Pregnancy Morbidity

Update on Antiphospholipid Syndrome (APS)

e antiphospholipid syndrome (APS) is an autoimmune disease de ned by two major elements: the occurrence of clinical features, categorised as recurrent vascular thrombosis and/or pregnancy morbidity, and the presence of antiphospholipid antibodies (aPL) in plasma (Devreese 2009). Antiphospholipid syndrome is sometimes referred to as Hughes syndrome, after the rheumatologist Dr. Graham R.V. Hughes. Clinical criteria for APS includes pregnancy loss – either as miscarriage, intrauterine fetal death or stillbirth – and/or obstetric complications, such as intrauterine growth restriction (IUGR), uteroplacental insu ciency, pre-eclampsia and pre-term birth (before 30 weeks) (Carp 2008, Yasuda 1995) (See Table 1). Signi cant associations between recurrent miscarriages and pregnancy complications have been reported with each autoantibody, detectable by di erent assays, in the aPL family including lupus anticoagulant (LA), anti-cardiolipin (aCL) and anti-beta2 glycoprotein I (β2GPI) (Tincani 2003) (See Table 2). Assays of the various aPL are not only diagnostic of APS, but are believed to have a pathogenic role, mediating several clinical manifestations of the syndrome (Meroni 2010).

Antibody Measurements in APS

Antiphospholipid syndrome was rst identi ed more than 20 years ago when the lupus anticoagulant (LA), known to prolong prothrombin time (PT), was found in patients with a history of thrombosis and recurrent second trimester pregnancy loss (Tincani 2003). It is currently considered more appropriate to assess a combination of antibodies rather than one antibody for adequate laboratory detection of APS as no antibody is pathognomic for pregnancy loss or reproductive complications (Carp 2008) (See Table 3).

LA recognition in particular has several disadvantages. Handling and preparation of plasma samples is complicated and labourintensive (Devreese 2009).

e diagnostic value of the aCL antibody test is currently under debate, partly because of methodological problems (Devreese 2009); however, aCL have been shown to help predict cases of Systemic lupus erythematosus (SLE) shifting to secondary APS (Harel 2006).

Antibodies against β2GPI seem to be particularly important, especially when aCL and LA are negative and APS is strongly suspected (Bas de Laat 2004, de Groot 2005). In 3% to 10% of APS patients, anti-β2GPI antibodies might be the only positive test (Ebeling 2003, Lee 2003, Nash 2004). e anti-β2GPI antibody ELISAs (Enzyme-linked immunosorbent assay) detect all antibodies reactive with the protein, making it less speci c, and probably not suitable as a general diagnostic test (de Laat 2008).

Combining the pro le for all three of the tests may enable correct interpretation of results and clinical management (Pengo 2007). A full positive pro le (ie. presence of LA, aCL and β2GPI antibodies) is associated with thrombosis and obstetric complications and appears to re ect the presence of large amounts of antibodies speci cally against β2GPI. LA shows the strongest correlation with thrombosis and pregnancy morbidity (Galli 2003). Patients positive for aCL and β2GPI antibodies, with no history of thromboembolic complications, presented only with obstetric complications (Pengo 2005, Ru atti 2006).

Pathogenic Mechanisms

The thrombophillic e ect of aPL in intraplacental thrombosis, impairing maternal-fetal blood exchange, was originally thought to be the main pathogenic mechanism of fetal loss (Meroni 2010). Histopathological ndings failed to nd thrombosis as the cause of all reproductive failure in samples of miscarried fetuses and placentas from women with APS however (Park 2006). Though thrombosis is indeed a part of the pathophysiology, it is well recognized that different mechanisms are responsible for the vascular and the obstetrical manifestations of APS (Meroni 2010).

Thrombosis

In vivo models of thrombosis induced in mice and hamsters have confirmed that aPL are able to increase thrombus formation in venous and arterial trees (Fischetti 2005, Jankowski 2003,Ramesh 2011). Infusion with and without β2GPI revealed altered expression of endothelial adhesion molecules, and an upregulated expression of nitric oxide and tissue factor (TF) have been reported in arterial endothelia, supporting a key role for aPL in causing vascular abnormalities (Ramesh 2011, Romay- Penabad 2011, Vega-Ostertag 2007). It is the β2GPI, of all the aPL subpopulations, that appears to be most responsible for the thrombotic manifestations of APS (Meroni 2010).

Impaired Trophoblast Invasiveness

Trophoblast invasion is a dynamic process that is tightly controlled by a complex series of interactions between trophoblast and decidual tissues; defective placentation may occur as a result of default in any of them (Meroni 2010, Pierangeli 2008). The differentiation of the trophoblast into an invasive phenotype is related to the expression of cell surface adhesion and signalling molecules (Aplin 2000, Castellucci 2000). Placental invasion might then be affected by abnormal integrin and cadherin expression caused by aPL activity (Di Simone 2002). The failure to express the correct adhesion molecule phenotype by the trophoblast is the disruption that is thought to prevent proper decidual invasion (Meroni 2004). These mechanisms have been suggested to play a role in early fetal loss, while thrombotic events would be responsible for miscarriages late in pregnancy (Meroni 2004).

Uncontrolled Inflammatory Balance

Evidence for the delicate balance between proinflammatory and anti-inflammatory mediators during gestation on the outcome of pregnancy exist (Chaouat 2007). Proinflammatory mediators (such as complement, tumor necrosis factor [TNF], and CC chemokines) have been shown to have a role in animal models of aPL-induced fetal loss (Meroni 2010).

Endogenous Protective Mediator

Annexin V or placental anti-coagulant protein I (PAP-I) is a protein that is expressed on the surface of villous syncitiotrophoblasts. It displays a strong anticoagulant activity in APS by binding to the negatively charged phospholipids, thereby producing a protective shield against aPLs that would otherwise bind to these same phospholipids (Tincani 2003). In APS patients, a decreased quantity of Annexin V has been reported at the placental level (Krikun 1994).

Conventional Treatment of APS

In spite of the general consensus on the management of pregnant aPL-positive women, few well-designed clinical trials have been reported and there is also insufficient data about the positive predictive value (PPV) of treatment (Carp 2008). To date, concomitant administration of heparin and aspirin are used in the treatment of APS. This followed a 1992 controlled trial using 20,000 U/day heparin and 81 mg aspirin that revealed improved pregnancy outcome (Cowchock 1992). The rationale for heparin use was originally founded on the pathogenic role of thrombotic phenomena in aPL-associated pregnancy loss (Hughes 1983), but it was the anticomplement, rather than the anticoagulant, effect of heparin that was later credited in experimental models with mice for the positive pregnancy outcomes (Girardi 2004).

Aspirin has been shown to stimulate Interleukin-3 (IL-3) production (Fishman 1995). IL-3 is a known growth factor for the trophoblast (Wegmann 1989) and IL-3 levels are reduced in women diagnosed with APS during pregnancy (Fishman 1996). In vivo studies in experimental models revealed compelling results such as the elimination of aPL-related obstetrical complications through the addition of exogenous IL-3 (Fishman 1993) that upheld the continued use of aspirin in APS. Some in vitro studies however were unable to provide evidence that IL-3 prevented aPL effect on the trophoblast (Chamley 2001), while others could (Di Simone 2000).

Low corticosteroid doses (<20 mg/day) are occasionally used, particularly in women unresponsive to the standard low-dose aspirin and heparin therapy (Meroni 2011), but there is no sound evidence to support the routine use of corticosteroids in APS (Cowchock 1992, Ruiz-Irastorza 2010). Intravenous immunoglobulin use as a prophylactic treatment of fetal loss in APS patients has been discussed (Tincani 2003). This treatment, added to conventional heparin/aspirin treatment, was unable to improve reproductive prognosis in APS patients (Branch 2000). It is thought that such treatment should be reserved for cases in which conventional therapy has failed or to treat acute problems of pregnancy, especially acute problems of pregnant APS patients (Tincani 2003).

