However, by taking statins, one or more patients will develop diabetes and 20% or more will experience disabling symptoms, including muscle weakness, fatigue, and memory loss

Ref: JAMA 2012; 307: 1489-4532

Although some foods, such as milk and orange juice, are fortified with vitamin D, studies have shown that many individuals still consume low amounts of this nutrient or have insufficient vitamin D serum levels. This may in part be related to changing dietary patterns in this United States, such as low consumption of milk and foods rich in vitamin D (eg, salmon, eel, tuna, and mackerel). Since most biologically active vitamin D comes from skin exposure to sunlight, the increased widespread use of broad-spectrum, high sun-protection-factor sunscreens in recent years may also contribute to the rise in vitamin D deficiency.

Several guidelines have been issued by national organizations that recommend varying amounts of vitamin D intake. Perhaps the most current, authoritative consensus report has been issued by the Institute of Medicine. This guideline recommends a daily dietary allowance of vitamin D of 600-800 IU/day for most patients. However, increased amounts are necessary for treating insufficiency and deficiency. Although much attention has been given to vitamin D intake, most consensus statements do not delineate the differences between the 2 major oral formulations: vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol).

Vitamin D is produced cutaneously and converted to active metabolites in the liver and kidney. On exposure to ultraviolet irradiation, provitamin D₃ (7-dehydrocholesterol) in the skin is converted to previtamin D₃, which is then isomerized to more stable vitamin D₃ via a thermally induced transformation. Vitamin D₃, whether cutaneously formed or obtained in the diet as cholecalciferol, is subsequently hydroxylated in the liver to 25-hydroxyvitamin D. This is the major circulating form of vitamin D that is assayed to detect deficiency. 25-hydroxyvitamin D is hydroxylated again in the kidney to form 1,25-dihydroxyvitamin D₃, the major biologically active form of vitamin D, also known as calcitriol.Thus, in the setting of severe renal impairment, formulations of calcitriol are preferred over ergocalciferol and cholecalciferol because the terminal hydroxylation occurs in the kidney.

Regarding the manufacturing of oral vitamin D formulations, ergocalciferol is made from ultraviolet irradiation of ergosterol in yeast. Cholecalciferol is made from irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol. Traditionally, oral formulations of vitamin D₂ and D₃ have long been regarded as equivalent in their clinical activity. However, studies indicate that ergocalciferol (vitamin D₂) is much less potent and has a shorter duration of action than cholecalciferol.

Historically, ergocalciferol has been used instead of cholecalciferol for severe vitamin D deficiency. This is out of convention, or perhaps because high-dose ergocalciferol is more widely available in doses of up to 50,000 IU per softgel capsule from multiple manufacturers. Although this dose of cholecalciferol is available from at least 1 manufacturer, it is often challenging to find in retail outlets. Based on this author’s experience, and verified by others, it is often difficult to raise 25-hydroxyvitamin D levels with ergocalciferol in patients with severe vitamin D deficiency.

Armas and colleaguesadministered single oral doses of 50,000 IU of the respective vitamin D preparations to 20 healthy male volunteers, and followed the time course of 25-hydroxyvitamin D levels over a period of 28 days. A pharmacokinetic analysis was also done. Both ergocalciferol and cholecalciferol produced similar initial increases in serum levels of 25-hydroxyvitamin D over the first 3 days, indicating equivalent absorption. However, levels continued to increase with cholecalciferol and peaked at day 14, whereas levels decreased rapidly with ergocalciferol and were no different from baseline at day 14. The investigators concluded that ergocalciferol potency is less than 30% of that of cholecalciferol and that it has a markedly shorter duration of action.

This study is consistent with other single, high-dose studies that indicate the mean time to peak concentration of ergocalciferol to be about 3 days compared with 14 days for cholecalciferol. A review by Houghton and Viethestimated that cholecalciferol is more than 3 times as effective as ergocalciferol in elevating 25-hydroxyvitamin D and maintaining those levels for a longer time. These authors also note that cholecalciferol metabolites have superior affinity for vitamin D-binding proteins in plasma, relative to ergocalciferol.

In conclusion, ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃) are not bioequivalent and should not be considered interchangeable. Although few head-to-head trials exist, based on pharmacokinetic studies and limited clinical evidence, cholecalciferol is preferred over ergocalciferol. Because of its shorter half-life and decreased potency, this is especially relevant in the setting of severe deficiency, where high-dose ergocalciferol is often only given once weekly. Health professionals should encourage use of cholecalciferol over ergocalciferol in all patients without severe renal failure, either as a general supplement or as a treatment for vitamin D deficiency.

What form of vitamin D is recommended in chronic kidney disease?

