Can Vitamin D Benefit Patients with Prediabetes?

Posted on February 1, 2016 by Maurice Preter MD

 

Can Vitamin D Benefit Patients with Prediabetes?

No Effect of High-Dose Vitamin D Treatment on β-Cell Function, Insulin Sensitivity, or Glucose Homeostasis in Subjects With Abnormal Glucose Tolerance: A Randomized Clinical Trial

Henrik Wagner1⇑, Michael Alvarsson1, Buster Mannheimer2, Marie Degerblad1 and Claes Göran Östenson1

http://care.diabetesjournals.org/content/early/2016/01/07/dc15
-1057.abstract

Abstract

OBJECTIVE There has been conflicting evidence regarding the potential role of vitamin D in glucose homeostasis. This study was designed to investigate the effect of high-dose vitamin D3 treatment on β-cell function, insulin sensitivity, and glucose tolerance in subjects with prediabetes or diet-treated type 2 diabetes.

RESEARCH DESIGN AND METHODS Subjects (n = 44) were randomized to 30,000 IU vitamin D3 once weekly or placebo for 8 weeks. Hyperglycemic clamp assessed first-phase (0–12 min) and second-phase (12–120 min) insulin response, insulin sensitivity, and disposition index (DI). An oral glucose tolerance test assessed glucose tolerance and glycosylated hemoglobin assessed glycemic control.

RESULTS A total of 21 (vitamin D) and 22 (placebo) subjects completed the study, respectively. Season-adjusted 25-OH-vitamin D [25(OH)D] levels were doubled in the active treated group (43–82 nmol/L). No effect of vitamin D treatment, compared with placebo, was seen on first-phase or second-phase insulin secretion. There were no group differences in insulin sensitivity, DI, or any measures of glycemic control. No hypercalcemia or other adverse effects of vitamin D treatment were seen compared with placebo. Subgroup analyses of those with the lowest basal and greatest increase in 25(OH)D levels did not change these results.

CONCLUSIONS This study gives no support for any substantial effect of high-dose vitamin D treatment for 8 weeks in prediabetes or diet-treated type 2 diabetes on β-cell function, insulin sensitivity, or glycemic control.

  • Received May 19, 2015.
  • Accepted December 4, 2015.
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True Risk of Serious Harms with Antidepressants Still Uncertain

Posted on January 31, 2016 by Maurice Preter MD

True Risk of Serious Harms with Antidepressants Still Uncertain

http://www.bmj.com/content/352/bmj.i65

Abstract

Objective To study serious harms associated with selective serotonin and serotonin-norepinephrine reuptake inhibitors.

Design Systematic review and meta-analysis.

Main outcome measures Mortality and suicidality. Secondary outcomes were aggressive behaviour and akathisia.

Data sources Clinical study reports for duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine obtained from the European and UK drug regulators, and summary trial reports for duloxetine and fluoxetine from Eli Lilly’s website.

Eligibility criteria for study selection Double blind placebo controlled trials that contained any patient narratives or individual patient listings of harms.

Data extraction and analysis Two researchers extracted data independently; the outcomes were meta-analysed by Peto’s exact method (fixed effect model).

Results We included 70 trials (64 381 pages of clinical study reports) with 18 526 patients. These trials had limitations in the study design and discrepancies in reporting, which may have led to serious under-reporting of harms. For example, some outcomes appeared only in individual patient listings in appendices, which we had for only 32 trials, and we did not have case report forms for any of the trials. Differences in mortality (all deaths were in adults, odds ratio 1.28, 95% confidence interval 0.40 to 4.06), suicidality (1.21, 0.84 to 1.74), and akathisia (2.04, 0.93 to 4.48) were not significant, whereas patients taking antidepressants displayed more aggressive behaviour (1.93, 1.26 to 2.95). For adults, the odds ratios were 0.81 (0.51 to 1.28) for suicidality, 1.09 (0.55 to 2.14) for aggression, and 2.00 (0.79 to 5.04) for akathisia. The corresponding values for children and adolescents were 2.39 (1.31 to 4.33), 2.79 (1.62 to 4.81), and 2.15 (0.48 to 9.65). In the summary trial reports on Eli Lilly’s website, almost all deaths were noted, but all suicidal ideation events were missing, and the information on the remaining outcomes was incomplete.

Conclusions Because of the shortcomings identified and having only partial access to appendices with no access to case report forms, the harms could not be estimated accurately. In adults there was no significant increase in all four outcomes, but in children and adolescents the risk of suicidality and aggression doubled. To elucidate the harms reliably, access to anonymised individual patient data is needed.

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Quetiapine safety in older adults?

Posted on January 31, 2016 by Maurice Preter MD

Quetiapine safety in older adults?