Populations at Greatest Risk for APS

The link between the presence of anti-thyroid antibodies and either isolated or recurrent pregnancy loss has been reproducibly demonstrated (Bussen 1995, Glinoer 1991, Singh 1995, Stagnaro-Green 1990). Presence of anti-thyroid antibodies are significantly correlated with an increased rate of miscarriage in women in their first trimester of pregnancy (Stagnaro-Green 1990) and an increased rate of spontaneous pregnancy loss was reported in women with detectable thyroid autoantibodies compared with controls (Glinoer 1991). Approximately one-third of women diagnosed with APS had anti-thyroid antibodies in a study by De Carolis and colleagues. Women with anti-thyroid antibodies (associated or not with aPL) had significantly lower percentages of pregnancies, and the overall success rate of pregnancy in patients positive for thyroid autoimmunity (alone or association with aPL) was 59% (De Carolis 2004). The presence of anti-thyroid antibodies have an overall PPV of 40% for pregnancy loss (Carp 2008).

That women with systemic lupus erythematosus (SLE) are at greater risk of experiencing pregnancy loss is nothing new. SLE has been known for decades to predispose to spontaneous abortions (Gleicher 1999). It is now known, however, that the risk for pregnancy loss precedes the clinical occurrence and/or diagnosis of SLE as well (Hardy 1999). This bidirectional phenomena is termed reproductive autoimmune failure syndrome (RAFS) and is thought to extend to autoimmune conditions beyond SLE (Gleicher 1999). Many authors suggested that, in addition to other causes, infertile patients might suffer from subclinical autoimmune disease and, in turn, those subclinical autoimmune patients could be at risk of implantation failure or of early post-implantation loss (Geva 1997).

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Hibiscus

An emerging new botanical medicine

The Hibiscus genus (family Malvaceae) is comprised of several species, many of which have been used historically for their culinary and medicinal properties. The species Hibiscus sabdariffa is an important medicinal plant grown in Africa, the Middle East, South East Asia and Central America (Ojeda 2010). Traditionally, the aqueous extract of H. sabdariffa, colloquially known as sour tea, has been used to treat hypertension, liver disease and fever (Mozaffari-Khosravi 2009).

More recently, the anti-oxidant, lipid and blood pressure lowering effects of Hibiscus sabdariffa have been investigated. H. sabdariffa extracts have demonstrated anti-oxidant properties, hypolipidemic effects, ACE inhibition and inhibition of vascular smooth muscle cell proliferation and migration secondary to hyperglycemia (Huang 2009, Kao 2009, Ojeda 2010, Yang 2010). Considering its nutritional profile, pharmacological properties and safety, H. sabdariffa shows promise as a cardio-protective agent and potential diabetic therapy (Mozaffari- Khosravi 2009).

Chemistry

H. sabdariffa contains various phytochemicals, including phenolics, organic acids, sterols, terpenoids, polysaccharides and some minerals (Ojeda 2010). The phenolic content is composed mainly of anthocyanins delphinidin-3-O-sambubioside (85%) and cyanindin-3-O-sambubioside, plant pigments that are isolated from dried calyces (Frank 2005). Anthocyanins, a subgroup of flavonoids, are water-soluble glycosides and acylglycosides of anthocyanidins (Frank 2005). Other phenols include protocatechuic acid, catechin, gallocatechins, caffeic acid and gallocatechin gallates (Yang 2010).

An aqueous extract of H. sabdariffa (HSE) contains varying concentrations of anthocyanins and polyphenols depending on the processing method and storage time (Frank 2005). Regardless, HSEs contain effective antioxidants, radical scavengers and ferric-reducing compounds, the properties which likely impart their therapeutic benefit (Frank 2005).

Preclinical evidence

Anti-oxidant Effects

Oxidation of low-density lipoprotein (oxLDL) occurs in the early stages of atherosclerotic lesion formation. Scavenger receptors have been identified that bind and internalize oxLDL, mediating its uptake into macrophages and leading to the formation of macrophage-derived foam cells. CD36 has been identified as the predominant scavenger receptor for oxidized LDL and its regulation plays an essential role in the formation of macrophage foam cells and atherosclerosis (Kao 2009).

The most recent study investigating the anti-oxidant activity of H. sabdariffa and LDL oxidation was completed by Kao et al (2009). Hibiscus anthocyanin-rich extracts (HAs) prevented lipid accumulation, significantly decreased CD36 mRNA gene and protein expression and significantly decreased PPARγ protein levels, the CD36 upstream transcription factor, in mouse cells treated with oxidized LDL. The study demonstrated that the antioxidant activity of HAs may ultimately inhibit the formation of oxLDL-foam cells.

Hypolidemic Effects

The hypolipidemic effect of a Hibiscus sabdariffa 74% polyphenol extract (HPE), composed mostly of protocatechuic acid (PCA), caffeic acid and gallocatechin gallate (GCG) were investigated in an animal model (Yang 2010). Hamsters were fed a high fat diet for 10 weeks with or without HSE or HPE; both HSE and HPE fed hamsters experienced a decrease in serum triglycerides and total cholesterol in a dose-dependent manner. However, the HPE had a greater effect on decreasing plasma and LDL cholesterol and increasing HDL than a crude extract (HSE) containing only 2% polyphenols.

At 0.5 mg/mL, HPE decreased fatty acid synthase and HMG-CoA reductase 75% and 69% respectively. The HSE did not alter the protein expression of fatty acid synthase, but rather altered the phosphorylation of AMP-activated protein kinase (AMPK). Previous reports have outlined the importance of AMPK in regulating lipid metabolism; activation (phosphorylation) of AMPK simultaneously inhibits fatty acid and cholesterol synthesis in rat hepatocytes by inactivating the acetyl CoA carboxylase and HMG CoA reductase, respectively (Yang 2010).

In addition the activation of AMPK by HPE decreased the expression of sterol regulatory element binding protein (SREBP), a membrane bound transcription factor which regulates lipid metabolism, and the transcription of its target genes, HMG CoA reductase and fatty acid synthase. Further investigation revealed that HPE also enhances the expression of the LDL-receptor, increasing LDL uptake and hepatic clearance (Yang 2010).

ACE-Inhibition Effects

The inhibition of angiotensin I converting enzyme (ACE) by H. sabdariffa has been demonstrated in vitro with a crude hydroethanol extract from the plant calyces (Ojeda 2010). Using an aqueous extract of H. sabdariffa, delphinidin-3-O-sambubioside and cyanidin-3-O-sambuioside were identified as the two most abundant anthocyanins. Evaluation of in vitro ACE inhibition was completed by quantifying the hydrolysis of N-[3-(2-furyl) acryloyl]-L-phenylalanylglycylglycine (FAPGG) by ACE, both of which were isolated from rabbit lung. A combined anthocyanin-rich fraction, as well as isolated extracts of each anthocyanin were used to inhibit ACE activity in a dose-dependent manner. Both anthocyanins were more effective on their own than the combined extract, and delphinidin-3-O-sambubioside was more effective than cyanidin-3-O-sambubioside, likely owing to the fact that it has more hydroxyl groups. Kinetic analysis suggested ACE was inhibited by the anthocyanins via competition for the enzyme’s active site, most likely due to the rigid planar structure of the anthocyanins and the presence of ortho-dihydroxylation on the aromatic ring.

Inhibition of Vascular Smooth Muscle Cell Proliferation In hyperglycemia of metabolic syndrome or diabetes mellitus, high-glucose conditions mediate the growth and extracellular matrix (ECM) gene expression of vascular smooth muscle cells (VSMC) to promote anti-apoptotic signalling, chemotaxis and migration. Hyperglycemia also promotes the formation of advanced glycation end (AGE) products, which is believed to play a role in atherosclerotic plaque formation when they interact with their specific receptor (Receptor for Advanced Glycation End Products- RAGE) (Huang 2009).

