper respiratory tract, and stomach. Handbook of Pharmaceutical Excipients, 3rd edition, Kibbe AH, ed; 2000, 487-89.

subset: commoncrawl


text:
NWAR: Trench Warfare
Detective Nwar gets his hands dirty for a political campaign.
4.41 / 5.00 2,749 ViewsForgiveness is a hard road, only the love between a man and his wave can calm these waters.
your animation altho relatively simple runs super smooth and is still impressive, the walk cycles are pretty generic and stiff though, but dont really matter because ur plot is still delivered more or less the same and the average viewer doesnt noticed, great work very funny the crabs are very well animated and the last scene is very well done . good job on pushing this one
To be honest, i didnt really enjoy the ending. You had me going for a dramatic movie, and i was satisfied with it until the crabs came. I didnt get it and it was like a slap in the face.


text:
Monday, 12 Dec 2011 07:02 AM
It's likely a sum that puts Cain in a position to still have some influence on the 2012 race by donating to other candidates or traveling to promote his ideas.
Cain's role would be similar to that of 2008 Republican vice-presidential nominee Sarah Palin, whose political action committee spent $1.6 million through June 30, much of it on travel expenses, contributions to candidates and communications with her supporters.
"You can fly around, you can support candidates, you can play kingmaker and you can sell books, which he's already done and she's already done as well," said Alex Vogel, a Republican consultant. "He can absolutely continue to make sure that his vision is reflected in the campaign."
Cain told supporters in an e-mail Dec. 6 that he planned to remain active.
"It is my strong intent going forward to assist not only other campaigns, but to influence the entire political landscape," Cain said. "We will continue to evaluate that influence, how it can be improved, and what can be done to persuade others to promote and implement our bold solutions."
Remaining Active
J.D. Gordon, Cain's spokesman, wouldn't disclose how much money is left in the campaign account. "Mr. Cain intends to be part of the debate and, through Cainsolutions.org, he plans to change Washington from the outside," he said.
Cain reported raising $4.7 million through Sept. 30 with $1.3 million in the bank. His cash-on-hand swelled as he took in another $9.4 million through Nov. 10, after he surged to first place in most public opinion polls. Cain also lent his campaign $675,000.
The next financial disclosure reports will be released in mid-January.
Cain pulled out of the race Dec. 4 following allegations that he sexually harassed four women and had an affair with a fifth. His exit came before he had time to expand his staffs in Iowa and New Hampshire or began extensive television advertising.
While he initially announced a "suspension" of his candidacy, Cain said on Fox News Dec. 8 that his campaign has ended.
"There are no plans to re-emerge," he said. "For right now, I am going to still be a voice, a very strong voice on behalf of the people who got me this far."
Harassment Allegations
Republican consultant Craig Shirley said accusations against Cain shouldn't keep him from playing an active role going forward.
"The allegations never stopped Bill Clinton; why should they stop Herman Cain?" Shirley said. "They only stop him if he allows them to stop him. This is America. You can reinvent yourself."
As others have done, Cain could convert his campaign committee into a political action committee. That would allow him to more than double his giving to candidates to $5,000 per election from $2,000. It would also provide a vehicle for his supporters' continued donations; Palin's PAC collected $1.7 million through June 30.
"The wisest thing for him to do is create a political action committee," said Eddie Mahe, a Republican consultant. "Use that money to travel, to support candidates, to promote his 9-9-9 idea," a reference to Cain's proposal to change the tax code to include 9 percent individual, business and sales taxes.
Donating to Candidates
Former Representative Jim Walsh, a New York Republican, turned his unspent campaign funds into a PAC after declining to seek re-election in 2010. Walsh, now with the lawyer-lobbying firm K&L Gates LLP, used his PAC to give $8,750 to members of Congress during the first months of the year.
"You can contribute. You can go to fundraisers. You can see your former colleagues. You can see people who are involved in national politics," Walsh said. "Familiarity doesn't necessarily bring contempt."
