text:
Parkland RCMP charge five in impaired driving sting
The Parkland RCMP joined detachments from across the country in sending impaired drivers a clear message.
On Dec. 7, the RCMP banded together from coast to coast to launch National Impaired Driving Enforcement Day, a day where officers make a concerted effort to keep dangerous drivers off the roads.
The Parkland RCMP set up nine check tsp points where a total of 365 vehicles were checked, resulting in 15 roadside suspensions and five criminal charges for impaired driving.
"Our goal is to detect impaired drivers, get these drivers off of our roads and keep our community safe," said Inspector Mike Lokken.
This brings the total number of complaints of impaired driving to 627 in 2019, resulting in a total of 189 charges laid. The detachment is one of the provincial leaders when it comes to enforcement, media contact Constable Shelley Nasheim said they are fully equipped to continue getting the job done.
"Mandatory Alcohol Screening and Standard Field Sobriety Testing has assisted those officers with a talent for impaired detection and those that are developing the skills," Nasheim said.
According to Mothers Against Drunk Driving, every day there are four Canadians killed and 175 injured in impaired driving collisions. Those numbers get worse in Alberta, where MADD estimates one in five drivers involved in fatal collisions had consumed alcohol before the collision. They add as the severity of a crash increases, the likelihood there was alcohol involved goes up as well.
In further efforts to drive the message home, the RCMP will partner with MADD for the thirteenth straight year as they hit the streets to give out candy canes and anti drinking and driving ribbons. The annual Candy Cane Event will once again make stops in Spruce Grove and Stony Plain.
As for the check stops, the RCMP added National Impaired Driving Enforcement Day is just another in a long line of operations aiming to keep impaired drivers off of the roads. Just because the day has come and passed, does not mean residents will not find themselves driving through a checkpoint sooner or later.
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The Grow Lab GL80 is perfect for producing cuttings, holding mother plants or growing a small number of plants.
Perfect for holding one 2' x 2' tray, this room works great with one 250 or 400 watt lighting system, or with a 2' T5 fluorescent lighting system (the 8 lamp fixture fits perfect!), or with one or more compact fluorescents.Material:
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250 or 400 watt HPS or T5 fluorescent systemDimensions:
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Intake windows: 3
Doors: 1
- Increased weight capacity - roof cross-members easily support 100 pounds.
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The GrowLab utilizes thermal film on the interior which is highly reflective, waterproof, and extremely insulative (offering 97% thermal protection). This film is also non-toxic and won't release any harmful gasses that can damage sensitive plants. All of the zippers used in the tent are extremely durable.
The GrowLab utilizes intake/exhaust ports that allows them to adjust to fit various sizes of ducting. Drawstrings eliminate the need for duct hose clamps and make installation of ducting and fans quick and easy. The GrowLab also utilizes the same type of socks to allow cords and tubing to enter or exit the structure while keeping light from doing the same. All GrowLab models have a sock port in the back corner of the roof where the exhaust fan can be attached. Instead of strapping the fan to the interior of the tent you can simply sit the fan in the port on the roof for an easy and effective mounting solution.
Item Number: 136751
International Article Number: 4260220920748
Manufacturer: GrowLab Horticultural
Manufacturer's Part Number: GL80
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Moussa Thiam is a civil engineer and holder of a Master's degree in Mathematics from AIMS-Senegal. He is currently a PhD candidate in Civil and Environmental Engineering at the University of Ottawa, in collaboration with the National School of Engineering of Mali, where he is Assistant Professor. He is working on developing tools to transform environmental constraints into an opportunity in Africa, such as this "CABA project", which consists of developing climate models making it possible to optimize the use of water resources, especially in agriculture, the forecasting of extreme events, such as flooding.


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Elaine Faye Burke Lott, of Graniteville, SC, 67, entered into rest May 15, 2020, at her home. Elaine was born on October 31, 1952, in Millen, GA. She attended schools in Waynesboro, graduating in 1970 from Waynesboro High School and was a graduate... View Obituary & Service Information
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DNA taken from baby born to girl who belonged to polygamist sect
SAN ANTONIO €" Investigators from the Texas attorney general's office on Monday took DNA samples from a baby born to a member of a polygamist sect months after a high-profile raid, thwarting efforts by the baby's mother to prevent the sample from being collected.
Jerry Strickland, a spokesman for the office, confirmed late Monday that investigators executed a search warrant and gathered a DNA swab. The attorney general's office is handling the prosecution of some members of the Fundamentalist Church of Jesus Christ of Latter Day Saints accused of charges including bigamy and sexual assault of a child.
Child-welfare authorities previously tried to examine and collect a sample from the baby born June 14, saying they wanted to establish paternity, but the baby's 17-year-old mother refused to disclose the child's whereabouts. A standoff in court in San Angelo on Nov. 25 led to an undisclosed agreement between the two sides.
But the search warrant, obtained in criminal court, forced the issue.
Child Protective Services said in court filings that investigators believe the girl was married to a man in the sect when she was 14. In Texas, someone younger than 17 generally cannot consent to sex with an adult.
Twelve FLDS men, including the sect's jailed prophet, Warren Jeffs, have been indicted on charges related to underage marriages and bigamy. Jeffs, convicted in Utah as an accomplice to rape, awaits trial in Arizona on other charges related to the marriages of sect girls there.
We appreciate your support
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A 61-year-old man drowned when a tugboat towing a 'Ro-Pax' ferry vessel capsized near Dahej jetty in Bharuch district of Gujarat, police said today.
The accident occurred yesterday afternoon, just two days ahead of the launch of the Ro-Pax (roll-on roll-off passenger) ferry service between Ghogha and Dahej. Chief Minister Vijay Rupani is scheduled to inaugurate the service tomorrow.
Of the total seven sailors on board the tugboat pulling the vessel, six were rescued after they jumped into the sea immediately after the tugboat overturned near Dahej jetty, around 230 kms from Ahmedabad, police said.
"However, the master of the tugboat, Hira Jethwa, drowned," an official of Dahej marine police station said. Police inspector RK Ladva said the deceased was a resident of Ghogha village in Bhavnagar district and was working as the master of the tugboat that was deployed for moving the ferry vessel at Dahej jetty.
"Jethwa's body was recovered from beneath the overturned tugboat late last night. While six sailors jumped into the sea and were saved by rescuers, Jethwa somehow could not escape and drowned," he said.
Police have registered a case of accidental death and launched a probe into the incident.
The Ro-Pax ferry service will connect Ghogha in Saurashtra and Dahej in south Gujarat via sea route that passes from the Gulf of Cambay.
A 'passenger only' Ro-Ro ferry service was inaugurated by Prime Minister Narendra Modi in October last year ahead of the Gujarat Assembly polls. Now, the Ro-Pax ferry service will transport both- passengers as well as vehicles.
Indigo Seaways Pvt Ltd (ISPL) a Surat-based firm, and the Gujarat Maritime Board are operating the project on the Public Private Partnership (PPP) model.


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You are here: Home > Prescription(RX) Drugs > S > Simcor (Abbott Laboratories)
niacin and
simvastatin tablet, film coated, extended release
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
1.1 Patients with Hypercholesterolemia Requiring Modifications of Lipid Profiles
SIMCOR is indicated to reduce Total-C, LDL-C, Apo B, non-HDL-C, TG, or to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate.
SIMCOR is indicated to reduce TG in patients with hypertriglyceridemia when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate.
No incremental benefit of SIMCOR on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin monotherapy and niacin monotherapy has been established.
2.1 Recommended Dosing
SIMCOR should be taken as a single daily dose at bedtime, with a low fat snack. Patients not currently on niacin extended-release and patients currently on niacin products other than niacin extended-release should start SIMCOR at a single 500/20 mg tablet daily at bedtime. Patients already taking simvastatin 20 to 40 mg who need additional management of their lipid levels may be started on a SIMCOR dose of 500/40 mg once daily at bedtime. [See Warnings and Precautions (5.2)]. The dose of niacin extended-release should not be increased by more than 500 mg daily every 4 weeks - see Table 1.