A polyphenolic extract of H. sabdariffa was examined for its protective activity against high-glucose-treated VSMC. The extract reduced the high-glucose-stimulated cell proliferation and migration in a dose and time dependent manner (Huang 2009). Proliferating cell nuclear antigen (PCNA), a marker of proliferation, and activation of matrix metalloproteinase (MMMP)-2, the ECM-degrading enzyme during the process of migration, were suppressed by treatment with the H. sabdariffa extract. Furthermore, expression of connective tissue growth factor (CTGF) and RAGE, usually enhanced by hyperglycemia, were also suppressed by treatment with the extract.

Pharmacology

In a study examining the pharmacokinetics of monomeric anthocyanins after consumption of H. sabdariffa extracts, the anthocyanins were incorporated and excreted in urine in their intact glycosidic forms. 147.4 mg of total anthocyanins were administered to six healthy subjects and maximum excretion rates occurred at 1.5-2.0 hours after ingestion. While oral absorption of H. sabdariffa anthocyanins was fast, maximum plasma concentrations were low, between 1.3-3.4 ng/ml. Peak plasma concentrations occurred almost simultaneously as urinary excretion rates, with maximum excretion rates occurring at 1.5-2.0 hours after ingestion (Frank 2005).

Some evidence suggests that deglycosylation is the rate-limiting step for the absorption of dietary flavonoid glycosides in the small intestine. β-glucosidases, lactase-phlorizin hydrolase (LPH), and the cytosolic β-glucosidase (CBG) are found in the epithelial cells of the small intestine and normally function to deglycosylate flavonoid glycosides during passage across the gut wall (Nemeth 2003). Anthocyanins are not substrates for these β-glucosidases and this may explain the low bioavailability of these compounds, as they were not hydrolyzed to their aglycones and were absorbed only as intact glycosides in small amounts (Frank 2005). However, it is known that most polyphenols ingested from flavonoid-rich beverages are metabolised in the colon (Rechner 2002).

The half-life of total anthocyanins from the H. sabdariffa extract was derived from urinary excretion and was determined to be 2.63 hours (Frank 2005). In a separate study, H. sabdariffa calyx extracts demonstrated a very low degree of toxicity, with an LD50 above 5000 mg/kg in rats (Onyenekwe 1999). Further studies are needed on human plasma and urinary intact glycosides and their in vivo metabolites and/or conjugates in order to fully characterize the pharmacokinetics of H. sabdariffa (Frank 2005).

Human evidence We identified seven controlled human clinical trials evaluating hibiscus preparations. See Table 1. Five of the trials evaluated impact on blood pressure, three trials evaluated impact on serum lipid profiles, and one trial evaluated impact on plasma glucose levels. Only one trial failed to demonstrate a positive outcome; the trial evaluated impact to cholesterol levels and was compounded by recommendations to achieve reductions in body weight. Therefore both the hibiscus group and the control group experienced significant improvement in cholesterol profiles, with no significant difference between the two groups (Kuriyan 2010).

All five trials evaluating blood pressure demonstrated significant benefit, with a magnitude of effect ranging from 5-15% for reductions to systole and diastole (Faraji 1999, Herrera-Arellano 2007, Herrera-Arellano 2004, Mozaffari-Khosravi 2009b, McKay 2010). The two trials demonstrating positive impact to cholesterol levels revealed reductions in total cholesterol, LDL- cholesterol and triglyceride, as well as increased HDL-C levels (Gurrola-Diaz 2010, Mozaffari-Khosravi 2009a). The only trial to evaluate glucose levels likewise demonstrated significant improvement to glucose control (Gurrola- Diaz 2010).

Discussion Hibiscus, delivered in an array of dosage forms (standardized extracts, teas, decoctions), has demonstrated an impressive magnitude of benefit to key metabolic abnormalities, notably the constellation of abnormalities comprising the diagnostic criteria of the metabolic syndrome; glucose control, blood pressure, and plasma cholesterol levels, specifically triglyceride and HDL- cholesterol (as defined by Grundy 2004). The ease of delivery, the marginal cost of the medicine (especially in tea or decoction dosage forms), and an impressive safety profile make hibiscus a promising medicine for an array of very common clinical presentations. Longer- term trials are needed to determine if the effects of hibiscus are sustained beyond 30 days. Also, impact to blood glucose control deserves more research attention.

References:

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Frank T, Janben M, Netzel M, Strab G, Kler A, Kriesl E, Bitsch I. Pharmacokinetics of anthocyanidin-3-glycosides following consumption of Hibiscus sabdariffa L. extract. J Clin Pharmacol 2005 Feb;45(2):203-10.

Gurrola-Diaz CM, Garcia-Lopez PM, Sanchez-Enriquez S, Troyo-Sanroman R, Andrade-Gonzalex I, Gomez-Leyva JF. Effects of Hibiscus sabdariffa extract powder and prevention treatment (diet) on the lipid profiles of patients with metabolic syndrome (MeSy). Phytomedicine 2010 Jun;17(7):500-5.

Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. American Heart Association; National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004 Jan 27;109(3):433-8.

Herrera-Arellano A, Flores-Romero S, Chavez-Soto MA, Tortoiello J. Effectiveness and tolerability of a standardized extract from Hibiscus sabdariffa in patients with mild to moderate hypertension: a controlled and randomized clinical trial. Phytomedicine 2004 Jul;11(5):375-82.

Herrera-Arellano A, Miranda-Sanchez J, Avila-Castro P, Herrera-Alvarez S, Jimenez-Ferrer JE, Zamilpa A, Roman-Ramos R, Ponce-Monter H, Tortoriello J. Clinical effects produced by a standardized herbal medicinal product of Hibiscus sabdariffa on patients with hypertension. A randomized, double-blind, lisinopril-controlled clinical trial. Planta Med 2007 Jan; 73(1): 6-12.

Huang CN, Chan KC, Lin WT, Su SL, Wang CJ, Peng CH. Hibiscus sabdariffa inhibits vascular smooth muscle cell proliferation and migration induced by high glucose – a mechanism involves connective tissue growth factor signals. J Agric Food Chem 2009 Apr 22;57(8):3073-9.

Kao ES, Tseng TH, Lee HJ, Chan KC, Wang CJ. Anthocyanin extracted from Hibiscus attenuate oxidized LDL-mediated foam cell formation involving regulation of CD36 gene. Chem Biol Interact 2009 May 15;179(2-3):212-8.

Kuriyan R, Kumar DR, R R, Kurpad AV. An evaluation of the hypolipidemic effect of an extract of Hibiscus Sabdariffa leaves in hyperlipidemic Indians: a double blind, placebo controlled trial. BMC Complement Altern Med. 2010 Jun 17;10:27.

McKay DL, Oliver Chen CY, Saltzman E, Blumberg JB. Hibiscus sabdariffa L. tea (Tisane) lowers blood pressure in prehypertensive and mildly hypertensive adults. J Nutr 2010 Feb;140(2):298-303.

Mozaffari-Khosravi H, Jalali-Khanabadi BA, Afkhami-Ardekani M, Fatehi F. Effects of sour tea (Hibiscus sabdariffa) on lipid profile and lipoproteins in patients with type II diabetes. J Altern Complement Med 2009a Aug;15(8):899-903.

Mozaffari-Khosravi H, Jalali-Khanabadi BA, Afkhami-Ardekani M, Fatehi F, Noori-Shadkam M. The effects of sour tea (Hibiscus sabdariffa) on hypertension in patients with type II diabetes. J Hum Hypertens 2009b Jan;23(1):48-54.

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Ojeda D, Jimenez-Ferrer E, Zamilpa A, Herrera-Arellano A, Tortoriello J, Alvarez L. Inhibition of angiotensin converting enzyme (ACE) activity by the anthocyanins delphinidin- and cyaniding-3-O-sambubiosides from Hibiscus sabdariffa. J Ethnopharmacol 2010 Jan 8;127(1):7-10.