Vitamin D is produced endogenously in the skin and converted to active metabolites in the liver and kidney. Upon exposure to ultraviolet irradiation, provitamin D3 (7-dehydrocholesterol) in the skin is converted to previtamin D3, which is then isomerized to vitamin D3 (cholecalciferol). Vitamin D3, whether cutaneously formed or obtained in the diet as cholecalciferol, is subsequently hydroxylated in the liver to 25-hydroxyvitamin D (25-OH VD). This is the major circulating form of vitamin D that is assayed to detect deficiency.

A subsequent hydroxylation of 25-OH VD occurs in the kidney to form 1,25-dihydroxyvitamin D, the major biologically active form of vitamin D, also known as calcitriol.Thus, in the setting of severe chronic kidney disease (CKD), formulations of calcitriol may be preferred over vitamin D2 and D3 to treat deficiency because the terminal hydroxylation occurs in the kidney.

In the setting of CKD it is important to estimate glomerular filtration rate (GFR) and to determine serum 25-OH VD, calcium, phosphorous, and intact PTH levels when choosing the most optimal regimen. Supplementation of vitamin D plays a major role in the prevention of secondary hyperparathyroidism in patients with CKD. According to clinical practice guidelines from the National Kidney Foundation, the preferred form of supplementation is guided by serum 25-OH VD levels, stage of kidney failure, and presence or absence of secondary hyperparathyroidism. Before and during supplementation, both serum calcium and phosphorous levels should be drawn every 3 months. If levels of these minerals rise, vitamin D supplementation may need to be withheld or the dosage modified.

In the presence of secondary hyperparathyroidism, which usually begins in stage 3 or 4 of CKD (GFR 30-59 mL/min and 15-29 mL/min, respectively), the preferred agent for supplementation is an activated vitamin D sterol (eg, calcitriol or paricalcitol). Supplementation should begin when serum levels of 25-OH VD fall below 30 ng/mL. The vitamin D sterol dose depends on the serum levels of 25-OH VD, PTH, calcium, and phosphorus. Likewise, in stage 5 of CKD (GFR < 15 mL/min and patients treated with hemodialysis or peritoneal dialysis), an activated vitamin D sterol is also preferred in lieu of vitamin D2 or D3.

However, in the absence of secondary hyperparathyroidism, as is often the case in patients with GFR > 60 mL/min or only mild renal impairment, either oral vitamin D2 or D3 can be used. Studies indicate that vitamin D2 (ergocalciferol) is much less potent and has a shorter duration of action than D3 (cholecalciferol) and that vitamin D3 more effectively raises 25-OH VD levels. Thus, cholecalciferol is preferred in patients with normal or mild renal impairment (GFR > 60 mL/min) with a normal intact PTH level.

This randomized controlled, open-label trial compares the effect of bedtime vs morning administration of BP medications on a composite of cardiovascular disease (CVD) outcomes and BP control.

According to Dr. Hermida and colleagues, “treatment at bedtime is the most cost-effective and simplest strategy of successfully achieving the therapeutic goals of adequate asleep BP reduction and preserving or re-establishing the normal 24-hour BP dipping pattern.”

The authors suggest that a potential explanation for the benefit of nighttime treatment may be associated with the effect of nighttime treatment on urinary albumin excretion levels. “We previously demonstrated that urinary albumin excretion was significantly reduced after bedtime, but not morning, treatment with valsartan,” they note. In addition, this reduction was independent of 24-hour changes of BP, but correlated with a decline in BP during sleep.

Refer: J Am Soc Nephrol. Published online October 24, 2011

The dihydroxy bile acid, ursodeoxycholic acid (UDCA), has been in widespread clinical use in the Western world since the mid 1980s, when it was initially used for gallstone dissolution [1,2] and subsequently for the treatment of chronic cholestatic liver diseases. Many clinical trials of UDCA in a variety of cholestatic disorders established biochemical and clinical improvements, and most importantly showed a significant prolongation of transplant-free survival after four years of treatment with UDCA in patients with primary biliary cirrhosis. Despite its clinical efficacy, the precise mechanism(s) by which UDCA improves liver function during cholestasis is still a matter of debate. It was initially considered that the choleretic effect of UDCA, coupled with its ability to cause a marked shift in the composition of the bile acid pool towards hydrophilicity, accounted for its mechanism of action. In recent years, however, it has become evident that UDCA and its conjugated derivatives are capable of exerting direct effects at the cellular, subcellular, and molecular levels by stabilising cell membranes, affecting signal transduction pathways, and regulating immune responses. In addition, we have shown that UDCA plays a unique role in modulating the apoptotic threshold in both hepatic and non-hepatic cells. The purpose of this article is to examine the mechanism(s) by which UDCA prevents apoptotic cell death associated with cholestasis. In addition, we will also review a potentially novel and, heretofore, unrecognised role of UDCA as a therapeutic agent in the treatment of non-liver diseases associated with increased levels of apoptosis as a pathogenesis of the disorder.

