Month: November 2010

Tumours grow their own blood vessels

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Finding explains failure of drugs that target host vasculature.

 

blood vesselsFor some tumours at least, a lack of host blood supply is not a problem.CLOUDS HILL IMAGING LTD / SCIENCE PHOTO LIBRARY

Tumours don’t just rely on their host’s blood vessels for nourishment — they can make their own vasculature, according to two independent studies from the United States and Italy. The findings offer an explanation for why a class of drug once heralded as a game-changer in cancer treatment is proving less effective than had been hoped.

Almost four decades ago, Judah Folkman, a cell biologist at Harvard Medical School in Boston, Massachusetts, proposed that tumours were dependent on the blood vessels surrounding them, and that choking off that blood supply would kill the cancer1. Bevacizumab (Avastin), the first drug to block blood-vessel growth, was approved in 2004, but it and other ‘angiogenesis inhibitors’ have proved disappointing in the clinic, extending patients’ lives for at best a few months.

Now two studies published online today in Nature2,3 have identified blood vessels grown directly from cancer cells. So Avastin and drugs like it may be targeting a pathway that is not present in those tumour-made vessels, says David Cheresh, a cancer biologist at the University of California, San Diego, who was not involved in either study.

When it comes to treatment, “most people agree that a single pathway is not going to do it,” he says.

Telltale markers

In both studies, researchers worked with tumour samples from patients with an aggressive type of brain cancer called glioblastoma. They found that many of the blood-vessel cells within the tumours contained genetic markers characteristic of the cancer cells, suggesting that the blood vessels were of tumour origin.

The researchers then used markers to identify a subset of tumour cells known to have stem-cell-like properties — that is, the ability to develop into cells with different functions. In a dish, these cells could make blood vessels and, when they were injected into the brains of mice, tumours developed with blood vessels that clearly came from the original human cells. Those stem-like cells, the researchers concluded, could form both tumour and blood vessel.

Such cells seemed to be first making blood-vessel precursor cells, and then differentiating into blood-vessel cells. One of the groups, led by Viviane Tabar, a neurosurgeon and stem-cell researcher at the Memorial Sloan-Kettering Cancer Center in New York City, applied Avastin to cells in a dish to try to block these events. Although the drug did affect differentiation into blood-vessel cells, “we found that Avastin does not alter that first process whatsoever,” says Tabar.

In the second study, Ruggero De Maria from the Italian National Institute of Health in Rome and his colleagues selectively killed the tumour-related blood-vessel cells. This caused the tumours to shrink, showing their reliance on those blood vessels. However, the number of tumour-derived blood-vessel cells in each tumour sample varied from 20% to 90%, suggesting that blood-vessel formation was more important for some tumour cells than others.

Tabar says that it is not clear whether this self-vascularizing capacity is widely present in other tumour types, although there are some hints that this is the case. “It would be very exciting if other tumour cells exhibit the same phenomenon,” she says.

Two-pronged attack

This isn’t the first time researchers have suggested that cancer cells can make their own blood vessels. In 1999, Mary Hendrix, a cancer researcher now at Northwestern University in Chicago, Illinois, and her colleagues reported a similar effect in melanoma cells which they called “vascular mimicry”4.

At the time, says Hendrix, her group predicted that these vascular cells would prevent drugs such as Avastin from being fully effective, but their findings were controversial. The two latest studies support the idea’s validity, she says, as well as demonstrating “an example of the functional plasticity of tumour cells”.

Such plasticity means that researchers must look for a combination therapy that can target both the host vasculature, as Avastin does, and the stem-like cancer cells that can create both vasculature and tumour tissue, Hendrix adds.

Cheresh agrees. Today’s findings in glioblastoma are not the only recent strike against anti-angiogenesis drugs. In the last two years, a handful of studies have reported that, counterintuitively, such drugs can speed tumour growth (see Cutting off cancer’s supply lines, 2009)5,6,7,8. But that doesn’t mean that the strategy of targeting the blood supply is inherently faulty, says Cheresh, who co-authored two such studies.

“There are many more ways to affect the vasculature” than through such drugs, he notes: “It means we need to identify either more than one drug” to shut down blood vessels of tumour and non-tumour origin, “or a common molecular mechanism affecting both the tumour and the vasculature”.

source: nature

Invasive Dental Treatment and Risk for Stroke or MI

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Risk for ischemic stroke or myocardial infarction was transiently increased during the first 4 weeks after treatment.

Studies have suggested that intensive periodontal treatment leads to endothelial dysfunction and elevated markers of inflammation. Whether these changes raise risk for vascular events is not known. Using U.S. Medicaid claims data, researchers evaluated risk for adverse vascular events during the 24 weeks after invasive dental work. Individual patients served as their own controls (rates of vascular events were assessed during periods with and without exposure to invasive dental procedures). The final sample consisted of 1152 patients (41% with histories of coronary artery disease [CAD]) who were hospitalized for ischemic stroke or myocardial infarction (MI) and had undergone invasive dental procedures.

