Nearly one in four adults worldwide suffers from hypertension. It is also called silent killer as it does not show any symptoms until it has caused damage to many organs. Hypertension remains uncontrolled in nearly 70% patient who suffers from this. Hypertension increases the probability of heart
attack, heart failure, stroke, , kidney failure and death. Tekturna ,an antihypertensive drug which acts by inhibiting renin got its approval from FDA in march 2007,it is the first high blood pressure drug approved by FDA, it is the first new drug over a decade for treating hypertension. On May 2007 a single tablet combination of tekturna and hydrochlothiazide (often called water pill) has been accepted for regulatory
review by FDA.
Aliskerin the active component of tekturna is present in tekturna as its active hemifurate salt. It is orally active potent, non peptide renin inhibitor. it is available in market as single tablet containing 150mg and 300mg aliskerin as base.
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Mechanism of action
Aliskerin inhibit rennin decreasing plasma rennin activity and inhibiting angiotensinogen conversion to Ang1.All agents that inhibit renninangiotension aldosteron system suppress the negative feed back loop (i.e. Ang ll inhibiting rennin release by kidney) leading to increase in plasma rennin concentration. When this rise in plasma concentration occur during treatment with ACE inhibitor and ARB's, the result is increased level of plasma rennin activity. Aliskerin blocks the effect of increased plasma level so that PRA, Ang l, Ang ll are all reduced.
Properties of the tablet include:
1. Each film-coated tablet contains 150 mg aliskiren.
2.Its pharmaceutical form include light pink, biconvex, film coated round tablet with "IL" imprinted on one side and "NVR" on the other side .
3. The recommended dose of Tekturna is 150 mg once daily. If the blood pressure of the patient is not adequately controlled the dose is increased to 300mg once daily. The antihypertensive effect of the tablet can be seen within two weeks (85-90%) after initiating therapy with 150 mg once daily. Tekturna may be used alone or in combination with other antihypertensive agents .Tekturna should be taken with a light meal once a day, preferably at the same time each day. Tekturna doesn't require any intial dose adjustment
in suffering from mild to severe renal impairment. It is the same in patients suffering from mild to severe hepatic impairment. Due to lack of data on safety and efficacy of the tablet in pediatric patients it is not recommended in children and adolescents below 18 years. It is contraindicated in patient hypersensitive to the active substance and excipients present in tekturna tablet and to the pregnant women at second and third trimester
In the pre clinical test carcinogenic potential of tekturna was assessed in a 2-year rat study and a 6-month transgenic mouse study. No carcinogenic potential was detected. Although aliskiren has known irritation potential,safety margins obtained in humans at the dose of 300 mg during a study in healthy volunteers were considered to be appropriate at 9-11-fold based on faecal concentrations or 6-fold based on mucosa concentrations in comparison with 250 mg/kg/day in the rat carcinogenicity study. In vitro and in vivo mutagenicity studies showed aliskerin having no mutagenic potential. Bacterial and mammalian cells were included in in vitro assays and in vivo assessment was done in rats. Reproductive toxicity studies did
not reveal any evidence of embryofoetal toxicity or teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-natal development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. The doses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than the maximum recommended human dose (300 mg). Safety pharmacology studies did not reveal any adverse effects on central nervous, respiratory or cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with the known local irritation potential or the expected pharmacological effects of aliskiren. This information was submitted to FDA in the IND application requesting to proceed with human clinical trials. The FDA reviews the preclinical researchdata and then makes a decision as to whether to allow the clinical trials to proceed.
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After getting approval from FDA and IRB clinical trials on human was conducted:
In the first phase the antihypertensive effect of alikerin was studied in two
short term phase II randomized controlled trial. The first trial evaluated the
BP effects and safety of aliskiren. The study was done in several hospital
clinics in Ireland. Treatment groups were given aliskiren (37.5 mg, 75 mg,
150 mg, and 300 mg daily) or losartan 100 mg daily for four weeks. The
study population were adult Patients with mild to moderate hypertension
without diabetes or coronary artery disease. The efficacy endpoint, which
was the change in daytime ambulatory systolic BP from baseline,was
reported for 197 patients. No significant BP reduction was reported in the
group receiving aliskiren 37.5 mg daily. Aliskiren 75 mg, 150 mg, and 300
mg daily, and losartan treatment groups showed significant BP reduction
relative to baseline (p<0.05). Safety results were obtained fromsss all of the
226 patients who were randomized. Among the 29 excluded patients, 14 had
withdrawn from the trial, and an additional 15 were excluded because of
invalid BP monitoring
In the second trial the study population was patient with mild to moderate
hypertension but no other cardiac risk factor. The trial was a randomized
single blind, eight week trial comparing BP effects and safety. This trial
included 652 patients, who were randomized to receive aliskiren (150
mg,300 mg, or 600 mg) once daily, irbesartan 150 mg daily, or placebo. The
result showed patient in the treatment group receiving aliskeren had a
significant reduction in trough mean systolic BP and diastolic BP as
compared to the group receiving placebo(p<0.001). The group receiving
iresartan also showed significant reduction in BP as compared to the placebo
group(p<0.05).The reduction in BP was significantly greater in the aliskiren
300 mg per day group compared with the aliskiren 175 mg per day group,
with no further BP reduction in the aliskiren 600 mg per day group. BP
control was defined as trough mean sitting diastolic BP <90 mm Hg and
systolic BP <140 mm Hg. It was achieved in 20.8% of the placebo group,
33.8% of the irbesartan group, 37.8% of the aliskiren 150 mg per day group,
50% of the aliskiren 300 mg per day group, and 45.8% of the aliskiren 600
mg per day group. All treatments were significantly better than placebo.
Safety results were reported for all 652 patients; there were 66 patients who
discontinued treatment. Published data are limited to the two phase II trials
that have been described.9,10 In the first trial, 22% to 32% of patients in
each treatment group reported that they experienced adverse events.9 The
most common adverse events were fatigue, gastrointestinal disorders,
or headaches. Three patients experienced serious adverse events. One patient
on aliskiren 300 mg daily had chest pain with electrocardiogram (ECG)
changes, and another in the same group collapsed and was found to be
hypotensive. One patient on losartan died from a ruptured aneurysm of the
Data for phase 3 trial are are still confidential and is not available for general