Mahe said that if Cain withdraws from the political arena altogether, the money he spent on his candidacy will amount to a waste of cash. Instead, spending his leftover campaign funds to help shape the race is an investment in his political future.
"The only way to get a return on the money is invest it," Mahe said. "Use the money he has left and keep on going. As a businessman, he would understand return on investment."
To contact the reporter on this story: Jonathan D. Salant in Washington at email@example.com.
To contact the editor responsible for this story: Mark Silva at email@example.com.
© Copyright 2015 Bloomberg News. All rights reserved.
Friday, 04 Jan 2013 13:06 PM
Tens of thousands of Fatah supporters rallied in the Hamas stronghold of Gaza on Friday for the first time since they we . . .
Tuesday, 17 Jul 2012 18:11 PM
. . .
Friday, 13 Jul 2012 12:27 PM
RUBIO........Stay the hell OUT of sexual politics !!!! Taking ANY position on...
I'm glad I retired. I wouldn't want much to do with the military of today. Obozo...
When "liberals" are in charge, they are in charge, and you no longer have an...
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text:
Bruce Killen "Into the Abyss" Bronze Sculpture Limited Edition
- Item Category: Fine Art
This is a fantastic bronze sculpture by artist sculptor Bruce Killen, who was not only an artist, but a well know conservationist, naturalist, and outdoorsman. Bruce Killen passed away on June 8th of this year, and this sculpture was one that was auctioned by Wall Auctioneers of Medford, Oregan from his estate. It is a limited edition 12/100. It measures 26" x 11.5". It is solid bronze on a marble base.


text:
Latest News
Bharatiya Vidya Bhavan Chandigarh
- Bhavan Chandigarh Ranked No. 1.
- Registration for Class XI extended till 16th March 2015
- List of Eligible candidates for Class Pre Nursery
- Dear Parents/Guardians, I have pleasure in informing that the facility of online deposit of fee for your wards is now available. This facility is being provided in collaboration with "State Bank Collect" facility of State Bank of India.


text:
8 Weeks Pregnant: What to Expect During Pregnancy
Filed under: Week By Week
What's happening to baby: Your baby is now the size of a bean. His ears, bones, fingers, toes, eyes, ears, lips and nose are all in the process of forming.
What's happening to Mom: You've got up to 50 percent more blood circulating in your body and your uterus is now the size of a grapefruit (it will get much, much bigger).
9 Weeks Pregnant:What to Expect During Pregnancy


text:
AMSTERDAM, January 28 /PRNewswire-FirstCall/ -- Elsevier announced today that Scopus Custom Data, the underlying source of Scopus.com, the world's largest abstract and citation database, was chosen by Japan Science and Technology (JST) to conduct citation linkage analysis between scientific articles and patents. JST, as the funding agency for promoting innovation and providing research support to many organizations from industry and academia, selected Scopus Custom Data because it provides wider coverage and clear relations between authors and their affiliations.
According to a paper published by JST in the January edition of Journal
of Information Processing and Management , an analysis of research papers
cited in patents, shows the linkage between Japan's scientific articles and
technology is increasing every year and enabling Japan to maintain its
international competitiveness. It has also become clear that research papers
written by researchers funded by JST are having greater effects on technology
every year; and that JST is playing the political role of promoting the
creation of innovation as a funding agency. For details of the published
research paper, please refer to the website of Journal of Information
Processing and Management
. The analysis was conducted by using the integrated search system for
research papers and patents developed by JST. JST plans to introduce this
system at the American Association for the Ad
SOURCE Elsevier Copyright©2010 PR Newswire. All rights reserved |


text:
Pronunciation: /ˌhēlēəˈzōə/
Definition of Heliozoa in English:
A class of single-celled aquatic animals that are related to the radiolarians. They have a spherical shell with fine radiating needlelike projections.