The recommended maintenance dose for SIMCOR is 1000/20 mg to 2000/40 mg (two 1000/20 mg tablets) once daily depending on patient tolerability and lipid levels. The efficacy and safety of doses of SIMCOR greater than 2000/40 mg daily have not been studied and are therefore not recommended.
If SIMCOR therapy is discontinued for an extended period of time (> 7 days), re-titration as tolerated is recommended. SIMCOR tablets should be taken whole and should not be broken, crushed, or chewed before swallowing.
Due to the increased risk of hepatotoxicity with other modified-release (sustained-release or time-release) niacin preparations or immediate-release (crystalline) niacin, SIMCOR should only be substituted for equivalent doses of niacin extended-release (NIASPAN).
Flushing [See Adverse Reactions (6.1)] may be reduced in frequency or severity by pretreatment with aspirin up to the recommended dose of 325 mg (taken approximately 30 minutes prior to SIMCOR dose). Flushing, pruritus, and gastrointestinal distress are also reduced by gradually increasing the dose of niacin (refer to Table 1) and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of SIMCOR ingestion.
2.2 Coadministration with Other DrugsPatients taking Amlodipine or Ranolazine
SIMCOR tablets are formulated for oral administration in the following strength combinations:
SIMCOR is contraindicated in the following conditions:
SIMCOR should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to SIMCOR, therapy with SIMCOR should be initiated at 500/20 mg and appropriately titrated to the desired therapeutic response. Patients already taking simvastatin 20-40 mg who need additional management of their lipid levels may be started on a SIMCOR dose of 500/40 mg once daily at bedtime. Doses of SIMCOR greater than 2000/40 mg are not recommended.
5.1 Myopathy/Rhabdomyolysis
Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with ZOCOR (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day; the incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) was approximately 0.4% in patients on 80 mg/day compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
All patients starting therapy with SIMCOR, or whose dose of SIMCOR is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report symptoms promptly. SIMCOR therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
The combined use of SIMCOR with amiodarone, verapamil, or diltiazem is contraindicated, because dosages of simvastatin are not to exceed 10 mg when these drugs are co-administered and all doses of SIMCOR contain simvastatin in excess of 10 mg. [See Contraindications (4) and Drug Interactions (7.2) ].
The combined use of SIMCOR with drugs that cause myopathy/rhabdomyolysis when given alone, such as fibrates, should be avoided [See Drug Interactions (7.3)].
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing SIMCOR with colchicine [see Drug Interactions (7.8)].
The benefits of the combined use of SIMCOR with amlodipine or ranolazine should be carefully weighed against the potential risks of combination. [See Drug Interactions (7.4)]. Periodic CK determinations may be considered in patients starting therapy with or increasing the dose of these agents, but there is no assurance that such monitoring will prevent myopathy.
Myopathy and/or rhabdomyolysis have been reported when simvastatin is used in combination with lipid-altering doses (≥ 1 gram/day) of niacin. Physicians contemplating the use of SIMCOR, a combination of simvastatin and niacin extended-release (NIASPAN), should weigh the potential benefits and risks, and should carefully monitor for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial month of treatment or during any period of upward dosage titration of either drug. Periodic determination of serum creatine kinase (CK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent myopathy.
Patients starting therapy with SIMCOR should be advised of the risk of myopathy, and told to report promptly unexplained muscle pain, tenderness, or weakness. A CK level above ten times the upper limit of normal (ULN) in a patient with unexplained muscle symptoms indicates myopathy. SIMCOR therapy should be discontinued if myopathy is diagnosed or suspected.
In patients with complicated medical histories predisposing to rhabdomyolysis, such as renal insufficiency, dose escalation requires caution. Also, as there are no known adverse consequences of brief interruption of therapy, treatment with SIMCOR should be stopped for a few days before elective major surgery and when any major acute medical or surgical condition supervenes (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).
5.2 Liver Dysfunction
Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release (modified-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses. Patients previously receiving niacin products other than niacin extended-release (NIASPAN) should be started on SIMCOR at the lowest recommended starting dose. [See Dosage and Administration (2)]
SIMCOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of SIMCOR. [See Contraindications (4)]
Niacin extended-release (NIASPAN) and simvastatin can cause abnormal liver tests. In a simvastatin-controlled, 24 week study with SIMCOR in 641 patients, there were no persistent increases (to more than 3x the ULN) in serum transaminases. In three placebo-controlled clinical studies of niacin extended-release, patients with normal serum transaminases levels at baseline did not experience any transaminase elevations greater than 3x the ULN. Persistent increases (to more than 3x the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminases levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.
Liver function tests should be performed on all patients during therapy with SIMCOR. It is recommended that liver function tests be performed before treatment begins, every 12 weeks for the first 6 months, and periodically thereafter (e.g., at approximately 6-month intervals). Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality returns to normal. Should an increase in transaminase levels of more than 3x ULN persist, or if transaminase elevations are associated with symptoms of nausea, fever, and/or malaise, withdrawal of SIMCOR therapy is recommended. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1) ].
5.3 Laboratory Abnormalities
Increase in Blood Glucose: Niacin treatment can increase fasting blood glucose. In a simvastatin-controlled, 24-week study with SIMCOR the change from baseline in glycosylated hemoglobin levels was 0.2% for SIMCOR-treated patients and 0.2% for simvastatin-treated patients. Diabetic or potentially diabetic patients should be observed closely during treatment with SIMCOR, particularly during the first few months of therapy. Adjustment of diet and/or hypoglycemic therapy or discontinuation of SIMCOR may be necessary.
Reduction in platelet count: Niacin can reduce platelet count. In a simvastatin-controlled, 24-week study with SIMCOR the mean percent change from baseline for patients treated with 2000/40 mg daily was -5.6%.
Increase in ProthrombinTime (PT): Niacin can cause small increases in PT . In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen.
Increase in Uric Acid: Elevated uric acid levels have occurred with niacin therapy. In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen. Nevertheless, in patients predisposed to gout, SIMCOR therapy should be used with caution.
Decrease in Phosphorus: Small dose-related reductions in phosphorous levels were seen in clinical studies with niacin. In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen.
In a controlled clinical study, 14% of patients randomized to SIMCOR discontinued therapy due to an adverse event. Flushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse reactions, occurring in up to 59% of patients treated with SIMCOR. Spontaneous reports with niacin extended-release and clinical studies of SIMCOR suggest that flushing may be accompanied by symptoms of dizziness or syncope, tachycardia, palpitations, shortness of breath, sweating, burning sensation/skin burning sensation, chills, and/or edema.
6.1 Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
The safety data described below reflect exposure to SIMCOR in 403 patients in a controlled study for a period of 6 months.
Flushing: Flushing (warmth, redness, itching and/or tingling) occurred in up to 59% of patients treated with SIMCOR. Flushing resulted in study discontinuation for 6.0% of patients.
More Common Adverse Reactions: In addition to flushing, adverse reactions occurring in ≥ 3% of patients (irrespective of investigator causality) treated with SIMCOR are shown in Table 4 below:
In pre-marketing controlled clinical studies and their open extensions (2,423 patients with mean duration of follow-up of approximately 18 months) 1.4% of patients discontinued due to adverse reactions. The most commonly reported adverse reactions (incidence > 1%) in simvastatin controlled clinical trials were: headache (3.5%), abdominal pain (3.5%), constipation (2.3%), upper respiratory infection (2.1%), diarrhea (1.9%), and flatulence (1.9%).
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment.
In placebo-controlled clinical trials (n=245), flushing episodes were the most common treatment-emergent adverse events (up to 88% of patients) for niacin extended-release. Other adverse events occurring in 5% or greater of patients treated with niacin extended-release are headache (9%), diarrhea (7%), nausea (5%), rhinitis (5%), and dyspepsia (4%) at a maintenance dose of 1000mg daily.
