BUY NOW For Sale 70%!
buy viagra

Psychedelische pilze dosierung ciprofloxacin



Mechanism of Action

Actonel has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Actonel inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g., lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that Actonel treatment reduces bone turnover (activation frequency, i.e., the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.



Absorption after an oral dose is relatively rapid (tmax 1 hour) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, 2.5 to 30 mg; multiple dose, 2.5 to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution. The extent of absorption of a 30 mg dose (three 10 mg tablets) when administered 0.5 hours before breakfast is reduced by 55% compared to dosing in the fasting state (no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. Actonel is effective when administered at least 30 minutes before breakfast.


The mean steady-state volume of distribution is 6.3 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [14C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%.


There is no evidence of systemic metabolism of risedronate.


Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine over 28 days. Mean renal clearance is 105 mL/min (CV = 34%) and mean total clearance is 122 mL/min (CV = 19%), with the difference primarily reflecting nonrenal clearance or clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed drug is eliminated unchanged in feces. Once risedronate is absorbed, the serum concentration-time profile is multi-phasic, with an initial half-life of about 1.5 hours and a terminal exponential half-life of 480 hours. This terminal half-life is hypothesized to represent the dissociation of risedronate from the surface of bone.


Calcium is a major substrate for mineralization and has an antiresorptive effect on bone. Calcium suppresses PTH secretion and decreases bone turnover. Increased levels of PTH are known to contribute to age-related bone loss, especially at cortical sites, while increased bone turnover is an independent risk factor of fractures.



Calcium is released from calcium complexes during digestion in a soluble, ionized form, for absorption from the small intestine. Absorption can be by both passive and active mechanisms. Active absorption of calcium is highly dependent on vitamin D, and vitamin D deficiency decreases the absorption of calcium. As calcium intake increases, the active transfer mechanism becomes saturated and an increasing proportion of calcium is absorbed via passive diffusion. Absorption of calcium carbonate is dose-dependent, with fractional absorption being highest when at doses up to 500 mg. Absorption of calcium is also dependent on pH with reduced absorption in alkaline conditions. The absorption of calcium from calcium carbonate is increased when taken with food.


Approximately 50% of calcium in the serum is in the physiologically active ionized form; about 10% is complexed to phosphate, citrate or other anions. The remaining 40% is bound to proteins, primarily albumin.


Unabsorbed calcium from the small intestine is excreted in the feces. Renal excretion depends largely on glomerular filtration and calcium tubular reabsorption with more than 98% of calcium reabsorbed from the glomerular filtrate. This process is regulated by active vitamin D and PTH.

Special Populations



Risedronate pharmacokinetics have not been studied in patients < 18 years of age.


Bioavailability and pharmacokinetics following oral administration are similar in men and women.


Bioavailability and disposition are similar in elderly ( > 60 years of age) and younger subjects. No dosage adjustment is necessary.


Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency

Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. Actonel is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance ≥ 30 mL/min.

Hepatic Insufficiency

No studies have been performed to assess risedronate's safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts ( < 0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.


Absorption of calcium from calcium carbonate is poor in patients with achlorhydria unless taken with food.


Absorption of calcium from calcium carbonate has not been adequately studied with respect to gender.


There are no clinically significant differences in bioavailability following administration of 1 g elemental calcium as calcium carbonate between young (20 to 27 years) and elderly (63 to 71 years) females.


The effect of race on calcium absorption from oral calcium carbonate has not been studied.

Renal Insufficiency

Renal disease affects calcium homeostasis through its effects on vitamin D metabolism, phosphorus excretion, and PTH. Calcium should be administered cautiously to patients with renal disease (creatinine clearance < 30 mL/min) to avoid elevations of the calcium-phosphorus ion product (Ca x Phos) and the development of calcinosis.



Treatment and Prevention of Osteoporokis in Postmenopausal Women

Osteoporosis is characterized by decreased bone mass and increased fracture risk, most commonly at the spine, hip, and wrist.

The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture.