Journal of Clinical Pharmacy and Therapeutics

Volume 41,  Issue 1, pages 7–18, February 2016

http://onlinelibrary.wiley.com/doi/10.1111/jcpt.12357/abstract

Abstract

WHAT IS KNOWN AND OBJECTIVE:

Quetiapine is a second-generation antipsychotic that is commonly prescribed for a range of approved and off-label indications in older adults. However, little is known about its safety in this population. The available evidence on quetiapine safety is based on studies on second-generation antipsychotics as a group, often in the general population and for approved indications. There are no systematicreviews on the safety of quetiapine in older adults, and therefore, there is a need for systematically assessing quetiapine safety in this group of patients to establish an appropriate safety profile for this vulnerable population. The aim of this paper was to review and describe adverse drug events associated with quetiapine use in older adults.

METHODS:

A systematic literature search was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases searched were CINAHL, PubMed, Medline, PsycInfo and the Cochrane Library.

RESULTS AND DISCUSSION:

Sixty-nine papers met the inclusion criteria. The majority of the studies (n = 36, 52%) were observational, and 11 (16%) were randomized controlled trials (RCTs). Most of the reported indications (75%) were off-label. The most commonly reported adverse events were somnolence (25-39%), dizziness (15-27%), headache (10-23%), postural hypotension (6-18%) and weight gain (11-30%). From the included RCTs, comparing quetiapine with placebo, quetiapine resulted in significantly greater cognitive impairment, higher rates of falls and injury and increased mortality in patients with parkinsonism, but not in patients with dementia. Compared with risperidone and olanzapine, quetiapine had significantly lower risk of mortality, reduced rate of cerebrovascular events, increased rate of falls and injury and less metabolic disorders compared with olanzapine, but higher metabolic disorders compared with risperidone.

WHAT IS NEW AND CONCLUSION:

This work provides full characterization of quetiapine safety in older people, which may help healthcare providers better anticipate, prevent and manage ADEs in this population.

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Severe parkinsonism due to Reglan (metoclopramide): the importance of early recognition.

Posted on January 15, 2016 by Maurice Preter MD

A reminder.. The well-established but under-appreciated dopamine-blocking effect of metoclopramide.

Ned Tijdschr Geneeskd. 2013;157(26):A6037.

Severe parkinsonism due to Reglan (metoclopramide): the importance of early recognition.

[Article in Dutch]

de Ronde MW1, Kingma HJ, Munts AG.

Author information

1Kennemer Gasthuis, afd. Neurologie, Haarlem, the Netherlands. mwjderonde@gmail.com

Abstract

In this article, we present 3 women aged 73, 85 and 88 years who developed metoclopramide-induced parkinsonism. Shortly after starting metoclopramide, bradykinesia and rigidity developed in all 3 patients; tremor and postural instability in 2 of them. We discontinued the metoclopramide after 3-6 months; 2 of the patients had fully recovered 4-6 months later. The 3rd patient died from pneumonia, however, 2 months after discontinuation. Metoclopramide, a dopamine D2-antagonist, is a frequently prescribed anti-emetic drug; however, evidence of its efficacy is limited. In many patients, domperidone, another dopamine D2-antagonist, seems to be a better alternative. Movement disorders due to domperidone are uncommon, presumably because it does not cross the blood-brain barrier. It is likely that metoclopramide-induced parkinsonism is not uncommon; however, it is under-recognized. Risk factors are female sex, advanced age, diabetes mellitus and polypharmacy. Follow-up on patients using metoclopramide is advised.

Zhonghua Nei Ke Za Zhi. 1988 Jun;27(6):358-60, 390.

Adverse neurologic effects of Reglan (metoclopramide). Report of 60 cases.

[Article in Chinese]

Sun B, Cao QL, Ou XR.

Am J Gastroenterol. 2013 Jun;108(6):866-72. doi: 10.1038/ajg.2012.300.

The metoclopramide black box warning for tardive dyskinesia: effect on clinical practice, adverse event reporting, and prescription drug lawsuits.

Ehrenpreis ED1, Deepak P, Sifuentes H, Devi R, Du H, Leikin JB.

Author information

1Department of Gastroenterology, Evanston Hospital, NorthShore University HealthSystem, Evanston, Illinois 60201, USA. ehrenpreis@gipharm.net

Abstract

OBJECTIVES: We examined the effects of the black box warning about the risk of tardive dyskinesia (TD) with chronic use of metoclopramide on management of gastroparesis within a single clinical practice, and on reporting of adverse events.

METHODS: Medical records of gastroparesis patients were evaluated for physician management choices. The FDA Adverse Event Reporting System (FAERS) was analyzed for event reports, and for lawyer-initiated reports, with metoclopramide from 2004 to 2010. Google Scholar was searched for court opinions against metoclopramide manufacturers.