Clinical Laboratory Abnormalities:
Elevations in serum transaminases [See Warnings and Precautions (5.2)], CK, fasting glucose, uric acid, alkaline phosphatase, LDH, amylase, γ-glutamyl transpeptidase, bilirubin, and reductions in phosphorus, and abnormal thyroid function tests.
Reductions in platelet counts and prolongation of PT. [See Warnings and Precautions (5.3)]
6.2 Postmarketing Experience
See also the full prescribing information for niacin extended release (Niaspan) and simvastatin products.
Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following additional adverse reactions have been identified during postapproval use of simvastatin. Hypersensitivity reaction including one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, vasculitis, purpura, thrombocytopenia, leucopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, photosensitivity, chills, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, urticaria, fever, dyspnea, and arthralgia; pancreatitis, hepatitis, hepatic failure, pruritus, cataracts, polymyositis, dermatomyositis, polymyalgia rheumatica, global amnesia, tendon rupture, peripheral neuropathy, memory impairment, erectile dysfunction, depression, interstitial lung disease, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), muscle cramps, vomiting, malaise.
The following additional adverse reactions have been identified during post-approval use of NIASPAN. Hypersensitivity reaction including one or more of the following features: anaphylaxis, dyspnea, angioedema, tongue edema, larynx edema, face edema, laryngismus; tachycardia, atrial fibrillation, other cardiac arrhythmias, palpitations, hypotension, postural hypotension, dizziness, syncope, flushing, burning sensation/skin burning sensation, paresthesia, urticaria, vesiculobullous rash, maculopapular rash, sweating, dry skin, skin discoloration, blurred vision, macular edema, myalgia, myopathy, peptic ulcers, eructation, flatulence, hepatitis, jaundice, peripheral edema, asthenia, nervousness, insomnia, migraine, gout, and decreased glucose tolerance.
No drug interaction studies were conducted with SIMCOR. However, the following interactions have been noted with the individual components of SIMCOR:
7.1 Strong CYP3A4 Inhibitors, cyclosporine, or danazol
Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.
Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of SIMCOR. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)]. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with SIMCOR must be suspended during the course of treatment.
Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentration of simvastatin. It is recommended that dose adjustment of SIMCOR be considered during concomitant use of voriconazole and SIMCOR to reduce the risk of myopathy, including rhabdomyolysis. [see Warnings and Precautions (5.1).]
Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated. [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]
7.2 Amiodarone, Verapamil, or Diltiazem
The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of amiodarone, verapamil, or diltiazem with doses of simvastatin exceeding 10 mg. Because all doses of SIMCOR contain simvastatin in excess of 10 mg, concomitant use of these drugs is contraindicated.[see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]
7.3 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
Gemfibrozil: Contraindicated with SIMCOR [see Contraindications (4) and Warnings and Precautions (5.1)]. Other fibrates: Combined use with SIMCOR should be avoided. [see Warnings and Precautions (5.1).]
7.4 Amlodipine or Ranolazine
The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amlodipine or ranolazine [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)and Table 3 inClinical Pharmacology (12.3)].
7.5 Propranolol
In healthy male volunteers there was a significant decrease in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors with concomitant administration of single doses of simvastatin and propranolol. The clinical relevance of this finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.
7.6 Digoxin
Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation (less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when SIMCOR is initiated.
7.7 Coumarin Anticoagulants
In normal volunteers and hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants since the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteers and patients, respectively. With other reductase inhibitors, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting SIMCOR and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of SIMCOR is changed or discontinued, the same procedure should be repeated.
7.8 Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing SIMCOR with colchicine.[see Warnings and Precautions (5.1)
7.9 Aspirin
Concomitant use of aspirin may decrease the metabolic clearance of niacin. The clinical relevance of this finding is unclear.
7.10 Antihypertensive Therapy
Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension.
7.11 Bile Acid Sequestrants
An in vitro study was carried out investigating the niacin-binding capacity of colestipol and cholestyramine. About 98% of available niacin was bound to colestipol, with 10 to 30% binding to cholestyramine. These results suggest that 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of SIMCOR.
8.1 Pregnancy
Pregnancy Category X – [See Contraindications (4)]
SIMCOR is contraindicated in women who are or may become pregnant. Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of SIMCOR use during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to HMG-CoA reductase inhibitors in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. SIMCOR may cause fetal harm when administered to a pregnant woman. If SIMCOR is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
SIMCOR contains simvastatin (a HMG-CoA reductase inhibitor) and niacin (nicotinic acid). There are rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. It is not known whether niacin at doses used for lipid disorders can cause fetal harm when administered to a pregnant woman.
Simvastatin was not teratogenic in rats or rabbits at doses that resulted in 3 times the human exposure based on mg/m2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice. Animal reproduction studies have not been conducted with niacin.
Women of childbearing potential, who require SIMCOR treatment for a lipid disorder, should use effective contraception. Patients trying to conceive should contact their prescriber to discuss stopping SIMCOR treatment. If pregnancy occurs, SIMCOR should be immediately discontinued.
8.3 Nursing Mothers
It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Niacin is excreted into human milk but the actual infant dose or infant dose as a percent of the maternal dose is not known. Because of the potential for serious adverse reactions in nursing infants, nursing mothers who require SIMCOR treatment should not breastfeed their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. [see Contraindications (4)].
8.4 Pediatric Use
The safety and effectiveness of SIMCOR in pediatric patients have not been established.
8.5 Geriatric Use
There were 281 (30.8%) patients aged 65 years and older treated with SIMCOR in Phase III clinical studies. No overall differences in safety and effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age.
Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, SIMCOR should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
8.6 Gender
Data from the clinical trials suggest that women have a greater hypolipidemic response than men at equivalent doses of niacin extended-release. No consistent gender differences in efficacy and safety were observed in SIMCOR studies.
8.7 Renal Impairment
No pharmacokinetic studies have been conducted in patients with renal impairment for SIMCOR. Caution should be exercised when SIMCOR is administered to patients with renal disease. For patients with severe renal insufficiency, SIMCOR should not be started unless the patient has already tolerated treatment with simvastatin at a dose of 10 mg or higher. Caution should be exercised when SIMCOR is administered to these patients and they should be closely monitored.
8.8 Hepatic Impairment
No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for SIMCOR. [See Warnings and Precautions (5.2).]
Supportive measures should be taken in the event of an overdose. The dialyzability of niacin, or of simvastatin and its metabolites, is not known.
A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.
SIMCOR tablets contain niacin extended-release (NIASPAN) and simvastatin in combination. Simvastatin, an inhibitor of HMG-CoA reductase, and niacin are both lipid-altering agents.
Niacin is nicotinic acid, or 3-pyridinecarboxylic acid. Niacin is a white, nonhygroscopic crystalline powder that is very soluble in water, boiling ethanol, and propylene glycol. It is insoluble in ethyl ether. The empirical formula of niacin is C6H5NO2 and its molecular weight is 123.11. Niacin has the following structural formula:
Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3-7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*4S*),-8aβ]]. Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water and freely soluble in chloroform, methanol, and ethanol. The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57. Simvastatin has the following structural formula:
SIMCOR is available for oral administration as tablets containing 500 mg of niacin extended-release (NIASPAN) and 20 mg simvastatin (SIMCOR 500/20 mg), 500 mg of niacin extended-release (NIASPAN) and 40 mg simvastatin (SIMCOR 500/40 mg), 750 mg of niacin extended-release (NIASPAN) and 20 mg simvastatin (SIMCOR 750/20 mg), 1000 mg of niacin extended-release (NIASPAN) and 20 mg simvastatin (SIMCOR 1000/20 mg) and 1000 mg of niacin extended-release (NIASPAN) and 40 mg simvastatin (SIMCOR 1000/40 mg). Each tablet contains the following inactive ingredients: hypromellose, povidone, stearic acid, polyethylene glycol, butylated hydroxyanisole, FD&C Blue #2, lactose monohydrate, titanium dioxide, triacetin. SIMCOR 500/20 mg, SIMCOR 750/20 mg, and SIMCOR 1000/20 mg also contain iron oxide.