Example sentences
- Heliozoa have axopodia, long stiff projections of cytoplasm.
- Some groups found in vernal pools are Vorticella, Heliozoa, and Ameoba phylum.
- However, due to the discovery of many new species, and discoveries regarding the morphology of the Heliozoa, the classic scheme is no longer deemed acceptable.
Modern Latin (plural), from Greek hēlios 'sun' + zōion 'animal'.
Definition of Heliozoa in:
- British & World English dictionary
What do you find interesting about this word or phrase?
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The ****, there as much people hating on pacquaio's win against oscar as Floyd's win against Marquez. Really are you blind from all the ****ing OSCAR is weight drain threads. really both *******s and *****s need to look themselves in the mirror before they call any fan retards. |
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im not sure what youre asking but ill fire away with hits and misses, yes they first fought at 125 pounds thats when pacquiao scored 3 knockdowns and their second fight was at 130 pounds when they both moved up to superfeatherweight and pac scored another kd
in the context of what the TS posted saying manny couldnt knockout marquez.. at the very least.. pac moved up in weight and found marquez who has been there for quite sometime at 125 pounds. and he manage manage to knock him down 3 times while he was still green , he was 22 pounds less heavier compare to mayweather when he v.s marquez cus mayweather made marquez fight him at 147, it was supposedly a catchweight at 143 but mayweather cheated the weigh-in and came in at 147.. what a disgrace mayweather had the weight advantage, reach advatage over marquez by 6 inches, the height advantage by 2, the better skills against marquez( pac at 125 is nowhere near the level of mayweather at 147) oh and of course, marquez didnt have the leisure of fighting at the weightclass he made a career at which is exactly why he gave pacquiao a war and got outpointed by mayweather.. what a joke why did mayweather not knockout or at the very least score 10 kds with all the advantages? doesnt make sense, does that mean pacquiao at 125 is stronger than may at 147? and now look at the pac who's a legit 147 pounder.. floyd himself said after the fight he tried to go for a knockout but he just couldnt knockout marquez lmao soo.. 125> 147 id be scared too to face manny if i was may and bring up bs testing to derailed negotiation so i wont fight him llmaooo Last edited by flour; 04-19-2010 at 10:09 AM. |
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Joint venture | |
Industry | Wireless Semiconductors |
Fate | Dissolved |
Predecessor | Ericsson Mobile Platforms, ST-NXP Wireless |
Successor | STMicroelectronics, Ericsson Modems |
Founded | 3 February 2009 |
Defunct | 2 August 2013 |
Headquarters | Geneva, Switzerland |
Key people
Didier Lamouche (President and CEO) |
Revenue | $1.7 billion US$ (2011)[1] |
Number of employees
5,000 (as of end 2012) |
Parent | STMicroelectronics (50%) Ericsson (50%) |
Website | ST-Ericsson at the Wayback Machine (archived June 13, 2013) |
ST-Ericsson was a multinational manufacturer of wireless products and semiconductors, supplying to mobile device manufacturers.[1] ST-Ericsson was a 50/50 joint venture of Ericsson and STMicroelectronics established on 3 February 2009 and dissolved 2 August 2013. Headquartered in Geneva, Switzerland, it was a fabless company, outsourcing semiconductor manufacturing to foundry companies.
Both Ericsson and STMicroelectronics appointed four directors to the board with Hans Vestberg, President and CEO of Ericsson, serving as the chairman of the board and Carlo Bozotti, President and CEO of STMicroelectronics, as the vice-chairman.
ST-Ericsson was formed on 3 February 2009 when STMicroelectronics and Ericsson completed the merger of Ericsson Mobile Platforms and ST-NXP Wireless into a 50/50 joint venture.
On 20 August 2008, STMicroelectronics and Ericsson announced their intention to merge their wireless semiconductor businesses. ST contributed its multimedia and connectivity products as well as their 2G/EDGE platform and 3G offering. Ericsson contributed its 3G and 3GPP Long Term Evolution (LTE) platform technology. The merger followed an existing strategic co-operation between Ericsson Mobile Platforms and ST-NXP Wireless.[2]
Ericsson also had a venture with Sony called Sony Ericsson during 2001–2012.