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When patients want to get off their psychotropic medication(s)

Effective strategies for limiting withdrawal and destabilization

For over a decade I have focussed the majority of my clinical practice on the evaluation and treatment of mental health disorders. One of the most common requests I receive from patients is their desire to reduce or discontinue their psychotropic medications. It is entirely appropriate for patients to request this. eir psychotropic drugs might be doing more harm than good and creating many objectionable side e ects, which are limiting rather than enhancing quality of life (Moncrie 2006a). ey might want to see how they feel and function once their psychotropic drugs are reduced and/or discontinued. ey might also wish to be drug-free. When this request it made, I usually tell then something along the lines of:

“I need to see that you are stable for at least six-months before there is any consideration for reducing and/or discontinuing your psychotropic medication. By stability I mean: getting along well with family and friends; maintaining some type of regular work or employment, such as school, a volunteer position, or a career; and having no more disabling symptoms of your psychiatric disorder.”

This is usually well received since most patients prefer to work in a slow, methodical fashion, rather than becoming destabilized should this process be rushed.

Difficulties in Overcoming Pharmacological Dependence

Pharmacological dependence is an expected and biological adaptation of the body becoming long habituated to the presence of psychotropic drugs (O’Brien 2005). Since psychotropic drugs can induce unpredictable global reactions when used properly (Moncrieff 2006b, Moncrieff 2009), there are no reliable ways to predict how patients will overcome pharmacological dependence once their psychotropic drugs are tapered and eventually withdrawn. Every patient’s withdrawal process is unique as is their susceptibility to develop withdrawal side effects (Read 2005).

Discontinuation Reactions Following Cessation of Psychotropic Drugs

Some patients do fine and experience little withdrawal, while other patients have become so habituated and dependent on their psychotropic drugs that stopping them is paramount to disaster. While no ethical clinician would tell a patient to abruptly stop his/ her psychotropic drugs, it is important for clinicians to recognize discontinuation reactions from the common classes of psychotropic drugs (Table 1).

Tapering Patients off their Psychotropic Drugs

When it is appropriate for this to happen, I usually communicate in writing to the patient’s prescribing clinician (i.e., the general/ family practitioner or psychiatrist) that the patient is doing well and wants to try discontinuing one of his/her psychotropic drugs. If the prescribing clinician does not agree to any plan of psychotropic drug tapering, despite the patient’s wishes and noted stability, it is entirely appropriate for the patient and non-prescribing clinician to proceed with a tapering plan. In such a circumstance, it might be suitable to draft a waiver outlining all potential risks and benefits of psychotropic drug tapering with the patient. The waiver would have to clearly delineate that this is what the patient wants, and that the patient is willing to assume all risks (e.g., destabilization and hospitalization) associated with the tapering process.

Since there is a scarcity of clinical research pertaining to tapering patients off their psychotropic drugs, there are no clearly defined standards informing clinicians about the best and most appropriate method of tapering. Patients are just as likely to succeed in coming off their psychotropic drugs whether or not they have the support and endorsement from their prescribing clinicians (Darton 2005). The published data from one organization found that 53% of patients were successful in coming off their psychotropic drugs – even though this was either against their doctors’ advice or occurred without their doctors’ knowledge – compared to 44% that had their doctors’ approval (Read 2005).

The tapering plan should involve one drug at a time and should involve the drug with the longest elimination half-life first. Psychotropic drugs with longer elimination half-lives (i.e., more than 24 hours) are easier to taper from since their withdrawal reactions tend to be less severe than drugs with shorter elimination half-lives (i.e., 24 hours or less). Psychotropic drugs with short elimination half-lives can produce significant and quick withdrawal reactions. Considerations should be made to switch patients from psychotropic drugs with short elimination half-lives to drugs with longer elimination half-lives prior to tapering, as this will increase the chances of a positive experience and successful outcome. A psychotropic drug like vanlafaxine (has an elimination half-life of around five hours) can cause significant withdrawal and possible destabilization. A psychotropic drug like fluoxetine, on the other hand, can be used as a substitute for vanlafaxine, allowing for a more successful tapering plan since the elimination half-life of this drug is four to six days (Darton 2005).

Overall, the tapering plan needs to be very slow and gradual, which reduces the potential for relapse (Moncrieff 2006a). The patient should never be made to feel like a failure during this process since coming off of psychotropic drugs is very difficult due to the “physiological and psychological manifestations of the biological effects caused by the withdrawal of a regularly administered drug” (Moncrieff 2006a). For patients to successfully come of their psychotropic drugs they need to: (1) be well prepared and informed of the process; (2) have a positive attitude; (3) be mindful that they will experience strong emotions throughout tapering and possibly for months after; and (4) receive some type of regular psychological support (e.g., psychotherapy, art therapy, support groups, etc) during the tapering and perhaps beyond (Darton 2005, Hall 2007).

A good rule of thumb is for the tapering duration to be for the same length of time of previous psychotropic use (Hall 2007). For example, if a patient was on a psychotropic drug for six months, the tapering process should be six months. The only exception involves patients that have been on psychotropic drugs for five or more years. The tapering process for these patients should be approximately 18-24 months (Hall 2007).

One report suggests that for each unspecified tapering period, there should be a 10% reduction in dose, and that the psychotropic drug is reduced by subsequent 10% reductions until the patient is comfortably off his/her medication (Darton 2005). Another report suggests that the psychotropic drug is tapered down every two weeks, and that with each two-week tapering period, the dose is reduced by 10% (Hall 2007). If a patient, for example, begins the tapering process on a drug that is 400 mg once daily, than the dose to take for two weeks would be 360 mg. After two weeks, the dose would be further reduced by another 10% to 320 mg and so on. This process would continue until the psychotropic drug is fully discontinued. If, at any time during the tapering, the patient feels that the reduction is too marked or there are troublesome withdrawal reactions such as anxiety and sleep disturbances, the patient can remain on the previous tapered dose until he/she feels well enough to proceed.

Improving the Odds of a Successful Outcome

It is not uncommon for patients to experience problems even from small reductions in their psychotropic drugs. This is usually misattributed to a re-emergence of their underlying psychiatric disorder as opposed to problems related to psychotropic drug withdrawal (Moncrieff 2006a). When this happens, it is common for such patients to be shamed by family members, psychiatrists, and support workers into the notion that they cannot maintain their psychological health without depending on psychotropic drugs for the rest of their lives, thus forcing patients back onto long-term treatment (Moncrieff 2006a). Darton (2005) reported that patients with mental health issues are too often denied the chance to come off their medications, to take risks, and potentially make their own mistakes. If, on the other hand, family members are helpful, supportive, and encouraging, this will reduce risks associated from tapering off psychotropic drugs (Darton 2005).

chance to come off their medications, to take risks, and potentially make their own mistakes. If, on the other hand, family members are helpful, supportive, and encouraging, this will reduce risks associated from tapering off psychotropic drugs (Darton 2005).

Supporting the Tapering Process with Specific Natural Health Products

There are specific natural health products that I have found helpful when used during and after the tapering process to mitigate withdrawal, and prevent potential relapses, and possibly the need to resume previous psychotropic drugs. Melatonin is being formally studied to ascertain its benefits among schizophrenic patients withdrawing from long-term benzodiazepine use (Baandrup 2011). Previous reports have shown some efficacy in reducing benzodiazepine-withdrawal-associated sleep disruption (Dagan 1997, Peles 2007). Ideally, controlled- or prolongedrelease preparations should be used, with doses varying from 1-5 mg at bedtime. Sometimes it might be preferable to use quick release melatonin, as this might help patients that have difficulty falling asleep.

Niacinamide (nicotinamide) is sometimes very useful among patients withdrawing from benzodiazepines since it possess benzodiazepine-like effects (Prousky 2004). One case report demonstrated its clinical effectiveness in allowing a patient to remain clinically stable after tapering off clonazepam (Prousky 2004). With the approval of his psychiatrist, the patient weaned himself off clonazepam in two weeks while increasing his daily amounts of niacinamide until he was taking 2500 mg each day. When this report was published, the patient had been free of clonazepam for six months and had remained stable on only the niacinamide.