12.1 Mechanism of Action
Niacin functions in the body after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. The mechanism by which niacin alters lipid profiles is not completely understood and may involve several actions, including partial inhibition of release of free fatty acids from adipose tissue, and increased lipoprotein lipase activity (which may increase the rate of chylomicron triglyceride removal from plasma). Niacin decreases the rate of hepatic synthesis of VLDL-C and LDL-C, and does not appear to affect fecal excretion of fats, sterols, or bile acids.
Simvastatin is a prodrug and is hydrolyzed to its active ß-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.
12.2 Pharmacodynamics
A variety of clinical studies have demonstrated that elevated levels of Total-C, LDL-C, and Apo B promote human atherosclerosis. Similarly, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C, and inversely with the level of HDL-C.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoprotein (IDL), and their remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (CHD). As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
SIMCOR reduces Total-C, LDL-C, non-HDL-C, Apo B, TG, and Lp(a) levels and increases HDL-C in patients with primary hyperlipidemia, mixed dyslipidemia, or hypertriglyceridemia.
Niacin (but not nicotinamide) in gram doses reduces LDL-C, Apo B, Lp(a), TG, and Total-C, and increases HDL-C. The magnitude of individual lipid and lipoprotein responses may be influenced by the severity and type of underlying lipid abnormality. The increase in HDL-C is associated with an increase in apolipoprotein A-I (Apo A-I) and a shift in the distribution of HDL subfractions. These shifts include an increase in the HDL2:HDL3 ratio, and an elevation in lipoprotein A-I (Lp A-I, an HDL-C particle containing only Apo A-I). Niacin treatment also decreases serum levels of apolipoprotein B-100 (Apo B), the major protein component of the very low-density lipoprotein (VLDL) and LDL fractions, and of Lp(a), a variant form of LDL independently associated with coronary risk. In addition, preliminary reports suggest that niacin causes favorable LDL particle size transformations, although the clinical relevance of this effect requires further investigation.
Simvastatin reduces elevated Total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients with primary heterozygous familial and nonfamilial hypercholesterolemia and mixed dyslipidemia. Simvastatin reduces Total-C and LDL-C in patients with homozygous familial hypercholesterolemia. Simvastatin decreases VLDL, Total-C/HDL-C ratio, and LDL-C/HDL-C ratio.
12.3 Pharmacokinetics
Absorption and Bioavailability
The relative bioavailability of niacin (Nicotinuric acid, NUA, Cmax and total urinary excretion as the surrogate), simvastatin, and simvastatin acid was evaluated under a light snack conditions in healthy volunteers (n=42), following administration of two 1000/20 mg SIMCOR tablets. Niacin exposure (Cmax and AUC) after SIMCOR was similar to that of a niacin extended-release formulation. However, simvastatin and simvastatin acid AUC after SIMCOR increased by 23% and 41%, respectively, compared to those of a simvastatin immediate release formulation. The mean time to Cmax (Tmax) for niacin ranged from 4.6 to 4.9 hours and simvastatin from 1.9 to 2.0 hours. Following administration of 2 x 1000/20 mg SIMCOR, the mean Cmax, Tmax and AUC(0-t) for simvastatin acid, active metabolite of simvastatin, were 3.29 ng/mL, 6.56 hours and 30.81 ng.hr/mL respectively.
Bioequivalence has not been evaluated among different SIMCOR dosage strengths except between 1000/40 and 500/20 mg. SIMCOR tablets 1000/40 mg and 500/20 mg were bioequivalent following a single dose of 2000/80 mg. Therefore, dosage strengths of SIMCOR should not be considered exchangeable except between these two strengths.
Due to extensive and saturable first-pass metabolism, niacin concentrations in the general circulation are dose dependent and highly variable. Peak steady-state niacin concentrations were 0.6, 4.9, and 15.5 mcg/mL after doses of 1000, 1500, and 2000 mg NIASPAN once daily (given as two 500 mg, two 750 mg, and two 1000 mg tablets, respectively). To reduce the risk of gastrointestinal upset, administration of niacin extended-release with a low-fat meal or snack is recommended.
Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%). Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. Following an oral dose of 14C-labeled simvastatin in man, plasma concentration of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.
Following administration of SIMCOR, niacin and simvastatin undergo rapid and extensive first-pass metabolism as described in the following niacin and simvastatin sections. Following administration of 2 x 1000/20 mg SIMCOR in healthy volunteers, 10.2%, 10.7%, and 29.5% of the administered niacin dose was recovered in urine as niacin metabolites, NUA, N-methylnicotinamide (MNA), and N-methyl-2-pyridone-5-carboxamide (2PY), respectively. Following administration of 2 x 1000/20 mg SIMCOR, the mean Cmax, Tmax, and AUC(0-t) for the simvastatin metabolite, simvastatin acid were 3.29 ng/mL, 6.56hours, and 30.81ng·hr/mL respectively.
Niacin undergoes rapid and extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. In humans, one pathway is through a simple conjugation step with glycine to form NUA. NUA is then excreted, although there may be a small amount of reversible metabolism back to niacin. The other pathway results in the formation of nicotinamide adenine dinucleotide (NAD). It is unclear whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is further metabolized to at least MNA and nicotinamide-N-oxide NNO. MNA is further metabolized to two other compounds, 2PY and N-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans.
Simvastatin is a substrate of CYP3A4. Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives.
Following 2 x 1000/20 mg SIMCOR administration, approximately 54% of the niacin dose administered was recovered in urine in 96 hours as niacin and metabolites of which 3.6% was recovered as niacin.
After SIMCOR administration, the mean terminal plasma half-life for simvastatin was 4.2 to 4.9 hours and for simvastatin acid was 4.6 to 5.0 hours.
Niacin and its metabolites are rapidly eliminated in the urine. Following single and multiple doses of 1500 to 2000 mg niacin, approximately 53 to 77% of the niacin dose administered as NIASPAN was recovered in urine as niacin and metabolites; up to 7.7% of the dose was recovered in urine as unchanged niacin after multiple dosing with 2 x 1000 mg NIASPAN. The ratio of metabolites recovered in the urine was dependent on the dose administered.
Simvastatin is excreted in urine, based on studies in humans. Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces.
A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age.
Steady-state plasma concentrations of niacin and metabolites after administration of niacin extended-release are generally higher in women than in men, with the magnitude of the difference varying with dose and metabolite. Recovery of niacin and metabolites in urine, however, is generally similar for men and women, indicating that absorption is similar for both genders. The gender differences observed in plasma levels of niacin and its metabolites may be due to gender-specific differences in metabolic rate or volume of distribution.
Pharmacokinetic studies with a statin having a similar principal route of elimination to that of simvastatin have suggested that for a given dose level, higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance).
Drug Interaction
Simvastatin effect on other drugs:
In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.
Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL.
Niacin did not affect fluvastatin pharmacokinetics.
When NIASPAN 2000 mg and lovastatin 40 mg were co-administered, NIASPAN increased lovastatin Cmax and AUC by 2% and 14%, respectively, and decreased lovastatin acid Cmax and AUC by 22% and 2%, respectively. Lovastatin reduced NIASPAN bioavailability by 2-3%.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been conducted with SIMCOR regarding carcinogenesis, mutagenesis, or impairment of fertility.
Niacin, administered to mice for a lifetime as a 1% solution in drinking water, was not carcinogenic. The mice in this study received approximately 6 to 8 times a human dose of 3000 mg/day as determined on a mg/m2 basis. Niacin was negative for mutagenicity in the Ames test. No studies on impairment of fertility have been performed.