Osteoporosis occurs in both men and women but is more common among women following menopause. In healthy humans, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly-formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of bone fracture. After menopause, the risk of fractures of the spine and hip increases; approximately 40% of 50 year-old women will experience an osteoporosis-related fracture during their remaining lifetimes. After experiencing 1 osteoporosis-related fracture, the risk of future fracture increases 5-fold compared to the risk among a non-fractured population.

Actonel treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of Actonel to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone specific alkaline phosphatase (a marker of bone formation). At the 5 mg dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady-state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a 1-year study comparing daily versus weekly oral dosing regimens of Actonel for the treatment of osteoporosis in postmenopausal women, Actonel 5 mg daily and Actonel 35 mg once-a-week decreased urinary collagen cross-linked N-telopeptide by 60% and 61%, respectively. In addition, serum bone-specific alkaline phosphatase was also reduced by 42% and 41% in the Actonel 5 mg daily and Actonel 35 mg once-a-week groups, respectively. Actonel is not an estrogen and does not have the benefits and risks of estrogen therapy.

As a result of the inhibition of bone resorption, asymptomatic and usually transient decreases from baseline in serum calcium ( < 1%) and serum phosphate ( < 3%) and compensatory increases in serum PTH levels ( < 30%) were observed within 6 months in patients in osteoporosis clinical trials. There were no significant differences in serum calcium, phosphate, or PTH levels between the Actonel and placebo groups at 3 years. In a 1-year study comparing daily versus weekly oral dosing regimens of Actonel in postmenopausal women, the mean changes from baseline at 12 months were similar between the Actonel 5 mg daily and Actonel 35 mg once-a-week groups, respectively, for serum calcium (0.4% and 0.7%), phosphate (-3.8% and -2.6%) and PTH (6.4% and 4.2%).


Calcium administration decreases the elevated rate of bone turnover typically seen in postmenopausal women with osteoporosis. In randomized, placebo controlled studies in postmenopausal women, calcium administration (500 mg to 1600 mg) decreased biochemical markers of bone turnover, including urine N-telopeptide, urine free pyridinoline (markers of bone resorption), alkaline phosphatase and osteocalcin (markers of bone formation) relative to placebo treated women.

Calcium administration may transiently increase levels of serum calcium with compensatory reductions in serum PTH and an increase in urinary calcium. However, urinary and serum calcium levels usually remain within the normal reference range.

Clinical Studies


Treatment of Osteoporosis in Postmenopausal Women

The fracture efficacy of Actonel 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in 2 large, randomized, placebo-controlled, double-blind studies that enrolled a total of almost 4000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (Actonel 5 mg, n psychedelische pilze dosierung ciprofloxacin = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (Actonel 5 mg, n = 821). Patients were selected on the basis of radiographic evidence of previous vertebral fracture, and therefore, had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in VERT MN, and 2.5 in VERT NA, with a broad range of baseline bone mineral density (BMD) levels. All patients in these studies received supplemental calcium 1000 mg/day. Patients with low vitamin D levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 IU/day.

Positive effects of Actonel treatment on BMD were also demonstrated in each of 2 large, randomized, placebo-controlled trials (BMD MN and BMD NA) in which almost 1200 postmenopausal women (Actonel 5 mg, n = 394) were recruited on the basis of low lumbar spine bone mass (more than 2 SD below the premenopausal mean) rather than a history of vertebral fracture.

Actonel 35 mg once-a-week (n = 485) was shown to be therapeutically equivalent to Actonel 5 mg daily (n = 480) in a 1-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary efficacy analkysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 4.0% (3.7, 4.3; 95% confidence interval [CI]) in the 5 mg daily group (n = 391) and 3.9% (3.6, 4.3; 95% CI) in the 35 mg once-a-week group (n = 387) and the mean difference between 5 mg daily and 35 mg weekly was 0.1% (-0.42, 0.55; 95% CI). The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites.