Niacinamide can also be given to reduce withdrawal symptoms when other psychotropic drugs are tapered since it generally “calms” the nervous system and does not possess any concerning drug interactions. Effective daily doses of niacinamide range from 1500-2500 mg. It is rarely necessary to go beyond 2500 mg since such doses can be associated with nausea and potentially vomiting. The mean elimination half-life in human subjects given 3000 mg of the vitamin was 5.9 ± 0.6 hours (Horsman 1993). Since it has a very short half-life, niacinamide must be administered several times throughout the day; otherwise, its therapeutic effects will be lessened.

Neurapas® balance is a unique herbal medicine that contains three potent psychoactive herbal extracts. Each film-coated tablet contains 60 mg of the dry extract of Hypericum perforatum, 28 mg of the dry extract of Valerian officinalis, and 32 mg of Passiflora incarnata. There have been approximately 10 company-sponsored clinical studies (i.e., two controlled and eight observational cohort studies) and two experience reports, which have demonstrated this herbal combination to be safe and effective for both depression and anxiety (Pasco Neurapas® CTD Documentation 2005a). Each of the individual herbal extracts has well known postulated mechanisms of action (Werneke 2006). As the tapering process continues, I generally have my patients increase Neurapas® balance to two pills three times daily. Unfortunately, the elimination half-live is not known for this preparation.

Rhodiola rosea extract is an important intervention since clinical trials have shown it to attenuate mild and moderate depression, generalized anxiety, and burnout/fatigue (Bystritsky 2008, Darbinyan 2007, Olsson 2009); common withdrawal symptoms that many patients experience during tapering. It specifically works by inhibiting enzymes involved in the degradation of monoamine neurotransmitters (i.e., serotonin, dopamine, and norepinephrine) and prevents the depletion of adrenal catecholamines following acute stress (No authors listed 2002). The therapeutic dose range is somewhere between 500-680 mg of a standardized extract containing 3% percent total rosavins and 1% salidrosides, in divided doses. I recommend that Rhodiola rosea extract is taken with food, as it can cause considerable nausea and possibly vomiting on an empty stomach.

There are numerous other natural health products that could potentially be used alongside psychotropic drugs during the tapering process. Clinicians trained in clinical nutrition and botanical medicine must use their own discretion during psychotropic drug tapering, while also mitigating any potential interactions, and using available pharmacokinetic information to guide appropriate dosing.

Conclusion Helping patients taper from their psychotropic drugs is complicated by many factors, including their stability, support system, and the length of time they have been on psychotropic drugs. This is also controversial since family doctors and psychiatrists often oppose tapering due to concerns of ongoing stability, and their beliefs that psychotropic drugs are required over the long-term. From my perspective, all mentally competent patients have the right to choose what they think is best, even if such beliefs are not held by the clinicians providing care. This paper should assist and empower clinicians to develop effective tapering strategies on behalf of their willing patients.

References

Baandrup L, Fagerlund B, Jennum P, et al. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial – the SMART trial protocol. BMC Psychiatry. 2011;11:160.

Bystritsky A, Kerwin L, Feusner JD. A pilot study of Rhodiola rosea (Rhodax) for generalized anxiety disorder (GAD). J Altern Complement Med. 2008;14:175-180.

Dagan Y, Zisapel N, Nof D, et al. Rapid reversal of tolerance to benzodiazepine hypnotics by treatment with oral melatonin: a case report. Eur Neuropsychopharmacol. 1997;7:157-160.

Darbinyan V, Aslanyan G, Amroyan E, et al. Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J Psychiatry. 2007;61:343-348.

Darton K. Making sense of coming off psychiatric drugs. London, UK. Mind Publications. 2005.

Hall W. Harm reduction guide to coming off psychiatric drugs. The Icarus Project and Freedom Center. September 2007. Retrieved from: www.theicarusproject.net/ downloads/ComingOffPsychDrugsHarmReductGuide1Edonline.pdf (December 12, 2011).

Horsman MR, Høyer M, Honess DJ. Nicotinamide pharmacokinetics in humans and mice: a comparative assessment and the implications for radiotherapy. Radiother Oncol. 1993;27:131-139.

Howland RH. Potential adverse effects of discontinuing psychotropic drugs. Part 2: antidepressant drugs. J Psychosoc Nurs Ment Health Serv. 2010a;48(7):9-12.

Howland RH. Potential adverse effects of discontinuing psychotropic drugs. Part 3: antipsychotic, dopaminergic, and mood-stabilizing drugs. J Psychosoc Nurs Ment Health Serv. 2010b;48(8):11-14.

Lalive AL, Rudolph U, Lüscher C. Is there a way to curb benzodiazepine addiction? Swiss Med Wkly. 2011;141:w13277.

Moncrieff J. Why is it so difficult to stop psychiatric drug treatment? It may be nothing to do with the original problem. Med Hypotheses. 2006a;67:517-523.

Moncrieff J, Cohen D. Do antidepressants cure or create abnormal brain states? PLoS Med. 2006b;3(7):e240.

Moncrieff J, Cohen D. How do psychiatric drugs work? BMJ. 2009;338:1535-1537.

[No authors listed]. Rhodiola rosea. Monograph. Altern Med Rev. 2002;7:421-423. O’Brien CP. Benzodiazepine use, abuse, and dependence. J Clin Psychiatry. 2005;66 (Suppl 2):28-33.

Olsson EM, von Schéele B, Panossian AG. A randomised, double-blind, placebocontrolled, parallel-group study of the standardised extract shr-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med. 2009;75:105-112.

Pasco Neurapas® CTD Documentation. Module 2:2.7 Clinical Summary Neurapas® balance, film coated tablets. 2005a;1-165.

Pasco Neurapas® CTD Documentation. Module 2:2.5 Clinical Overview Neurapas® balance, film coated tablets. 2005b;1-39.

Peles E, Hetzroni T, Bar-Hamburger R, et al. Melatonin for perceived sleep disturbances associated with benzodiazepine withdrawal among patients in methadone maintenance treatment: a double-blind randomized clinical trial. Addiction. 2007;102:1947-1953.

Prousky J. Niacinamide’s potent role in alleviating anxiety with its benzodiazepinelike properties: a case report. J Orthomol Med. 2004;19:104-110.

Read J. Coping with coming off: mind’s research into the experiences of people trying to come off psychiatric drugs. London, UK. Mind Publications. 2005.

Werneke U, Turner T, Priebe S. Complementary medicines in psychiatry. Br J Psychiatry. 2006;188:109-121.

AGE, RAGE, and Diabetes

The Role of Advanced Glycation End Products and Therapeutic Strategies

Introduction

Advanced glycation end-products (AGEs) are groups of compounds that result from the non-enzymatic reaction of reducing sugars with free amino groups of biological molecules (Mendez 2010). ey are formed slowly by the Maillard reaction, which is dependent on glucose levels. ey also form rapidly by a pathway that involves reactive carbonyl compounds during oxidative stress (Smit 2010). AGEs can also accumulate in humans by exogenous intake from food and smoking tobacco (Uribarri 2005). Many AGEs are believed to be clinically signi cant in humans including 3-deoxy-glucosone, glyoxal, methylglyoxal, pentosidine, and N-carboxylmethyllysine (Goh 2008). Some of these compounds have intrinsic uorescence and as such skin auto uorescence (SAF) has been utilized to quickly and easily detect AGE accumulation in a point of care setting (Smit 2010).

Receptors of AGEs (RAGEs) are signal transduction receptors that belong to the immunoglobulin superfamily. ey are expressed in a variety of cell types, such as endothelial cells, smooth muscle cells, lymphocytes, monocytes, and neurons (Schmidt 2000). Ligands binding to RAGE can generate oxidative stress, synthesize and secrete proin ammatory cytokines, and cause chemotaxis (Jackus 2004). ese all contribute to the progression of vascular damage. erefore, AGEs are important because they do not simply re ect hyperglycemia, but represent a cumulative metabolic burden, oxidative stress, and systemic in ammation (Meerwaldt 2008).