In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.
In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other HMG-CoA reductase inhibitors. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.
13.2 Animal Toxicology and/or Pharmacology
No animal toxicology or pharmacology studies were done with SIMCOR.
No animal toxicology or pharmacology studies were done with niacin extended-release.
Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day. A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.
Central Nervous System (CNS) vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.
There were cataracts in female rats after two years of simvastatin treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).
Reproductive Toxicology Studies
Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day or in rabbits at doses up to 10 mg/kg/day. These doses resulted in 3 times (rat) or 3 times (rabbit) the human exposure based on mg/m2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice.
14.1 Modifications of Lipid Profiles
In a double-blind, randomized, multicenter, multi-national, active-controlled, 24-week study, the lipid effects of SIMCOR were compared to simvastatin 20 mg and 80 mg in 641 patients with type II hyperlipidemia or mixed dyslipidemia. Following a lipid qualification phase, patients were eligible to enter one of two treatment groups. In Group A, patients on simvastatin 20 mg monotherapy with elevated non-HDL levels and LDL-C levels at goal, per the NCEP guidelines, were randomized to one of three treatment arms: SIMCOR 1000/20 mg, SIMCOR 2000/20 mg, or simvastatin 20 mg. In Group B, patients on simvastatin 40 mg monotherapy, with elevated non-HDL levels per the NCEP guidelines regardless of attainment of LDL-C goals, were randomized to one of three treatment arms: SIMCOR 1000/40 mg, SIMCOR 2000/40 mg, or simvastatin 80 mg. Therapy was initiated at the 500 mg dose of SIMCOR and increased by 500 mg every four weeks. Thus patients were titrated to the 1000 mg dose of SIMCOR after four weeks and to the 2000 mg dose of SIMCOR after 12 weeks. All patients randomized to simvastatin monotherapy received 50 mg immediate-release niacin daily in an attempt to keep the study from becoming unblinded due to flushing in the SIMCOR groups. Patients were instructed to take one 325 mg aspirin 30 minutes prior to taking the double-blind medication to help minimize flushing effects.
In Group A, the primary efficacy analysis was a comparison of the mean percent change in non-HDL levels between the SIMCOR 2000/20 mg and simvastatin 20 mg groups, and if statistically significant, then a comparison was conducted between the SIMCOR 1000/20 mg and simvastatin 20 mg groups. In Group B, the primary efficacy analysis was a determination of whether the mean percent change in non-HDL in the SIMCOR 2000/40 mg group was non-inferior to the mean percent change in the simvastatin 80 mg group, and if so, whether the mean percent change in non-HDL in the SIMCOR 1000/40 mg group was non-inferior to the mean percent change in the simvastatin 80 mg group.
In Group A, the non-HDL-C lowering with SIMCOR 2000/20 and SIMCOR 1000/20 was statistically significantly greater than that achieved with simvastatin 20 mg after 24 weeks (p<0.05; Table 6). The completion rate after 24 weeks was 72% for the SIMCOR arms and 88% for the simvastatin 20 mg arm. In Group B, the non-HDL-C lowering with SIMCOR 2000/40 and SIMCOR 1000/40 was non-inferior to that achieved with simvastatin 80 mg after 24 weeks (Table 7). The completion rate after 24 weeks was 78% for the SIMCOR arms and 80% for the simvastatin 80 mg arm.
SIMCOR was not superior to simvastatin in lowering LDL-C in either Group A or Group B. However, SIMCOR was superior to simvastatin in both groups in lowering TG and raising HDL (Tables 8 and 9).
No incremental benefit of SIMCOR on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin monotherapy and niacin monotherapy has been established.
SIMCOR 500 mg/20 mg, 750 mg/20 mg and 1000 mg/20 mg tablets are available as blue, unscored, tablets, printed with black ink and packaged in bottles of 90 tablets. SIMCOR 500 mg/40 mg and 1000 mg/40 mg tablets are available as dark blue, unscored, tablets, printed with white ink and packaged in bottles of 90 tablets. Each tablet is printed on one side with the Abbott "A" and a code number specific to the tablet strength. Please see the table below:
Storage: Store at controlled room temperature 20º-25ºC (68º-77ºF).
Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.
Patients should be advised about substances they should not take concomitantly with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking SIMCOR.
17.1 Muscle Pain
All patients starting therapy with SIMCOR should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of myopathy, including rhabdomyolysis, occurring with the use of SIMCOR is increased when taking certain types of medication or consuming larger quantities of grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional.
17.2 Dosing Time
SIMCOR tablets should be taken at bedtime, after a low-fat snack. Administration on an empty stomach is not recommended.
17.3 Tablet Integrity
SIMCOR tablets should not be broken, crushed or chewed, but should be swallowed whole.
17.4 Dosing Interruption
If dosing is interrupted for any length of time, their physician should be contacted prior to re-starting therapy; re-titration is recommended.
17.5 Flushing
Flushing is a common side effect of niacin therapy that may subside after several weeks of consistent SIMCOR use. Flushing may vary in severity and is more likely to occur with initiation of therapy, or during dose increases. By dosing at bedtime, flushing will most likely occur during sleep. However, if awakened by flushing at night, the patient should get up slowly, especially if feeling dizzy, feeling faint, or taking blood pressure medications.
17.7 Diet
To avoid ingestion of alcohol, hot beverages and spicy foods around the time of taking SIMCOR to minimize flushing.
17.8 Supplements
To notify their physician if they are taking vitamins or other nutritional supplements containing niacin or nicotinamide.
17.11 Pregnancy
Women of childbearing age should use an effective method of birth control to prevent pregnancy while using SIMCOR. Discuss future pregnancy plans with your healthcare professional, and discuss when to stop SIMCOR if you are trying to conceive. If you are pregnant, stop SIMCOR and call your healthcare professional.
17.12 Breastfeeding
Women who are breastfeeding should not use SIMCOR. If you have a lipid disorder and are breastfeeding, speak with your healthcare professionals about your lipid disorder and whether or not you should breastfeed your infant.
Manufactured by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
Simcor® Niacin Extended-Release/Simvastatin Tablets
Do not accept if seal over bottle opening is broken or missing. Do not break, crush or chew tablet. Store at room temperature 20–25°C (68–77°F).
Simcor® Niacin Extended-Release/Simvastatin Tablets
Do not accept if seal over bottle opening is broken or missing. Do not break, crush or chew tablet. Store at room temperature 20–25°C (68–77°F).
Simcor® Niacin Extended-Release/Simvastatin Tablets
Do not accept if seal over bottle opening is broken or missing. Do not break, crush or chew tablet. Store at room temperature 20–25°C (68–77°F).
Revised: 06/2011 Abbott Laboratories
Reproduced with permission of U.S. National Library of Medicine
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text:
Xuan-de: Year 2, Month 9, Day 12
2 Oct 1427
2 Oct 1427
The Da Dian Postal Relay Station was established under the Lu-chuan/Ping-mian Military and Civilian Pacification Superintendency in Yun-nan with an establishment of one postal relay station master. The native person Dao Peng-qie was appointed to the post. This was ordered in accordance with a memorial from the pacification superintendent Chou An-fa (Alt: Dao An-fa).
Zhong-yang Yan-jiu yuan Ming Shi-lu, volume 17, page 804
Preferred form of citation for this entry:
Geoff Wade, translator, Southeast Asia in the Ming Shi-lu: an open access resource, Singapore: Asia Research Institute and the Singapore E-Press, National University of Singapore, http://epress.nus.edu.sg/msl/reign/xuan-de/year-2-month-9-day-12-0, accessed September 27, 2020


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Love (according to Merriam-Webster Dictionary)
noun\ ˈləv \
Definition of love
1 a (1): strong affection for another arising out of kinship or personal ties maternal love for a child
(2): attraction based on sexual desire : affection and tenderness felt by loversAfter all these years, they are still very much in love.