On 11 December 2012, ST-Ericsson was on the brink of shutdown after its parent company STMicroelectronics decided to move out of the JV, citing loss of market share due to ST-Ericsson failing to attain Break-even. Since ST-Ericsson came into being in 2009, STMicroelectronics has slipped from 5 to 7 in global semiconductor firms' rakings.[3]
On 18 March 2013, the parent companies announced that the joint venture was to be closed down, with the parent companies taking over parts, but not all, of its operation and products.[4]
On 28 May 2013, ST-Ericsson announced that they would sell the assets and intellectual property rights for its mobile connectivity Global Navigation Satellite System (GNSS) to Intel for $90 million.[5]
On 5 August 2013 Ericsson (NASDAQ:ERIC) and STMicroelectronics (NYSE:STM) announced the closing of the transaction for the split up of ST-Ericsson. This follows the announcement the companies made on 18 March 2013 on the chosen strategic option for the future of the joint venture.
Effective 2 August 2013 Ericsson has taken on the design, development and sales of the LTE multimode thin modem solutions, including 2G, 3G and 4G interoperability. ST has taken on the existing ST-Ericsson products, other than LTE multimode thin modems, and the GNSS (Global Navigation Satellite System) connectivity solution sold to a third party, and related business as well as certain assembly and test facilities. [6] [7]
ST-NXP Wireless[edit]
This section does not cite any references or sources. (April 2013) |
ST-NXP Wireless, a joint venture made up of the wireless operations of STMicroelectronics and NXP Semiconductors, began operations on 2 August 2008. NXP and STMicroelectronics announced on 10 April 2008 that they would combine their wireless operations in 2G, 2.5G, 3G, multimedia, connectivity and future wireless technologies. The combined venture was created from businesses that together owned significant portfolios of communication and multimedia patents.
Formerly a division of the semiconductor firm Royal Philips Electronics, NXP was established as an independent company in 2006. STMicroelectronics was formed in June 1987 by the merger of semiconductor companies SGS Microelettronica of Italy and Thomson Semiconductors, the semiconductor arm of France's Thomson.[8]
Ericsson Mobile Platforms[edit]
Ericsson Mobile Platforms had been formed in 2001 from Ericsson Mobile Communications during the European telecom crisis around the year 2000. It was a pure platform company after the transfer of all handset products to SonyEricsson, later Sony Mobile. At the forming of ST-Ericsson, Ericsson Mobile Platforms had roughly 3100 employees.[9] Some of EMPs customers were Flextronics, HTC, LG, NEC, Sagem, Sharp and of course Sony Ericsson. The main focus in the company was for the eight years it existed, to develop a platform for UMTS.[10] Their main development centers were situated in Lund, Sweden and with other three developments centers in Basingstoke (UK) and Research Triangle Park, North Carolina (US), and Nuremberg (Germany). In addition, it had R&D, sales and customer support teams in Tokyo (Japan), Shanghai (China), Taipei (Taiwan), Seoul (South Korea), Grimstad (Norway) and Nuremberg (Germany). It provided mobile terminal technology to customers who wanted to develop and produce mobile phones for the GPRS, EDGE and WCDMA mobile standards. EMP and, Ericsson as a whole, donated resources to standardization bodies such as 3GPP, OMA, JCP and OMTP.