Diabetic complications have long been believed to be the result of prolonged hyperglycemia. However, blood glucose levels alone do not reveal the whole picture. Even in patients with type II diabetes who have achieved HbA1c and glucose targets, trials have shown that those who have higher levels of AGEs su er from more microvascular and cardiovascular complications (Holman 2008). AGEs play a pivotal role in the cause of diabetic complications, including retinopathy, neuropathy, nephropathy, and other complications throughout the human body. AGEs also provide new possible targets for the treatment of both type I and type II diabetes. is paper examines the importance of AGEs in the development of diabetic complications and reviews the evidence for promising therapeutic interventions.

Diabetic Retinopathy Retinopathy is the most common microvascular complication of diabetes and involves vision impairment due to microaneurysms, blood barrier dysfunction, and capillary dropout (Stitt 2010). AGEs are elevated in the ocular tissues and vitreous collagen of diabetic subjects when compared to nondiabetic subjects (Stitt 2001). AGEs contribute to the pathogenesis of diabetic retinopathy through various mechanisms. ey accumulate heavily in Muller macroglia, which have a unique role in the architecture and physiology of the retina (de Gooyer 2006). In these locations, AGEs contribute to excitotoxicity in retinal neurons by promoting the synthesis of glutamate (Lieth 1998).

AGEs induce basement membrane thickening and contribute to the breakdown of the inner blood-retinal barrier (Stitt 1997). AGEs upregulate vascular endothelial growth factor (VEGF), which promotes retinal neovascularization and increases permeability to proteins across the retinal barrier (Lu 1998). With regards to oxidative stress, it has been shown that the concentration of superoxide is elevated in the retina of diabetic rats (Du 2003). By increasing oxidative stress, toxic e ects occur to retinal pericytes and cause subsequent apoptosis (Chen 2006). e inhibition of superoxide with antioxidants can protect against capillary degeneration during diabetic retinopathy (Kowluru 2001). Even at low concentrations, AGEs cause proangiogenic responses in retinal microvascular endothelial cells (Mamputu 2004).

Diabetic Neuropathy

Neuropathy is a common complication of diabetes in which nerves are damaged, partially as a result of decreased blood ow and hyperglycemia (Bansal 2006). Also associated with neuropathy is diabetic foot, a complication in which the foot becomes ulcerated, infected, or gangrenous. AGE levels are related to both peripheral and autonomic neuropathy, even before clinical manifestations of neuropathy (Meerwaldt 2005). Skin AGE accumulation is also linked to the severity of neuropathic foot ulceration. is is believed to be largely due to endothelial dysfunction that is caused and worsened by AGEs.

AGEs damage vascularity through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging RAGE, causing upregulation of the transcription factor NF-kB and its target genes. AGE-bound RAGE also increases endothelial permeability to macromolecules, blocks nitric oxide activity in the endothelium and causes the production of reactive oxygen species (Goldin 2006). Decreased nitric oxide production leads to impaired cutaneous vasodilation and decreased neurogenic vascular responses (Williams 2006). In addition, AGEs worsen diabetic neuropathy by reducing sensorimotor conduction velocity and decreasing blood ow to peripheral nerves (Chen 2004). e blockage of RAGE accelerates wound closure in diabetic mice and suppresses levels of cytokines such as tumor necrosis factor (Goova 2001).

Diabetic Nephropathy

Diabetic nephropathy is a syndrome characterized by persistent albuminuria, a progressive decline in glomerular ltration rate, and elevated arterial blood pressure. e kidney plays an important role in the clearance and metabolism of AGEs. Almost all renal structures are susceptible to the accumulation of AGEs and their consequences including basement membranes, mesangial cells, endothelial cells, podocytes, and tubules (Schleicher 1997). In intrarenal arteries, medial smooth muscle cells are injured by the interaction between glycoxidation and complement activation, which contributes to the progression of diabetic nephropathy (Uesugi 2004). Kidney podocytes and endothelial cells express speci c RAGEs. eir activation leads to multiple pathophysiological e ects including hypertrophy with cell cycle arrest and apoptosis, altered migration, and generation of proin ammatory cytokines (Busch 2010). RAGE drives the development of glomerulosclerosis and promotes podocyte activation in the course of diabetic nephropathy (Wendt 2003).

In the progression of renal disease, there is delayed protein turnover and accelerated oxidative stress. is leads to enhanced formation of AGEs, resulting in a vicious cycle (Kanwar 2008). In monitoring nephropathy, urinary protein-bound AGE concentrations closely parallel changes in albuminuria, re ecting the severity of diabetic nephropathy (Coughlan 2011). Skin auto uorescence (SAF) also independently predicts renal risk in diabetes and in chronic kidney disease (Smit 2010). Renal pathological changes are reduced by AGE formation inhibitors, as well as with agents that are postulated to reduce AGE accumulation (Soulis-Liparota 1995). Treatments targeting RAGE have also been shown to attenuate nephropathy (Flyvbjerg 2004).

Other Complications

AGE accumulation and subsequent RAGE activation has been associated with numerous other complications. AGEs have been shown to adversely a ect virtually all cells, tissues, and organ systems. Circulating AGEs are associated with an increased risk of developing many chronic diseases. e accumulation of AGEs accelerates the multisystem functional decline that occurs with aging (Semba 2009). For these reasons, it is important to screen all diabetic patients for these pathologies and to work with them clinically, focusing on prevention.

Both type I and type II diabetes have been associated with reduced cognitive performance (Kodl 2008). Type II diabetes is strongly associated with the risk of incident Alzheimer’s disease (Ott 1999). Studies of post-mortem samples have shown that brains of patients with the combination of Alzheimer disease and diabetes had higher AGE levels and an increased number of B-amyloid dense plaques (Valente 2010). Even in older adults without diabetes, high peripheral AGE levels are associated with greater cognitive decline (Ya e 2011). Patients with diabetes and renal disease show high concentrations of vitamin B12, but metabolic evidence of a de ciency that is reversible after treatment. Megalin mediates the uptake of vitamin B12 by cells. AGEs might overload megalin and lower vitamin B12 uptake by cells by preventing its delivery (Obeid 2011).

Among patients with diabetes, AGEs have been correlated to the risk of cardiomyopathy and peripheral arterial disease (Goh 2008). AGEs are linked to atherosclerosis by enhancing endothelial dysfunction, elevating vascular low-density lipoprotein, promoting plaque destabilization via effects on matrix metalloproteinases, inducing neointimal proliferation, and inhibiting vascular repair in response to injury. A correlation has been demonstrated between AGE concentration and the severity of atherosclerotic lesions (Stitt 1997). In addition, AGEs likely contribute to erectile dysfunction in patients with diabetes. Studies have shown the preservation of erectile function in animals treated with drugs that inhibit AGE formation (Usta 2003). In one study, diabetic men had significantly higher mean levels of RAGE protein and DNA fragmentation in spermatozoa. These were directly correlated, suggesting a central role for RAGE in disturbances in sexual function of men with diabetes (Karimi 2011). AGEs also play a role in the loss of lens transparency and in cataract formation (Hashim 2011).

AGEs are implicated in other disease processes throughout the body that are not typically associated with diabetes. Increased levels of AGEs have been found in rheumatoid arthritis (de Groot 2010). Experimental and clinical studies have highlighted the idea that RAGE is involved in the development of liver fibrosis and inflammation and leads to apoptosis (Basta 2011). RAGE has been implicated in acute lung injury both as a marker of alveolar injury and as an important contributor to alveolar inflammation (Uchida 2006). RAGE is highly expressed in colorectal cancer tissues and is associated with increased microvessel density. Knockdown of RAGE inhibited expression of VEGF and SP1 protein in colorectal cancer cells, suggesting that the silence of RAGE expression could effectively inhibit colorectal cancer angiogenesis (Liang 2011).