(3): affection based on admiration, benevolence, or common interests love for his old schoolmates
b: an assurance of affection
2: warm attachment, enthusiasm, or devotion love of the sea
3 a: the object of attachment, devotion, or admiration baseball was his first love
b(1): a beloved person : DARLING —often used as a term of endearment
4 a: unselfish loyal and benevolent concern for the good of another.
This week was all about Valentine's Day! We have been planning all week for the big Valentine's Day Party at school (on Wednesday, February 14th). It was a total hit! I feel fortunate enough to have anywhere between 22-26 Valentine's each day that I get to teach, to make laugh and who show me that they care by showering me with hugs and kisses (on a pretty regular basis). Most of my Valentine's are Czech, but we have quite the mix of international students too, including: a Czech-Venezuelan student, an Indian student, Turkish students, Russian students, Czech-American students and American students.
I suppose I can be a bit sappy for most holidays, but particularly Valentine's Day because it is about love. To me, it is not about huge and grand gestures or incredibly expensive gifts (although I'm sure that's important to some people), but it's the small, daily gestures that add up. Those daily gestures culminate in this day where you get to talk about why you love someone so much (romantically, but I'd also like to extend that to non-romantic love). While this year I am definitely and completely (totally) single, there are so many people that I love and care for. People who I adore and who I am so grateful for everything they do and for who they are. Friends and family that I deeply, truly and absolutely love.
On a larger scale, don't we all need to show each other a little more love? I don't just mean in the romantic sense (that is of course…beautiful and sacred and wonderful), but I mean love and kindness and compassion to our neighbors and our friends, family and people who aren't remotely related. Extending an extra, "Hello! How are you?" to the bus driver, postal worker, grocery store attendant, the people who help us accomplish our day. For me, Valentine's Day serves as a reminder that I/you/we can extend that kindness and be conduits for deep compassion.
But, back to my little Valentine Dumplings. On Valentine's Day, everyone wore red. We made Valentine's for "Spin the Cupid", and hearts for parents and friends. We played "Spin the Cupid"! I invented the game, to play it goes as follows: Everyone sits in a circle, one at a time a "Cupid" takes a turn to dress up (halo, wings, cupid-like loin cloth) and then begins to spin 2-5 times *as much as the individual wants to until they begin to laugh*, when they stop spinning they pick a seated person and hand them a Valentine and ask, "Can I give you a hug or high five?". The seated person chooses what makes them feel most comfortable, receives their Valentine and then they take a turn as "Cupid". The game is played until everyone has had a turn.
Valentine's Day 2019 (all photos), © Lucia Saldarriaga Photos
I made the halo, bow and arrow and wings from pipe cleaners, popsicle sticks, string and cardboard (the materials that we had around the school). But if you have different materials, I suppose you could use anything you have around the house or school.
My little students gave me Valentine's and one of my students (I'll call her "S.") made me a purple Valentine Heart necklace (in the photo) that I wore all day. S. drew my cat and a dog and her name and wrote, "I love you" on the piece of jewelry. It's perfect. I have since hung it up in my apartment, it makes me smile every time that I look at it.
We had special Valentine's Day snack time and lunch. My little students made Heart Trees by either tracing or painting their hands on paper and drawing the little hearts. We also danced a little salsa this week too. What a week of love.
How are you celebrating Valentine's Day with the one or ones you love?
Happy Valentine's Day to all! As always, be kind~


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--ancient proverb.
Congressman Eric Swalwell is being accused of the ol "one-cheek-sneak" during an a segment on impeachment during Chris Matthews' Hard Ball program on MSNBC.
But is Swalwell innocent of all charges? Is Matthews, in fact, the guilty party?
During the segment, Swalwell is in the midst of making the claim that President Trump used taxpayer dollars to cheat. At the point in question, the flatulent sound is heard when Swalwell pauses briefly, and shifts slightly...
"Chris, so far the evidence is uncontradicted that the president used taxpayer dollars to help him cheat...an election. And the complaint that I've heard from Republicans…"
Listen as the case is made during Armstrong & Getty's opening statements...


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Head coach Jenny Ryan, Northern Michigan University track and field programs add 6 recruits
MARQUETTE — Head coach Jenny Ryan and the Northern Michigan University women's track and field team has landed six recruits for the 2020-21 indoor and outdoors seasons that run from early December through the end of May.
"This incoming class will add depth and strength to many different events," Ryan said in a sports news release from the university. "Each of them will be great additions to their respective event groups. They are also all great people that will help continue our positive culture. We are very excited to have them become a part of our team."
This group will add to a squad that placed fourth at the GLIAC Indoor Championships, which was held barely a week before the coronavirus pandemic wiped out the NCAA Division II Indoor Championships along with the entire outdoor season.
Here are short sketches of each recruit:
Devin Hable of Oshkosh, Wisconsin, attended Oshkosh West High School, earning three all-conference honors, including first team in 2018 and 2019. She reached the Wisconsin state meet three times and was expected to accomplish the feat again before last season was canceled. As team captain, she was a member of the 4-by-200-meter relay that set a school record while helping two relays qualify for the New Balance Outdoor Nationals.
Mackenzie Lamphere of downstate Jackson is transferring from Spring Arbor University, where she competed in throwing events. In high school, she attended Jackson Christian and was team captain her junior and senior years. She finished sixth at the 2019 Michigan Indoor Track Series Indoor Championships and at the MHSAA Lower Peninsula Championships. In 2019, she was nominated as the 2019 SCAA Outstanding Athlete in the Field.
Jordan Parker of Marengo, Illinois, attended Marengo Community High School.
Sydney Romps of downstate Canton competed for Plymouth High School. She holds the school record in the 300 hurdles and was the 2019 MHSAA regional champion in the event. She was also a member of the school's hockey team.
Leah Root of downstate Haslett was a team captain on the Haslett High School team, a three-time state qualifier and earned all-region three times. She was also a two-time all-league honoree.
Jovana Vukas of the eastern European country of Serbia represented Team Serbia in international competition in 2017 and 2018 and was a representative of her country at the 2016 Junior Olympics. She was also a 2019 Cup Final winner for juniors in Serbia. Vukas received an award from the president of Serbia as the most successful sportswoman in their country.
Information compiled by Journal Sports Editor Steve Brownlee. His email address is email@example.com.


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With each home and neighborhood Peter Nagle builds,
he recruits the expertise of the most accomplished professionals, including architects,
sales associates, new home product specialists, interior designers and senior
production managers. Working closely with his land planners, he creates
environmentally sensitive home sites, ensuring the preservation of trees while
maximizing views and sun exposure.
Peter Nagle has
built over 200 homes, half of which were built for sale on speculation. In
order to ensure the sale of each home, Nagle has
remained committed to focusing on classic, traditional styling, efficient and
innovative floor plans, and intricate detailing. Nagle understands
what today's buyers need, want, and expect in a new home. Over 100 families
have worked with Nagle to
complete a custom designed home.
Peter Nagle understands
the importance of personal involvement with all interior and
exterior construction. He employs the most highly skilled craftsmen
and tradesmen and maintains quality custom care for each homeowner.
This professionalism, craftsmanship and attention to quality
and detail has made Peter Nagle Builders a
nationally recognized builder of award-winning homes.