Portfolio and mobile products[edit]
Before joining the joint venture, ST Microelectronics' wireless division had been working on the Nomadik application processor platform since the STn8800, which won the Microprocessor Report Analysts' Choice Awards in 2003.[11] Likewise, the NXP part of the company had worked on a product named Nexperia. The Nomadik platform was chosen as a starting point for development of new application processors within the company.[12]
October third, 2008 the predecessor Ericsson Mobile Platforms showcased a handheld prototype for LTE (fourth generation of mobile telephony). At this time, the company stated that the technology would reach the market by roughly 2011.[13] In December 2009 the LTE-platform had a name: M710 and it was presented as a multimode-device that would also be able to handle HSDPA.[14] 1 November 2010 there were statements about a product named M700 and it was said that this would deliver data speeds of 100Mbit/s downstream and 50 Mbit/s upstream.[15]
Starting 15 February 2011 the company presented a whole family of products:[16][17][18][19]
- A series of application processors under the brand name Nova such as A9600, A9540 and A9500.
- A series of modem products under the brand name Thor such as M5720, M5730, M5780, M7300, M7400 and M7450.
- A series of combined products with both application processor and modem under the brand name NovaThor such as T5008, U4500, U8500, L9540, L8540 and L8580.
Many of these products appear to have failed to reach the market. In the press release regarding the last product L8580 it is mentioned that U8500 has been mass-produced and that L8540 is available in samples since the end of 2012.[19] The quarterly results for the fourth quarter 2012 states that the company has shipped 10.7 million units of U8500 during that quarter.[20]
ST-Ericsson's Chinese subsidiary, T3G was acquired in December 2008 and has been developing platforms for the TD-SCDMA mobile standard since 2003.
This section does not cite any references or sources. (April 2013) |
Incorporated in Switzerland and headquartered in Geneva, ST-Ericsson employs around 6,700 people worldwide, more than 85 per cent of whom work in R&D.
ST-Ericsson's main centers are in France, Switzerland, Sweden, Finland, Germany, UK, India, Singapore, China, Japan and Korea.
See also[edit]
- STMicroelectronics Small Shareholders' Group (STM.S.S.G.)
- (French) Collectif Autonome et Démocratique de STMicroelectronics (CAD-ST)
- ^ a b "About us – General Information – ST-Ericsson". stericsson.com. Retrieved 24 February 2011.
- ^ "Ericsson and STMicroelectronics to Create World Leader in Semiconductors and Platforms for Mobile Applications". stericsson.com. 20 August 2008. Retrieved 2013-02-12.
- ^ Leila Abboud (10 December 2012). "STMicro to quit ST-Ericsson mobile chip venture". Reuters.
- ^ "Ericsson and STMicroelectronics agree on strategic way forward for ST-Ericsson". Ericsson. 18 March 2013.
- ^ "ST-Ericsson announces sale of its Connectivity (GNSS) business". Stericsson.com. Retrieved 2013-07-10.
- ^ "Ericsson and STMicroelectronics complete transaction to split up ST-Ericsson". ericsson.com. 5 August 2013. Retrieved 2013-08-05.
- ^ "Ericsson and STMicroelectronics Complete Transaction to split up ST-Ericsson". st.com. 5 August 2013. Retrieved 2013-08-05.
- ^ "STMicroelectronics and NXP Complete Deal to Create New Wireless Semiconductor Company". st.com. 28 July 2008.
- ^ Kroes, Neelie (2008). "Case No COMP/M.5332 – ERICSSON / STM / JV" (PDF) (32008M5332). Luxemburg: Office for Official Publications of the European Communities L-2985 Luxembourg. Retrieved 2012-12-13.
- ^ Kornby, Mikael (2005). "The EMP Story" (PDF). Ericsson Review (1). Ericsson AB. Retrieved 2012-04-07.
- ^ Glaskowsky, Peter N. (9 December 2003). "Microprocessor Report Announces Finalists for the Fifth Annual Analysts' Choice Awards". BusinessWire. Retrieved 2013-05-19.
- ^ Muppala, Nalini Kumar (11 September 2009). "ST-Ericsson (Part 2): Diverse Offering". Sramana Mitra's One Million by One Million Blog. Retrieved 2013-05-19.