Therapeutic Interventions

There are many potential therapies that can be used to treat the morbidity caused by AGEs. Multiple pharmaceuticals have been developed and studied for this purpose, including antiglycation agents, AGE inhibitors (Bicu 2010), sulfonylureas (Li 2008), statins (Ishibashi 2011 and Lu 2011), and angiotensin receptor blockers (Grossin 2010). In diabetes, the rate of formation of AGEs exceeds that of normal aging. Over time, even modest hyperglycemia results in a significant accumulation of AGEs (Monnier 2005). Therefore, it is highly likely that any pharmacological therapy that has shown benefit in treating diabetes or hyperglycemia will be beneficial for treating AGEs to some extent.

To treat AGE accumulation, the most obvious starting points for any health care practitioner are diet and lifestyle modification. A significant source of AGEs is smoking tobacco and thus patients should be encouraged to quit smoking. Since AGEs are also found in foods, a diet should be recommended that focuses on low-AGE containing foods in conjunction with low-AGE producing cooking methods. One study examined the AGE content of various foods. Meat groups contain the highest levels of AGEs, except for lamb. Fats contain more AGEs relative to carbohydrates. This may be due to the higher water content or higher level of antioxidants and vitamins in carbohydrate-containing foods, which may diminish new AGE formation. A reduced intake of dietary AGEs can also be achieved by increasing the consumption of fish, legumes, low-fat milk products, vegetables, fruit, and whole grains and by reducing intake of solid fats, fatty meats, full-fat dairy products, and highly processed foods (Uribarri 2010).

Incorporating dietary arginine has also been shown to decrease AGE and RAGE interactions and consequently reduce tissue damage in rats with type II diabetes (Pai 2010). Dietary rutin, found in buckwheat and asparagus, suppresses glycation, purportedly due to its high flavonoid content (Muthenna 2011). In terms of cooking methods, patients should be advised to boil, poach, stew, or steam food and to avoid frying, baking, or grilling. This strategy may limit dietary AGE intake by up to 50% (Uribarri 2011). Another lifestyle measure that should be recommended for patients is exercise. Moderate intensity aerobic physical activity for 150 minutes, or vigorous aerobic exercise for 90 minutes per week are recommended, distributed over at least three days, with no more than two close days of inactivity (Coccheri 2007).

In addition to these strategies, particular therapeutic options have been studied and have additional evidence to support their use. Aged garlic extract and S-allyl cysteine have been shown to prevent the formation of AGEs, in particular the formation of glucose-derived and methylglyoxal-derived AGEs, as well as the formation of carboxymethyllysine (Ahmad 2007). S-allyl cysteine has been reported to inhibit NF-kB activation in a dose-dependent manner and may protect against intracellular oxidative stress once RAGEs are activated (Ide 2001). Aged garlic extract contains approximately 50 times the amount of S-allyl cysteine compared to raw garlic and also contains other antioxidants.

One trial in diabetic rats showed that omega-3 fatty acids reduce AGEs (deAssis 2011). Alpha-lipoic acid has been studied and been demonstrated to have beneficial effects on the development of diabetic retinopathy by inhibiting the accumulation of oxidatively modified DNA and nitrotyrosine in the retina (Kowluru 2004). Similarly, N-Acetylcarnosine lubricant eye drops are able to decrease the complications of AGEs and have shown benefit in improving the quality of vision and length of life for diabetes mellitus patients (Babizhayev 2009).

Many botanical options have also been studied. Silymarin has antioxidant and reactive carbonyl trapping activities, which may contribute to its antiglycation effect (Wu 2011). Ilex paraguariensis water extracts are capable of inhibiting AGE formation in a dose-dependent fashion (Lunceford 2005). Hibiscus sabdariffa polyphenolic extract has been demonstrated to inhibit high glucosestimulated cellular changes in rats as well as AGE and RAGE formation (Peng 2011). Other herbal options that have been studied and shown to have a favourable effect on AGEs are curcumin (Mrdula 2007), cumin (Kumar 2009), and ginger (Saraswat 2010).

Finally, a novel therapy for treating AGE accumulation is chelation therapy. The chelation of transition metals means they are not available to participate in autooxidative glycation and glyco-oxidation reactions, which are capable of generating free radicals that accompany AGE formation during hyperglycemia. EDTA has shown benefit for this purpose in diabetic patients (Wolff 1991). Another chelating agent that has been studied is triethylenetetramine (TETA), which acts as a highly selective divalent copper chelator. TETA has been shown to suppress oxidative stress and prevent or reverse diabetic organ damage (Cooper 2011). More research is warranted to determine the most effective approaches in combating AGEs and RAGEs.

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GOUT

A Naturopathic Approach

Introduction

Among healthcare providers, gout is often thought of as a relatively benign condition that, while painful acutely, is transient and generally responds well to basic treatments. As a result, gout tends not to receive much attention among healthcare providers, or in the medical literature relative to other arthrides. For those a ected by gout, however, the condition has considerable impact on quality of life. Acute attacks are usually managed e ectively with non-steroidal anti-in ammatory drugs (NSAIDS), but frequent recurrent attacks signal the development of chronic gout (Eggebeen 2007); up to 60% of patients having a gout attack will have a recurrent attack within one year (Eggebeen 2007). Many patients e x p e r i e n c e more frequent a t t a c k s . Gout su erers can sometimes experience frequent attacks despite adhering to a low-purine diet and uric acid lowering therapy. Clinical experience with such a case led this author to review of the biology of gout and available naturopathic treatment options, which are summarized here.

Pathophysiology

Gout is a severely painful in ammatory arthride, most commonly a ecting the large toe (podagra) and more rarely the knee, and is caused by deposits of monosodium urate crystals within the joint space (Smith 2011). Urate crystals may also deposit in soft tissues, causing masses called tophi, and in the kidney, causing nephrolithiasis and urate nephropathy (Eggebeen 2007). Hyperuricemia can be de ned as serum uric acid > or = 7.0 mg/ dl in males and > or = 6.0 mg/dl in females, and a serum level <6.0 mg/dL (355 μmol/L) has been widely accepted as a therapeutic target for urate lowering. is concentration favours dissolution of deposited crystals (Pascual 2007).

The mainstay of uric acid lowering therapy is allopurinol in combination with prescription of a low-purine diet (Pascual 2007). Allopurinol (typically 50-300mg daily) is a purine analog and inhibitor of xanthine oxidase, thereby reducing the conversion of purines to uric acid (Eggebeen 2007, Rx List 2011); the dose of allopurinol should be based on an assessment of kidney function, with up to 300mg per day recommended for those with a creatinine clearance ≥90 mL per minute and less for those with lower kidney clearance (Eggebeen 2007). A low purine diet entails avoidance of meat, and seafood, yeast and yeast containing foods such as beer and alcohol, as well as select purine-rich vegetables including beans, peas, lentils, oatmeal, spinach, asparagus, cauliflower, and mushrooms (Emmerson 1996). Despite these well established treatment strategies, there is a growing recognition that gout is not simply a disorder of purine metabolism, as has traditionally been thought, but a more pervasive condition with considerable overlap with the metabolic syndrome.

Gout and the Metabolic Syndrome

Gout is strongly associated with a number of chronic diseases that also have metabolic components, most notably, metabolic syndrome and its components; hypertension; and cardiovascular disease (Saag 2006). The implications of this are two-fold. First, clinicians treating gout should be alert for such potential co-morbidities, and address them accordingly in order to reduce cardiovascular risk. Secondly, these conditions may share common underlying metabolic etiologies that can potentially be addressed in concert. Saag and Choi propose that obesity and insulin resistance are key factors in contributing to hyperuricemia and gout (Saag 2006).

Large observational studies demonstrate that body mass index (BMI) and insulin resistance have strong correlations with serum urate levels (Rathmann 1998, Saag 2006). In the Coronary Artery Risk Development in Young Adults (CARDIA) study, BMI, fasting insulin, and triglycerides were all significantly higher, and HDL cholesterol lower in subjects with hyperuricemia (p < 0.001 for all). After 10 years of follow up, these associations remained consistent (Rathmann 2007).