RESULTS: Before the black box warning, 69.8% of patients received metoclopramide for gastroparesis, compared with 23.7% after the warning. Gastroenterologists prescribed domperidone more often after than before the warning. Metoclopramide prescriptions decreased after 2008. Adverse event reporting increased after the warning. Only 3.6% of all FAERS reports but 70% of TD reports were filed by lawyers, suggesting a distortion in signal. Forty-seven legal opinions were identified, 33 from 2009-2010.

CONCLUSIONS: The black box warning for metoclopramide has decreased its usage and increased its rate of adverse event reporting. Lawyer-initiated reports of TD hinder pharmacovigilance.

Ned Tijdschr Geneeskd. 2002 Jan 26;146(4):175-7.

Severe parkinsonism due to Reglan (metoclopramide) in a patient with polypharmacy.

[Article in Dutch]

Hoogendam A1, Hofmeijer J, Frijns CJ, Heeringa M, Schouten-Tjin a Tsoi SL, Jansen PA.

Author information

1Afd. Klinische Geriatrie, Universitair Medisch Centrum, Utrecht. hoogendam-dekkers@zonnet.nl

Abstract

A 73-year-old woman, with tuberculosis of the large intestine, developed nausea as a side effect of the antituberculosis drugs. The nausea was treated with metoclopramide. Subsequently she developed severe medication-induced parkinsonism. As her symptoms initially mimicked a depressive disorder, drug-induced parkinsonism was only considered at a later stage. Due to drug-induced impaired function of the liver and kidney the patient had received a toxic dose of metoclopramide. Treatment with biperiden and withdrawal of the metoclopramide resulted in a reduction of the complaints within 3 months, after which the anti-tuberculosis medication could be reintroduced. Adjusting the dose of metoclopramide could possibly have prevented this severe side effect.

 

Psychiatry Clin Neurosci. 2007 Apr;61(2):193-5.

Persistent generalized anxiety after brief exposure to the dopamine antagonist Reglan (metoclopramide).

Kluge M1, Schüssler P, Steiger A.

Author information

1Max Planck Institute of Psychiatry, Munich, Germany. kluge@mpipsykl.mpg.de

Abstract

The authors describe a 31-year-old woman who developed persistent generalized anxiety after brief exposure to the dopamine antagonist metoclopramide. Independently of that, she had experienced a panic attack followed by dystonias, shortly after a single dose of that drug, 17 years before. Both temporal association and recurrence of anxiety symptoms after re-challenge with metoclopramide suggest a causal relationship. The case might provide an initial piece of evidence that dopaminergic neurotransmission can be involved in the pathogenesis of generalized anxiety disorder.

 

See comment in PubMed Commons below

Ceylon Med J. 1996 Sep;41(3):125.

Parkinsonism: an under-recognised complication of Reglan (metoclopramide) use.

[No authors listed

Acta Neurol (Napoli). 1992 Apr;14(2):130-3.

Reglan (Metoclopramide)-induced parkinsonism and depression.

Jibiki I1, Maeda T, Yamaguchi N.

Author information

1Department of Neuropsychiatry, Kanazawa University School of Medicine, Japan.

Abstract

A 46-year-old female patient with metoclopramide-induced parkinsonism and depression was reported in view of the rarity of the concurrent development of these side effects. A risk of metoclopramide administration is suggested

South Med J. 1989 Dec;82(12):1581-2.

Reglan (Metoclopramide)-induced parkinsonism.

Sethi KD1, Patel B, Meador KJ.

Author information

1Department of Neurology, Medical College of Georgia, Augusta 30912-2366.

Abstract

Metoclopramide hydrochloride (Reglan) is a widely prescribed drug for treatment of upper gastrointestinal symptoms. Although the drug is relatively safe, a growing body of literature has noted movement disorders after its administration. We have reported six cases of metoclopramide-induced parkinsonism seen in consultation over a two-year period. Five of these six patients had renal failure. Their parkinsonism improved on discontinuation of metoclopramide therapy. Metoclopramide-induced parkinsonism is not rare, and appropriate dose reduction in patients with renal failure will help reduce the incidence of this morbidity.

J Emerg Med. 2006 May;30(4):411-3.

Abdominal pain with rigidity secondary to the anti-emetic drug Reglan (metoclopramide).

Khan NU1, Razzak JA.

Author information

1Section of Emergency Medicine, Department of Medicine, The Aga Khan University, Karachi, Pakistan.