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TY - JOUR T1 - A DNA Aptamer for Cyclic Adenosine Monophosphate that Shows Adaptive Recognition. JF - Chembiochem Y1 - 2020 A1 - Sharma, Suruchi A1 - Zajac, Matthew A1 - Krishnan, Yamuna AB -
As a ubiquitous second messenger, cyclic adenosine monophosphate (cAMP) mediates diverse biological processes such as cell growth, inflammation, and metabolism. The ability to probe these pathways would be significantly enhanced if we had a DNA-based sensor for cAMP. Herein, we describe a new, 31-base long single-stranded DNA aptamer for cAMP, denoted caDNApt-1, that was isolated by in vitro selection using systemic evolution of ligands after exponential enrichment (SELEX). caDNApt-1 has an approximately threefold higher affinity for cAMP than ATP, ADP, and AMP. Using non-denaturing gel electrophoresis and fluorescence spectroscopy, we characterized the structural changes caDNApt-1 undergoes upon binding to cAMP and revealed its potential as a cAMP sensor.VL - 21 IS - 1-2 ER - TY - JOUR T1 - A structural map of oncomiR-1 at single-nucleotide resolution. JF - Nucleic Acids Res Y1 - 2017 A1 - Chakraborty, Saikat A1 - Krishnan, Yamuna AB -
The miR-17-92a cluster, also known as 'oncomiR-1', is an RNA transcript that plays a pivotal regulatory role in cellular processes, including the cell cycle, proliferation and apoptosis. Its dysregulation underlies the development of several cancers. Oncomir-1 comprises six constituent miRNAs, each processed with different efficiencies as a function of both developmental time and tissue type. The structural mechanisms that regulate such differential processing are unknown, and this has impeded our understanding of the dysregulation of oncomiR-1 in pathophysiology. By probing the sensitivity of each nucleotide in oncomiR-1 to reactive small molecules, we present a secondary structural map of this RNA at single-nucleotide resolution. The secondary structure and solvent accessible regions of oncomiR-1 reveal that most of its primary microRNA domains are suboptimal substrates for Drosha-DGCR8, and therefore resistant to microprocessing. The structure indicates that the binding of trans-acting factors is required to remodel the tertiary organization and unmask cryptic primary microRNA domains to facilitate their processing into pre-microRNAs.VL - 45 IS - 16 ER - TY - JOUR T1 - Quantum dot-loaded monofunctionalized DNA icosahedra for single-particle tracking of endocytic pathways. JF - Nat Nanotechnol Y1 - 2016 A1 - Bhatia, Dhiraj A1 - Arumugam, Senthil A1 - Nasilowski, Michel A1 - Joshi, Himanshu A1 - Wunder, Christian A1 - Chambon, Valérie A1 - Prakash, Ved A1 - Grazon, Chloé A1 - Nadal, Brice A1 - Maiti, Prabal K A1 - Johannes, Ludger A1 - Dubertret, Benoit A1 - Krishnan, Yamuna AB -
Functionalization of quantum dots (QDs) with a single biomolecular tag using traditional approaches in bulk solution has met with limited success. DNA polyhedra consist of an internal void bounded by a well-defined three-dimensional structured surface. The void can house cargo and the surface can be functionalized with stoichiometric and spatial precision. Here, we show that monofunctionalized QDs can be realized by encapsulating QDs inside DNA icosahedra and functionalizing the DNA shell with an endocytic ligand. We deployed the DNA-encapsulated QDs for real-time imaging of three different endocytic ligands-folic acid, galectin-3 (Gal3) and the Shiga toxin B-subunit (STxB). Single-particle tracking of Gal3- or STxB-functionalized QD-loaded DNA icosahedra allows us to monitor compartmental dynamics along endocytic pathways. These DNA-encapsulated QDs, which bear a unique stoichiometry of endocytic ligands, represent a new class of molecular probes for quantitative imaging of endocytic receptor dynamics.ER - TY - JOUR T1 - Rational design of a quantitative, pH-insensitive, nucleic acid based fluorescent chloride reporter JF - Chemical Science Y1 - 2016 A1 - Prakash, Ved A1 - Saha, Sonali A1 - Chakraborty, Kasturi A1 - Krishnan, Yamuna AB -
Chloride plays a major role in cellular homeostasis by regulating the lumenal pH of intracellular organelles. We have described a pH-independent, fluorescent chloride reporter called Clensor that has successfully measured resting chloride in organelles of living cells. Here, we describe the rational design of Clensor. Clensor integrates a chloride sensitive fluorophore called 10,10′-bis[3-carboxypropyl]-9,9′-biacridinium dinitrate (BAC) with the programmability, modularity and targetability available to nucleic acid scaffolds. We show that simple conjugation of BAC to a DNA backbone fails to yield a viable chloride-sensitive reporter. Fluorescence intensity and lifetime investigations on a series of BAC-functionalized structural variants yielded molecular insights that guided the rational design and successful realization of the chloride sensitive fluorescent reporter, Clensor. This study provides some general design principles that would aid the realization of diverse ion-sensitive nucleic acid reporters based on the sensing strategy of Clensor.VL - 7 ER - TY - JOUR T1 - Design of ultrasensitive DNA-based fluorescent pH sensitive nanodevices. JF - Nanoscale Y1 - 2015 A1 - Halder, Saheli A1 - Krishnan, Yamuna AB -
Here we tune the pH sensitivity of a DNA-based conformational switch, called the I-switch, to yield a set of fluorescent pH sensitive nanodevices with a collective, expanded pH sensing regime from 5.3 to 7.5. The expanded pH regime of this new family of I-switches originates from a dramatic improvement in the overall percentage signal change in response to pH of these nanodevices.VL - 7 IS - 22 ER - TY - JOUR T1 - Designing DNA nanodevices for compatibility with the immune system of higher organisms. JF - Nat Nanotechnol Y1 - 2015 A1 - Surana, Sunaina A1 - Shenoy, Avinash R A1 - Krishnan, Yamuna AB -
DNA is proving to be a powerful scaffold to construct molecularly precise designer DNA devices. Recent trends reveal their ever-increasing deployment within living systems as delivery devices that not only probe but also program and re-program a cell, or even whole organisms. Given that DNA is highly immunogenic, we outline the molecular, cellular and organismal response pathways that designer nucleic acid nanodevices are likely to elicit in living systems. We address safety issues applicable when such designer DNA nanodevices interact with the immune system. In light of this, we discuss possible molecular programming strategies that could be integrated with such designer nucleic acid scaffolds to either evade or stimulate the host response with a view to optimizing and widening their applications in higher organisms.VL - 10 IS - 9 ER - TY - JOUR T1 - Fast, Efficient, and Stable Conjugation of Multiple DNA Strands on Colloidal Quantum Dots. JF - Bioconjug Chem Y1 - 2015 A1 - Banerjee, Anusuya A1 - Grazon, Chloé A1 - Nadal, Brice A1 - Pons, Thomas A1 - Krishnan, Yamuna A1 - Dubertret, Benoit AB -
A novel method for covalent conjugation of DNA to polymer coated quantum dots (QDs) is investigated in detail. This method is fast and efficient: up to 12 DNA strands can be covalently conjugated per QD in optimized reaction conditions. The QD-DNA conjugates can be purified using size exclusion chromatography and the QDs retain high quantum yield and excellent stability after DNA coupling. We explored single-stranded and double-stranded DNA coupling, as well as various lengths. We show that the DNA coupling is most efficient for short (15 mer) single-stranded DNA. The DNA coupling has been performed on QDs emitting at four different wavelengths, as well as on gold nanoparticles, suggesting that this technique can be generalized to a wide range of nanoparticles.VL - 26 IS - 8 ER - TY - JOUR T1 - A pH-independent DNA nanodevice for quantifying chloride transport in organelles of living cells. JF - Nat Nanotechnol Y1 - 2015 A1 - Saha, Sonali A1 - Prakash, Ved A1 - Halder, Saheli A1 - Chakraborty, Kasturi A1 - Krishnan, Yamuna AB -
The concentration of chloride ions in the cytoplasm and subcellular organelles of living cells spans a wide range (5-130 mM), and is tightly regulated by intracellular chloride channels or transporters. Chloride-sensitive protein reporters have been used to study the role of these chloride regulators, but they are limited to a small range of chloride concentrations and are pH-sensitive. Here, we show that a DNA nanodevice can precisely measure the activity and location of subcellular chloride channels and transporters in living cells in a pH-independent manner. The DNA nanodevice, called Clensor, is composed of sensing, normalizing and targeting modules, and is designed to localize within organelles along the endolysosomal pathway. It allows fluorescent, ratiometric sensing of chloride ions across the entire physiological regime. We used Clensor to quantitate the resting chloride concentration in the lumen of acidic organelles in Drosophila melanogaster. We showed that lumenal lysosomal chloride, which is implicated in various lysosomal storage diseases, is regulated by the intracellular chloride transporter DmClC-b.VL - 10 IS - 7 ER - TY - JOUR T1 - Tuning the pH Response of i-Motif DNA Oligonucleotides. JF - Chembiochem Y1 - 2015 A1 - Lannes, Laurie A1 - Halder, Saheli A1 - Krishnan, Yamuna A1 - Schwalbe, Harald AB -
Cytosine-rich single-stranded DNA oligonucleotides are able to adopt an i-motif conformation, a four-stranded structure, near a pH of 6. This unique pH-dependent conformational switch is reversible and hence can be controlled by changing the pH. Here, we show that the pH response range of the human telomeric i-motif can be shifted towards more basic pH values by introducing 5-methylcytidines (5-MeC) and towards more acidic pH values by introducing 5-bromocytidines (5-BrC). No thermal destabilisation was observed in these chemically modified i-motif sequences. The time required to attain the new conformation in response to sudden pH changes was slow for all investigated sequences but was found to be ten times faster in the 5-BrC derivative of the i-motif.VL - 16 IS - 11 ER -


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- February 22, 2020
1:00 pm - 4:00 pm
This class will be held in the building with solar panels next to it on the left hand side of the road when you come in parking lot area.