- ^ Wessman, Johan (3 October 2013). "Vägen mot framtiden". Sydsvenskan. Retrieved 2013-05-19. Check date values in:
|year= / |date= mismatch
(help) - ^ "ST-Ericsson and Ericsson first to achieve LTE and HSPA mobility with a multimode device". 15 December 2009. Retrieved 2013-05-19.
- ^ "ST-Ericsson enables pioneering video applications demonstration on a TD-LTE tablet". 1 November 2010. Retrieved 2013-05-19.
- ^ "Changing the game: ST-Ericsson Unveils NovaThor™ Family of Smartphone Platforms Combining its Most Advanced Application Processors with the Latest Generation of Modems". 15 February 2011. Retrieved 2013-03-20.
- ^ "ST-Ericsson announces new highly integrated LTE NovaThor platform". 28 February 2012. Retrieved 2013-03-20.
- ^ "ST-Ericsson unveils ultrafast Thor M7450 LTE advanced modem with first single RF carrier aggregation solution". 24 February 2013. Retrieved 2013-03-20.
- ^ a b "ST-Ericsson opens the way for a new era of smartphones and announces the world's fastest, coolest integrated LTE Modem and Application Processor platform based on FD-SOI". 8 January 2013. Retrieved 2013-03-20.
- ^ "ST-Ericsson reports fourth quarter 2012 financial results". 30 January 2013. Retrieved 2013-03-21.
External links[edit]
- ST-Ericsson at the Wayback Machine (archived June 13, 2013)


text:
RCMP have arrested one man and are conducting a massive search of a rural Alberta farm in connection to a series of bombings of B.C. gas pipelines.
Insp. Tim Shields says a man in his 50s or 60s was taken into custody around 8 a.m. this morning on the farm about 25 kilometres east of the B.C.-Alberta boundary.
About a dozen officers are now searching the property.
There have been six pipeline bombings in the Tomslake area since October 2008 targeting Calgary-based Encana (TSX:ECA).
In a letter to local media, the bomber demanded that the company cease operations in the region.
Another letter sent to the Dawson Creek Daily News in July warned that things "could get a lot worse" if the company did not cease operations in the region.
RCMP make arrest, searching Alta. farm connection to BC pipeline bombings
Organizations: RCMP, Encana, TSX Creek Daily News
Geographic location: Alberta, Tomslake
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Tyler Shields is back at it again, destroying expensive stuff for shock value… we mean art… actually we're not certain what we mean. In the past, he fed a $100k Hermes handbag to an alligator. This time he's photographing the explosive destruction a Rolls Royce Silver Shadow.
Posts Tagged 'destroy'
Andean Bears Like Their Privacy, Caught Destroying WiIdlife Cameras
Looks like Kanye West and his ilk aren't the only ones with paparazzi issues. Newly released images from the Wildlife Conservation Society captured endangered Andean bears repeatedly trying (and sometimes succeeding) to destroy camera traps set up to monitor their behavior. Read more…
5 Great Ways to Destroy Your Camera
Many of us know that feeling. That gut punch of shock and denial as we watch our camera fall from our grip or swing to the earth from an unsecured tripod. We've watched as it impacted with the ground with a hard thud or bounced amongst the rocks collecting more damage with every tumble as it travels farther away from the safety of your hands.
Read more…
How Not to Paint Your Nikon D90 Pink
Kai at DigitalRev was recently given the challenge of painting a Nikon D90 pink magenta. He chooses to dismantle the camera in order to paint individual components, but works on it as carefully as one would work on a steak. At one point he even gets an electric shock from the components, though we're wondering why he didn't simply remove the battery. The camera miraculously looks somewhat normal in the end, but several parts are broken in the process (LCD won't turn on, and popup flash wont' go down).
What's interesting is that he takes the pink camera to the Nikon headquarters along with a hidden camera. His interaction with the customer service there is quite hilarious.
Here's the video of the whole "adventure". It's a bit long, and might anger you, but you get to see the internals of a Nikon D90 if you find that sort of thing interesting!