Abstract

We report a case of abdominal pain with rigidity, mimicking an acute abdomen, caused by metoclopramide, a common anti-emetic drug. Extrapyramidal symptoms are commonly reported side-effects of this medication. They generally include involuntary movements of limbs, torticollis, oculogyric crisis, rhythmic protrusion of tongue, trismus, or dystonic reactions resembling tetanus, etc. Abdominal rigidity due to this medication, resembling an acute abdomen, has not been reported previously. This case report illustrates the importance of considering medication side-effects when evaluating a patient with abdominal pain and rigidity.

Synapse. 2011 Feb;65(2):119-24. doi: 10.1002/syn.20825.

Antipsychotic drug binding in the substantia nigra: an examination of high Reglan (metoclopramide) binding in the brains of normal, Alzheimer’s disease, Huntington’s disease, and Multiple Sclerosis patients, and its relation to tardive dyskinesia.

Chen S1, Seeman P, Liu F.

Author information

1Department of Neuroscience, Centre for Addiction and Mental Health, Clarke Division, Toronto, Ontario, Canada M5T 1R8.

Abstract

This project was done in order to determine why the annual incidence of metoclopramide-associated tardive dyskinesia is much higher than that for the commonly used antipsychotics. To test the hypothesis that metoclopramide tardive dyskinesia may be associated with high concentrations of metoclopramide in the substantia nigra under clinical conditions, the nonspecific binding of tritiated antipsychotics to the dissected melaninized regions of postmortem human substantia nigra was measured. The nonspecific binding at 1 nM [³H]ligand was 7.3, 4.2, 2.6, 0.91 and 0.66 fmoles/mg for [³H]haloperidol, [³H]clozapine, [³H]raclopride, [³H]metoclopramide, and [³H]olanzapine, respectively. After adjusting these values for the known free concentrations of these drugs in plasma or spinal fluid, the amounts that would be bound under clinical conditions would be 231, 113, 15, 11, and 3.4 fmoles/mg for metoclopramide, clozapine, raclopride, haloperidol, and olanzapine, respectively. Using rat striatum as baseline to define antipsychotic binding to nonnigral tissue, the excess amount of binding to the Alzheimer nigral tissue under clinical conditions would be 209, 19, 0, 3.4 and 0.8 fmole/mg for metoclopramide, clozapine, raclopride, haloperidol, and olanzapine, respectively, with a similar pattern for nigral tissues from Huntington and Multiple Sclerosis patients. The high accumulation of metoclopramide is sufficiently high to cause nigral nerve cell membrane damage by metoclopramide’s detergent-like action, possibly explaining metoclopramide’s toxic ability to elicit early tardive dyskinesia. In addition, the nonspecific binding of metoclopramide was much higher in Alzheimer-diseased substantia nigra, consistent with the fact that older individuals are relatively more vulnerable to metoclopramide tardive dyskinesia.

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A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer’s disease

Posted on January 15, 2016 by Maurice Preter MD

A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer’s disease

http://nutritionandmetabolism.biomedcentral.com/articles/10.1186/1743-7075-2-28

  • Ingrid Van der Auwera,
  • Stefaan Wera,
  • Fred Van Leuven et al.
Nutrition & Metabolism20052:28

Abstract

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that primarily strikes the elderly. Studies in both humans and animal models have linked the consumption of cholesterol and saturated fats with amyloid-β (Aβ) deposition and development of AD. Yet, these studies did not examine high fat diets in combination with reduced carbohydrate intake. Here we tested the effect of a high saturated fat/low carbohydrate diet on a transgenic mouse model of AD.

Results

Starting at three months of age, two groups of female transgenic mice carrying the “London” APP mutation (APP/V717I) were fed either, a standard diet (SD) composed of high carbohydrate/low fat chow, or a ketogenic diet (KD) composed of very low carbohydrate/high saturated fat chow for 43 days. Animals fed the KD exhibited greatly elevated serum ketone body levels, as measured by β-hydroxybutyrate (3.85 ± 2.6 mM), compared to SD fed animals (0.29 ± 0.06 mM). In addition, animals fed the KD lost body weight (SD 22.2 ± 0.6 g vs. KD 17.5 ± 1.4 g, p = 0.0067). In contrast to earlier studies, the brief KD feeding regime significantly reduced total brain Aβ levels by approximately 25%. Despite changes in ketone levels, body weight, and Aβ levels, the KD diet did not alter behavioral measures.

Conclusion

Previous studies have suggested that diets rich in cholesterol and saturated fats increased the deposition of Aβ and the risk of developing AD. Here we demonstrate that a diet rich in saturated fats and low in carbohydrates can actually reduce levels of Aβ. Therefore, dietary strategies aimed at reducing Aβ levels should take into account interactions of dietary components and the metabolic outcomes, in particular, levels of carbohydrates, total calories, and presence of ketone bodies should be considered.

 

 

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