“[PPIs] and histamine 2 receptor antagonists (H2RAs) are the most popular [acid-suppressive drugs] available, and millions of individuals currently take these medications on a continuous or long-term basis,”

These potent drugs are used to treat various disorders, and indications for long-term maintenance therapy with this drug class continue to expand. The relationship between [acid-suppressive drug] use and bone health remains unclear

The final analyses included 5 case-control studies, 3 nested case-control studies, and 3 cohort studies selected from 1809 articles meeting the initial inclusion criteria. With use vs nonuse of PPIs, the pooled odds ratio (OR) for fracture was 1.29 (95% confidence interval [CI], 1.18 – 1.41) compared with 1.10 (95% CI, 0.99 – 1.23) for use vs nonuse of H2RAs.

Risk for any fracture and for hip fracture was increased with long-term use of PPIs (adjusted OR, 1.30 [95% CI, 1.15 - 1.48]; adjusted OR, 1.34 [95% CI, 1.09 - 1.66], respectively). Vertebral fracture risk was also increased by 54% with PPI use. In contrast, long-term use of H2RA was not significantly associated with fracture risk.

“We found possible evidence linking PPI use to an increased risk of fracture, but no association between H2RA use and fracture risk,” the study authors write. “Widespread use of PPIs with the potential risk of fracture is of great importance to public health. Clinicians should carefully consider their decision to prescribe PPIs for patients already having an elevated risk of fracture because of age or other factors.”

It is not necessary to treat patients to the point of an achlorhydric state to resolve acid reflux symptoms, so we recommend that drug doses be chosen thoughtfully with consideration of what is necessary to achieve desired therapeutic goals,” the study authors conclude.

PPIs have clear benefits in patients that require them, and they should not be denied to patients who are likely to benefit from them,” the editorialists write. “On the other hand, long-term PPI exposure may lead to other unwanted effects and should be reserved for patients likely to benefit from them. They should not be used long-term for undifferentiated dyspepsia, but neither should they be denied for patients with established persistent [gastroesophageal reflux disease], [nonsteroidal anti-inflammatory drugs] risk, and hypersecretory states, while aiming for the lowest effective maintenance dose.”

Ann Fam Med. 2011;9:257-267, 200-202

Refer: Experimental Biology 2011 Annual Meeting: Abstract 349.7.

The fixed-dose combination of aceclofenac and drotaverine is considered as a suitable, effective and well tolerated treatment option for primary dysmenorrhoea

STUDY OBJECTIVE: To evaluate the efficacy and safety of aceclofenac-drotaverine combination against aceclofenac alone in patients with primary dysmenorrhoea.

STUDY DESIGN: This double-blind, double-dummy, randomized, comparative, multicentric study enrolled 200 women (100 women in each arm) in the age range of 18-35 years with primary dysmenorrhoea at four centers. The patients were randomly allocated to either aceclofenac 100mg-drotaverine 80 mg b.i.d or aceclofenac 100mg alone b.i.d for a maximum of 3 days. Primary efficacy parameters were total area under pain relief (PR) score up to 4 and 8h (TOPAR/4 and TOPAR/8). Secondary efficacy measurements were pain-intensity difference (PID), sum of PID over 4 and 8h (SPID/4 and SPID/8), peak PID over 4 and 8h and peak PR over 4 and 8h, total study drug consumption, and patient’s and investigator’s global evaluation of the efficacy.

RESULTS: Both treatments showed significant improvement in baseline values in all efficacy parameters. The combination was significantly superior to monotherapy in terms of TOPAR/4 (24.0 vs 18.54) (p=0.000) and TOPAR/8 (40.3 vs 35.2) (p=0.003), SPID/4 (-17.9 vs -13.88) (p=0.000) and SPID/8 (-31.06 vs -26.8) (p=0.001), peak PID/4 (-6.60 vs -5.75) (p=0.001) and peak PR/4 (8.26 vs 7.10) (p=0.000). At the end of 8h, both treatments were comparable with respect to peak PID/8 and peak PR/8 (p>0.05). The total number of doses consumed by patients treated with combination therapy was less than with monotherapy (150 vs 168 doses). The combination was significantly superior to monotherapy with respect to patient’s and investigator’s global evaluation of the efficacy (p=0.002 and p=0.001, respectively). Both treatments were well tolerated.

- Reference on file

A: adequate studies in pregnant women have not demonstrated a risk to the foetus in the first trimester of pregnancy and there is no evidence of risk in later trimesters.

B: animal studies have not demonstrated a risk to the foetus but there are no adequate studies in pregnant women or, animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the foetus during the first trimester of pregnancy and there is no evidence of risk in later trimesters.

C: animal studies have shown an adverse effect on the foetus but, there are no adequate studies in humans; the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks or there are no animal reproduction studies and no adequate studies in humans.

D: there is evidence of human foetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.

X: studies in animals or humans demonstrate fetal abnormalities or adverse reaction reports indicate evidence of foetal risk; the risk of use in a pregnant woman clearly outweighs any possible benefit.