So anyhow, painting your camera like this is definitely something to be avoided. If you've successfully painted your camera without breaking it, leave a comment letting us know!
(via PopPhoto)


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Ancient Chinese Culture
Posts Tagged gentlemen plum blossom
Plum Blossom
Posted by ancient chinese culture in Painting on January 14, 2011
The plum blossom is reputed as a member of the Four Gentlemen in the world of flowers, along with orchid, chrysanthemum, and bamboo.
It braves snow and frost to bloom in the cold winter when most plants have shed their leaves and most flowers have not bloomed yet. Therefore, it is regarded as the symbol of rebirth and growth. It is also admired for its resilience and perseverance in the face of diversity. Read the rest of this entry »


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Genre/Form: | Feature films Drama Film adaptations |
Named Person: | David Lindsay-Abaire |
Material Type: | Videorecording |
Document Type: | Visual material |
All Authors / Contributors: |
Gigi Pritzker; David Lindsay-Abaire; John Cameron Mitchell; Anton Sanko; Ann Roth; Joe Klotz; Kalina Ivanov; Frank G DeMarco; Nicole Kidman; Aaron Eckhart; Dianne Wiest; Tammy Blanchard; Miles Teller; Giancarlo Esposito; Jon Tenney; Patricia Kalember; Julie Lauren; Sandra Oh; Lions Gate Films.; Olympus Pictures.; Blossom Films.; Odd Lot Entertainment (Firm); Lions Gate Entertainment (Firm); et al |
OCLC Number: | 698189536 |
Language Note: | English dialogue with optional English and Spanish subtitles; closed-captioned in English for the hearing impaired. |
Notes: | Originally produced as a motion picture in 2010. Based on the play "Rabbit Hole" by David Lindsay-Abaire. Special features: Filmmakers' commentary; Deleted scenes: Izzy confronts Debbie in supermarket, Driving Izzy home from jail, Bed, bath & beyond; Theatrical trailer; Also from Lionsgate. |
Credits: | Music by Anton Sanko ; costume designer, Ann Roth ; editor, Joe Klotz ; production designer, Kalina Ivanov ; director of photography, Frank G. De Marco. |
Cast: | Nicole Kidman, Aaron Eckhart, Dianne Wiest, Tammy Blanchard, Miles Teller, Giancarlo Esposito, Jon Tenney, Patricia Kalember, Julie Lauren, Sandra Oh. |
Awards: | 2011 Golden Globe & SAG Award Nomination Best Actress Nicole Kidman; 4 Spirit Award Nominations. |
Target Audience: | MPAA rating: PG-13; mature thematic material, some drug use and language. |
Description: | 1 videodisc (ca. 92 min.) : sd., col. ; 4 3/4 in. |
Details: | DVD; NTSC, Dolby digital 5.1, widescreen (1.78:1). |
Responsibility: | Lionsgate presents ; Olympus Pictures, Blossom Films, Oddlot Entertainment ; produced by Gigi Pritzker ... [et al.] ; screenplay by David Lindsay-Abaire ; directed by John Cameron Mitchell. |
WorldCat User Reviews (1)
Melancholy Hopefulness
Rabbit Hole invoked a feeling of thoughtful and gentle sadness...the personal horrors of everyday life, family feelings defined by loss and the mundane existence of ever passing moments. ...and just as life eventually makes a turn for the better, so does Rabbit Hole...a...
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Rabbit Hole invoked a feeling of thoughtful and gentle sadness...the personal horrors of everyday life, family feelings defined by loss and the mundane existence of ever passing moments. ...and just as life eventually makes a turn for the better, so does Rabbit Hole...a quiet lifting on the wings of honesty and hope. Rabbit Hole is a wonderful road trip into the country away from skyscrapers, sirens, crowds and pollution. Rabbit Hole is a "place" where you can spend an hour and relax...it is a wonderful movie to "visit".
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