Effect on Vertebral Fractures

Fractures of previously undeformed vertebrae (new fractures) and worsening of pre-existing vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (i.e., clinical fractures). Spinal radiographs were scheduled annually and prospectively planned analyses were based on the time to a patient's first diagnosed fracture. The primary endpoint for these studies was the incidence of new and worsening vertebral fractures across the period of 0 to 3 years. Actonel 5 mg daily significantly reduced the incidence of new and worsening vertebral fractures and of new vertebral fractures in both VERT NA and VERT MN at all time points (Table 1). The reduction in risk seen in the subgroup of patients who had 2 or more vertebral fractures at study entry was similar to that seen in the overall study population.

Table 1 : The Effect of Actonel on the Risk of Vertebral Fractures

VERT NA Proportion of Patients Absolute Risk Reduction (%) Relative Risk Reduction (%)
with Fracture (%)a
n = 678
Actonel 5 mg
n = 696
New and Worsening
0 to 1 Year 7.2 3.9 3.3 49
0 to 2 Years 12.8 8.0 4.8 42
0 to 3 Years 18.5 13.9 4.6 33
0 to 1 Year 6.4 2.4 4.0 65
0 to 2 Years 11.7 5.8 5.9 55
0 to 3 Years 16.3 11.3 5.0 41
VERT MN Placebo
n = 346
Actonel 5 mg
n = 344
Absolute Risk Reduction (%) Relative Risk Reduction (%)
New and Worsening
0 to 1 Year 15.3 8.2 7.1 50
0 to 2 Years 28.3 13.9 14.4 56
0 to 3 Years 34.0 21.8 12.2 46
0 to 1 Year 13.3 5.6 7.7 61
0 to 2 Years 24.7 11.6 13.1 59
0 to 3 Years 29.0 18.1 10.9 49
a Calculated by Kaplan-Meier methodology
Effect on Osteoporosis-Related Nonvertebral Fractures

In VERT MN and VERT NA, a prospectively planned efficacy endpoint was defined consisting of all radiographically confirmed fractures of skeletal sites accepted as associated with osteoporosis. Fractures at these sites were collectively referred to as osteoporosis-related nonvertebral fractures. Actonel 5 mg daily significantly reduced the incidence of nonvertebral osteoporosis-related fractures over 3 years in VERT NA (8% versus 5%; relative risk reduction 39%) and reduced the fracture incidence in VERT MN from 16% to 11%. There was a significant reduction from 11% to 7% when the studies were combined, with a corresponding 36% reduction in relative risk. Figure 1 shows the overall results as well as the results at the individual skeletal sites for the combined studies.

Figure 1: Nonvertebral Osteoporosis-Related Fractures
Cumulative Incidence Over 3 Years
Combined VERT MN and VERT NA

Nonvertebral Osteoporosis-Related Fractures - Illustration
Effect on Height

In the two 3-year osteoporosis treatment studies, standing height was measured yearly by stadiometer. Both Actonel and placebo-treated groups lost height during the studies. Patients who received Actonel had a statistically significantly smaller loss of height than those who received placebo. In VERT MN, the median annual height change was -1.3 mm/yr in the Actonel 5 mg daily group compared to -2.4 mm/yr in the placebo group. In VERT NA, the median annual height change was -0.7 mm/yr in the Actonel 5 mg daily group compared to -1.1 mm/yr in the placebo group.

Effect on Bone Mineral Density

The results of 4 randomized, placebo-controlled trials in women with postmenopausal osteoporosis (VERT MN, VERT NA, BMD MN, BMD NA) demonstrate that Actonel 5 mg daily increases BMD at the spine, hip, and wrist compared to the effects seen with placebo. Table 2 displays the significant increases in BMD seen at the lumbar spine, femoral neck, femoral trochanter, and midshaft radius in these trials compared to placebo. In both VERT studies (VERT MN and VERT NA), Actonel 5 mg daily produced increases in lumbar spine BMD that were progressive over the 3 years of treatment, and were statistically significant relative to baseline and to placebo at 6 months and at all later time points.