In the Verona Young Men Atherosclerosis Risk Factors Study, including 957 18-year old healthy men, Bonora et al found that “Serum uric acid concentration showed positive associations with BMI (r = 0.24; P < 0.0001), WHR (r = 0.19; P < 0.0001)” and other components of metabolic syndrome (1996). BMI was the strongest independent predictor of uric acid. Several additional studies corroborate this relationship across many ethnic groups (Cigolini 1995, Meshkani 2011, Yamada 2011).

Weight reduction reduces serum uric acid (Saag 2006, Dessein 2000, Krzystek-Korpacka 2011, Madero 2011, Yamashita 1986). Obesity can increase production and decrease renal excretion of urate (Yamashita 1986), while a hypocaloric diet decreases serum UA through increased renal excretion (2005). Johnson found that among morbidly obese subjects even a 5% reduction in body weight was associated with global improvements in cardiovascular risk factors as well as serum uric acid, such that uric acid decreased 5.7% with weight loss of between 5%-9.9%, and decreased 16.6% with weight loss of 20% or greater (2011). Again, Birketvedt found that among 53 moderately overweight women, caloric restriction (1200 kcal/d) resulting in between 5-8 kg weight loss led to significant reductions to serum uric acid (2000).

Diet & Lifestyle Recommendations

With respect to lifestyle recommendations for gout, Saag and Choi argue that the benefits of a “rigid purine restricted diet” (Saag 2006) must be weighed against the fact that a low-purine diet is often high in refined carbohydrates and saturated fat, potentially aggravating the underlying metabolic factors. Designing a diet that assists patients with weight loss, improves insulin sensitivity and lipid levels, and lowers uric acid is crucial in controlling gout symptoms as well as in managing cardiovascular risk. To this end, Choi has developed a “food pyramid” that incorporates both moderate restriction of purine intake, as well as strategies to improve insulin resistance that are characteristic of the diet used to control metabolic syndrome (2010). An adaptation of this pyramid is shown in Figure 1.

There are some notable inclusions in this dietary plan, namely, moderate amounts of purine rich legumes and vegetables, as well as fish and poultry. Choi argues that plant source purines do not increase risk of gout (2010). In a large observational study of over 47 thousand men, consumption of meat (RR 1.41, 95% CI 1.07-1.86) and seafood (RR 1.51 (1.17-1.95) but not purine rich vegetables and legumes were associated with risk of gout (Choi 2004). Increasing intake of dairy products was associated with reduced risk of gout, RR 0.56 (0.42-0.74). Choi proposes that “it would be difficult to justify a recommendation to avoid all fish intake” (2010) given its benefit on cardiovascular health, however, given the high-purine content of fish, a fish oil supplement (no protein content) seems a better strategy for patients with gout. Soft drinks and sweetened juices are discouraged, however regular consumption of coffee is allowable. Caffeine is a natural xanthine oxidase inhibitor; therefore as long as intake is consistent on a day-to-day basis, coffee may help lower uric acid levels. If intake is variable, however, coffee may in theory worsen gout, since this pattern results in unsteady changes in serum uric acid that may precipitate an attack (2010). Finally, adequate water intake is necessary to ensure uric acid excretion.

Specific Foods and Nutrients

Dairy foods An RCT recently compared the acute effect of four different kinds of milk on serum urate (Dalbeth 2010). Sixteen healthy participants received a single dose containing 80g protein of each of the following: soy milk (control); early season skim milk; late season skim milk, which contains high concentrations of orotic acid, a naturally occurring uricosuric agent; and ultrafiltrated skim milk. Soy increased serum urate approximately 10%, while the other three milks decreased urate approximately 10% (p<0.0001). Authors concluded that the urate-lowering effect of milk was due to its low purine content as well as its ability to increase urinary excretion of uric acid. In addition, certain dairy fractions including glyco-macropeptide and a milk fat extract possess anti-inflammatory properties in experimental models of acute gout (Dalbeth 2011).

Cherries A trial investigating the effect of cherry consumption was conducted in 10 healthy women (Jacob 2003). Subjects consumed two servings (280 g) of sweet cherries after an overnight fast, followed by periodic blood and urine testing. At 5h after cherry consumption, plasma urate decreased to 183 +/-15 micromol/L, compared to 214 +/-13 micro mol/L at baseline (P < 0.05). Urinary excretion of urate increased following cherries, with peak excretion of 350 +/-33 micro mol/mmol creatinine, compared to 202 +/-13 at baseline (P < 0.01).

Black tea/ Coffee In an RCT, three cups of black tea per day resulted in a significant decrease in serum uric acid such that those with baseline levels > 6 mg/dL had a 8.5% decrease (p < 0.05); while those with serum uric acid > 7 mg/dL had a decrease of 9.4% (men) and 7.1% (women) (Bahorun 2010). Coffee has been associated with decreased risk of gout, RR 0.41 (95% CI 0.19-0.88) for six or more cups per day (Choi 2007), as is expected based on its inhibition of xanthine oxidase. Since diuretic agents are known to aggravate gout, it is advisable to recommend a concomitant increase in water intake to patients consuming diuretic beverages in order to support adequate renal clearance.

Eicosapentanoic acid Although no human trials have investigated the effects of fish-derived omega-3 fatty acids on serum uric acid or risk of gout, there is good rationale for recommending EPA to gout patients on the basis of its cardioprotective and anti-inflammatory effects (Choi 2010). Studies in animal models of gout have shown that a combination of EPA and GLA reduced monosodium urate crystal-induced inflammation (Tate 1988).

Vitamin C Vitamin C is a relatively well recognized uricosuric agent, meaning that it promotes urinary excretion of uric acid. A recent meta analysis of 13 RCTs including 556 subjects and a median vitamin C dose of 500 mg/day found that there was a significant reduction in serum uric acid of -0.35 mg/dl (95%CI -0.66 to -0.03, p=0.032); in SI units this was equal to -20.8 μmoles/L (Juraschek 2011). Among trials that were placebo controlled, there were larger reductions in uric acid. Baseline serum uric acid values ranged from 2.9-7.0 mg/dl or 172.5- 416.4 μmoles/L.

Role of Food Sensitivities Although there is no reports in the literature on the association between food sensitivities and uric acid/ gout, the inflammatory state created by an immune reaction to food may aggravate gout-related inflammation and joint pain. For the case mentioned in the introduction, gluten sensitivity seems to have been an important contributing factor to the patient’s gout symptoms. These resolved dramatically on a gluten free diet combined with a selection of the other recommendations discussed here, and notably, subsequent re-exposure to gluten – while continuing other interventions, exercise, and dietary guidelines – led to a clear aggravation of the patient’s gout.

A Note on Drugs Because patients susceptible to gout generally have other cardiovascular risk factors such as hypertension and dyslipidemia, they are often given diruetics and/ or low-dose aspirin; however these medications may potentially precipitate gout. In a prospective study of 5789 hypertensive patients, those treated with a thiazide or loop diuretic had significantly increased risk of developing gout; HR for use of any diuretic 1.48 (95% CI 1.11-1.98), thiazide diuretic use HR 1.44 (95% CI 1.00- 2.10), and loop diuretic HR 2.31 (95% CI 1.36-3.91) (Demarco 2011). This relationship between diuretics and gout is well recognized (Saag 2006). Aspirin has been found to have a bimodal effect on excretion of uric acid: while at high doses (>3g/d) it promotes uric acid excretion (uricosuric action), at low doses (1-2g/d) it has been shown to increase retention of uric acid (Saag 2006). In another study, 75mg aspirin per day led to a 15% decrease in the rate of uric acid excretion (p=0.045) and increase in serum uric acid (p=0.009) (Caspi 2000, Saag 2006).

Conclusion Gout strongly impacts quality of life in affected patients. Because hyperuricemia is associated with the metabolic syndrome and cardiovascular risk factors, dietary strategies for gout need to be balanced in order to reduce purine intake but also reduce risk of cardiovascular disease. Weight loss is key in lowering uric acid levels. Therapeutic foods and nutritional supplements for gout include low fat dairy, black tea/ coffee, cherries, EPA, and vitamin C. The potential role of food sensitivities and medications should also be considered.

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