What good does it do for an Virginia Resident or a Non-Resident to receive a Utah concealed carry permit?
That's a good question, and the answer is: You can legally carry a concealed firearm in 38 states with the combination of both a Virginia and a Utah Permit. So, as you travel, a Utah concealed carry permit will allow you to protect yourself in more states than just a Virginia Concealed Handgun Permit alone.
All 50 States now issue Concealed Handgun Permits, and in every one of those states the crime rate has gone down when concealed handgun permits became more readily available to law abiding citizens.
Our Utah Concealed Carry Permit training class takes about 3 hours, and covers all of the requirements to obtain the Utah Non-Resident Concealed Carry Permit. The course is a classroom based course taught by NRA certified & Utah BCI certified instructors. Course instruction includes: handgun safety rules, handgun parts and operation, ammunition, fundamentals of shooting, safe firearms handling, Utah criminal & traffic code, practical and legal considerations, and more.
We do a lot more than just teach a Utah concealed carry permit training class. We also provide the required…
- Application
- Fingerprinting
- 2×2 Photos
All you have to do after taking our class is mail everything in to Utah with your application fee and wait!
Length of Course: ~3 hours. $115.00
Venue: Meadow Event Park


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Just because you like to be charitable with your private parts does not make you a cheater Well, what is a cheater? Someone who is unfaithful, someone who is guilty of infidelity, etc? Personally I think these descriptions are wrong. A cheater is a liar, simply put. Yes I simplified it as I believe that … Continue reading Are You A Cheater
Tag: cheat
Creep Squad
I've been requested, by my sister, to write about my view on creep squad. The original Creep squad name was coined by the perverted males in Love & Hip Hop, who thought it best defined their messy promiscuous behaviour. What do I think when we use the term creep? Promiscuity is a variable but … Continue reading Creep Squad
Securing the Beat
This post has been inspired by a debate I was having with a friend a couple days ago. It centred around guys who will go over and beyond just to secure a beat. For those who do not understand, "beat" is a term used for sex. We've all heard or witnessed the scenarios in which … Continue reading Securing the Beat


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Research Education Program
Building the capacity of our health workforce to engage in research is essential as we strive towards improved health outcomes in regional and rural Victoria. Providing research education and training in health settings is a key component of this approach. Whilst there have been many isolated efforts to address this, including those of the Western Alliance and individual health services, we lack a comprehensive, coordinated and evaluated approach to research education across regional and rural Victoria. We also lack online components, which can be essential for those across the region who have difficulty accessing face-to-face training.
Western Alliance has recently been successful in attracting $40,000 from the DHHS to conduct a scoping exercise to lay the foundations for a coordinated approach to research education. We will be conducting a literature review and benchmarking, a gap analysis of the current state, and a needs analysis to better understand what would work for the health workforce (at all parts of the research continuum) and how we can go about providing it. Whist we recognise that this is not a quick fix, we want to get this right and to make sure we can facilitate a meaningful research education program.
The Western Alliance will continue to support and provide research training throughout this process, but our focus will be on the longer term coordinated strategy.


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Hamburg Institute for Advanced Study (HIAS) - Fellowship
- Location
- Hamburg (DE)
- Posted
- 06 Feb 2020
- End of advertisement period
- 07 Mar 2020
- Academic Discipline
- Arts & Humanities, Art, Performing Arts & Design
- Job Type
- Academic Posts, Research Fellowships
- Contract Type
- Fixed Term
- Hours
- Full Time
The Hamburg Institute for Advanced Study (HIAS) invites applications for fellowships during the academic years 2020/2021 and 2021/2022.
The Hamburg Institute for Advanced Study (HIAS) promotes scholarship and research in the fields of the Humanities and Social Sciences, Life Sciences, Natural Sciences, Engineering and the Arts. HIAS is an interdisciplinary and internationally oriented Institute located in the heart of the northern German city of Hamburg. It appoints outstanding scholars from Germany and abroad as fellows who are granted full freedom to pursue their own research projects under excellent conditions on-site in Hamburg.
HIAS was founded in January 2019 by a group of top higher education institutions, including the Academy of Sciences and Humanities in Hamburg, Bucerius Law School, HafenCity University Hamburg, Hamburg University of Technology, Helmut-Schmidt-Universität/Universität der Bundeswehr, Hochschule für bildende Künste Hamburg, Hochschule für Musik und Theater Hamburg and Universität Hamburg. Starting in September 2020, HIAS aims to enable scholars and researchers as well as artists of distinction a space of intellectual freedom, entirely unimpeded by their usual professional duties, in which to pursue their own projects.
Established scholars, promising emergent early career researchers as well as musicians and visual artists are eligible for application. All applicants should be internationally visible in their respective fields, give evidence of creativity and originality as well as willingness to participate in a community of scholars, scientists and artists, and, in the form of lectures and other types of events, to engage with the broader public in the city of Hamburg.
Applications for the academic years 2020/2021 or 2021/2022 may be submitted to the administrative office until 15 March 2020. Only electronic submissions of single pdf-files will be accepted, and they should consist of the following documents:
- Cover letter
- CV, including awards and other distinctions
- List of publications (highlighting the two most relevant publications for the intended research project)
- Abstract of an intended research project (3 pages maximum)
Fellows will be appointed according to their own availability for either 3, 6 or 10 months within the time frame of 1 September 2020 until 30 June 2021 or 1 September 2021 until 30 June 2022. HIAS provides its fellows with living and working arrangements free of charge. Additional costs associated with the fellow's stay in Hamburg will also be compensated. This may include compensation of a fellow's salary or cost for a possible substitute at their home institution, the fellow's travel expenses, as well as a monthly stipend for daily expenses.
Any questions about the fellowship program may be addressed to the HIAS Secretary-General, Dr. Anna Neubauer, or to Sonja Gräber-Magocsi, Ph.D., at the administrative office.
By submitting your application, you agree to the processing of your data. This information will not be shared with any third party.


text: I will often steer clear of that mustard yellow for entrance doors and go together with a Daring happy mellow yellow. Wow, the color of the house would make all folks would like to consume or consume chocolate. It's because that brown house color is very tempting and try to http://exterior-painting-contrac81469.ka-blogs.com/18999611/not-known-details-about-behr-exterior-paint