Table 2 : Mean Percent Increase in BMD from Baseline in Patients Taking Actonel 5 mg or Placebo at Endpointa

n = 323
5 mg
n = 323
n = 599
5 mg
n = 606
n = 161
5 mg
n = 148
n = 191
5 mg
n = 193
Lumbar Spine 1.0 6.6 0.8 5.0 0.0 4.0 0.2 4.8
Femoral Neck -1.4 1.6 -1.0 1.4 -1.1 1.3 0.1 2.4
Femoral Trochanter -1.9 3.9 -0.5 3.0 -0.6 2.5 1.3 4.0
Midshaft Radius -1.5 0.2 -1.2 0.1 ND ND
a The endpoint value is the value at the study's last time point for all patients who had BMD measured at that time; otherwise the last postbaseline BMD value prior to the study's last time point is used.
b The duration of the studies was 3 years.
c The duration of the studies was 1.5 to 2 years.
BMD of the midshaft radius was measured in a subset of centers in VERT MN (placebo, n = 222; 5 mg, n = 214) and VERT NA (placebo, n = 310; 5 mg, n = 306)
ND = analysis not done

Bone biopsies from 110 postmenopausal women were obtained at endpoint. Patients had received daily Actonel (2.5 mg or 5 mg) or placebo for 2 to 3 years. Histologic evaluation (n = 103) showed no osteomalacia, impaired bone mineralization, or other adverse effects on bone in Actonel-treated women. These findings demonstrate that bone formed during Actonel administration is of normal quality. The histomorphometric parameter mineralizing surface, an index of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 23 patients treated with Actonel 5 mg and 21 treated with placebo. Mineralizing surface decreased moderately in Actonel-treated patients (median percent change: Actonel 5 mg, -74%; placebo, -21%), consistent with the known effects of treatment on bone turnover.

Prevention of Osteoporosis in Postmenopausal Women

Actonel 5 mg daily prevented bone loss in a majority of postmenopausal women (age range 42 to 63 years) within 3 years of menopause in a 2-year, double-blind, placebo-controlled study in 383 patients (Actonel 5 mg, n = 129). All patients in this study received supplemental calcium 1000 mg/day. Increases in BMD were observed as early as 3 months following initiation of Actonel treatment. Actonel 5 mg produced significant mean increases in BMD at the lumbar spine, femoral neck, and trochanter compared to placebo at the end of the study (Figure 2). Actonel 5 mg daily was also effective in patients with lower baseline lumbar spine BMD (more than 1 SD below the premenopausal mean) and in those with normal baseline lumbar spine BMD. Bone mineral density at the distal radius decreased in both Actonel and placebo-treated women following 1 year of treatment.

Figure 2 :Change in BMD from Baseline2-Year Prevention Study

Change in BMD from Baseline2-Year Prevention Study - Illustration

Actonel 35 mg once-a-week prevented bone loss in postmenopausal women (age range 44 to 64 years) without osteoporosis in a 1-year, double-blind, placebo-controlled study in 278 patients (Actonel 35 mg, n = 136). All patients were supplemented with 1000 mg elemental calcium and 400 IU vitamin D per day. The primary efficacy measure was the percent change in lumbar spine BMD from baseline after 1 year of treatment using LOCF (last observation carried forward). Actonel 35 mg once-a-week resulted in a statistically significant mean difference from placebo in lumbar spine BMD of +2.9% (least square mean for risedronate +1.83%; placebo -1.05%). Actonel 35 mg once-a-week also showed a statistically significant mean difference from placebo in BMD at the total proximal femur of +1.5% (risedronate +1.01%; placebo -0.53%), femoral neck of +1.2% (risedronate +0.22%; placebo -1.00%), and trochanter of +1.8% (risedronate +1.07%; placebo -0.74%).

Combined Administration with Hormone Replacement Therapy

The effects of combining Actonel 5 mg daily with conjugated estrogen 0.625 mg daily (n = 263) were compared to the effects of conjugated estrogen alone (n = 261) in a 1-year, randomized, double-blind study of women ages 37 to 82 years, who were on average 14 years postmenopausal. The BMD results for this study are presented in Table 3.

Table 3 : Percent Change from Baseline in BMD After 1 Year of Treatment

  Estrogen 0.625 mg
n = 261
ACTONEL 5 mg ± Estrogen 0.625 mg
n = 263
Lumbar Spine 4.6 ± 0.20 5.2 ± 0.23
Femoral Neck 1.8 ± 0.25 2.7 ± 0.25
Femoral Trochanter 3.2 ± 0.28 3.7 ± 0.25
Midshaft Radius 0.4 ± 0.14 0.7 ± 0.17
Distal Radius 1.7 ± 0.24 1.6 ± 0.28
Values shown are mean (± SEM) percent change from baseline.

Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received Actonel 5 mg plus estrogen or estrogen alone once daily for 1 year. Histologic evaluation (n = 47) demonstrated that the bone of patients treated with Actonel plus estrogen was of normal lamellar structure and normal mineralization. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 12 patients treated with Actonel plus estrogen and 12 treated with estrogen alone. Mineralizing surface decreased in both treatment groups (median percent change: Actonel plus estrogen, -79%; estrogen alone, -50%), consistent with the known effects of these agents on bone turnover.

Animal Pharmacology And/Or Toxicology


Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at oral doses up to 4 and 25 times the human recommended oral dose of 35 mg/week based on surface area, (mg/m²) for rats and minipigs, respectively. Risedronate treatment maintained the positive correlation between BMD and bone strength and did not have a negative effect on bone structure or mineralization. In intact dogs, risedronate induced positive bone balance at the level of the bone remodeling unit at oral doses ranging from 0.35 to 1.4 times the human 35 mg/week dose based on surface area (mg/m²).

In dogs treated with an oral dose of 1 mg/kg/day (approximately 5 times the human 35 mg/week dose based on surface area, mg/m²), risedronate caused a delay in fracture healing of the radius. The observed delay in fracture healing is similar to other bisphosphonates. This effect did not occur at a dose of 0.1 mg/kg/day (approximately 0.5 times the human 35 mg/week dose based on surface area, mg/m²).

The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested (5 mg/kg/day, subcutaneously), which was approximately 3500 times the lowest antiresorptive dose (1.5 mcg/kg/day in this model) and approximately 8 times the human 35 mg/week dose based on surface area (mg/m²). This indicates that Actonel administered at the therapeutic dose is unlikely to induce osteomalacia.


Published studies have demonstrated that changes in the dietary intake of calcium affect bone growth and skeletal development in animals, as well as bone loss in animal models of estrogendepletion/ovariectomy and aging.


BUY NOW For Sale 70%!
buy viagra

CIPRO (Ciprofloxacin) dosage, indication, interactions, side Ambroxol genericon saft beipackzettel ciprofloxacin

Psychedelische pilze dosierung ciprofloxacin Antibiotics: List of Common Antibiotics Types - m
Psychedelische pilze dosierung ciprofloxacin CIPRO 500 mg 14 tablet Aktif 2017 Yl Detayl Fiyat
Psychedelische pilze dosierung ciprofloxacin CIPC - Companies and Intellectual Property Commission - eServices
Psychedelische pilze dosierung ciprofloxacin What Is Cephalexin Used For?
Psychedelische pilze dosierung ciprofloxacin Ciprofloxacin: Side Effects, Dosages, Treatment
Psychedelische pilze dosierung ciprofloxacin Efudex Topical : Uses, Side Effects, Interactions, Pictures, Warnings
Psychedelische pilze dosierung ciprofloxacin Pinkeye (Conjunctivitis Check Your Symptoms and Signs)
Cefazolin for Injection, USPFOR INTRAMUSCULAR Elobact 250mg Dosier-Brief - Gebrauchsinformation - medikamio Ciproxin Tablets 500mg - Patient Information Leaflet (PIL) Cipro Ck1 Registration Form M ningite - Sympt mes, Causes, Risques, Traitements Cleaning up after C Diff! - Crohn s Disease Forum - Support
BUY NOW For Sale 70%!
buy viagra