Risk for ischemic stroke or MI was transiently increased during the first 4 weeks after an invasive dental procedure (incidence ratio, 1.5) but not during weeks 5 through 24, relative to baseline (periods more than 24 weeks after any invasive dental procedure). In sensitivity analyses, the findings did not change when analysis was limited to patients with no histories of having filled antiplatelet drug prescriptions, or when patients with recently diagnosed diabetes or CAD were excluded.

Comment: Periodontal disease is associated with excess risk for adverse cardiovascular events. This observational study suggests that people who undergo invasive dental procedures (possibly for treatment of periodontal disease) are transiently at increased risk for MI or ischemic stroke. If proven accurate, these results could lead to the use of antiplatelet agents in conjunction with invasive dental procedures in high-risk patients.

— Jamaluddin Moloo, MD, MPH

Published in Journal Watch General Medicine November 24, 2010

Rheumatoid arthritis: Can statin use help prevent RA onset?

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Evidence indicating that statins have anti-inflammatory and immunomodulatory effects, apparently manifested by decreased levels of C-reactive protein (CRP), has led to suggestions that these agents might represent an effective treatment approach in patients with rheumatoid arthritis (RA). While conflicting evidence has emerged regarding this particular application, the possibility that statin use might help prevent the onset of RA continues to be investigated. A large retrospective analysis of over 200,000 patients enrolled in an Israeli health maintenance organization suggests that persistent statin use may indeed have a protective effect against RA.

To minimize the effect of healthy user bias, the association between statin persistence and onset of osteoarthritis (OA)—a disease deemed unlikely to be affected by statin use—was also calculated. Persistent statin use was categorized as the proportion of days covered (PDC), defined as the quantity of dispensed statins divided by the interval between the first purchase of the drug and a diagnosis of RA or OA, death, or the end of the study.

The crude incident density rate of RA among nonpersistent statin users (PDC <20%) was 51% greater than in highly persistent users (PDC ≥80%). After adjustment for confounding variables, highly persistent users had a hazard ratio (HR) for RA of 0.58 (95% CI 0.52–0.65) compared with nonpersistent users. For comparison, the corresponding HR for OA incidence showed a far more modest decrease in risk associated with persistent statin use (HR 0.85, 95% CI 0.81–0.88).

These findings indicate that further prospective, controlled studies are warranted to elucidate this association between statin use and protection against RA onset.

source: nature

Endocannabinoids: Dual effects at different sites

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Endocannabinoids are released by neurons and are generally thought to inhibit synaptic transmission in many brain regions, including the hippocampus. Recent studies showed that in this region, both neurons and astrocytes express endocannabinoid 1 receptors (CB1Rs), but the role of astrocytic CB1Rs on synaptic transmission has remained unknown. Now, Navarrete and Araque show that endocannabinoid activation of astrocytic CB1Rs potentiates neurotransmission at synapses far away from the site of endocannabinoid release.

The authors first showed that in hippocampal slices, neuronal depolarization could evoke both suppression of excitation (depolarization-induced suppression of excitation (DSE)) and potentiation of transmitter release at synapses in an adjacent neuron. Both effects were blocked by inhibition of endocannabinoid release from the postsynaptic neuron with BAPTA or by perfusing hippocampal slices with a CB1R antagonist, indicating that endocannabinoids mediate both DSE and synaptic potentiation (endocannabinoid-mediated synaptic potentiation (eSP)).

The authors next examined whether DSE and eSP are mediated by neuronal and/or astrocytic CB1Rs. Activation of CB1Rs on astrocytes is known to increase intracellular Ca2+ levels, and depleting intracellular Ca2+ from astrocytes abolished eSP but not DSE. In astrocytes, Ca2+ elevation induces glutamate release, which subsequently activates mGluRs on presynaptic neurons and so potentiates neurotransmitter release. The authors showed that perfusing hippocampal slices with an antagonist of group I mGluRs blocked eSP, indicating that this pathway also underlies endocannabinoid-mediated synaptic potentiation. Activation of neuronal CB1Rs activates Gi/o proteins, which are sensitive to pertussis toxin. Treating hippocampal slices with this toxin inhibited endocannabinoid-mediated DSE but increased eSP. Together, these findings show that neuronal CB1Rs mediate DSE, whereas astrocytic CB1Rs — and subsequently neuronal mGluRs — mediate eSP.

If endocannabinoids released by a neuron can induce both potentiation and inhibition of transmission at other hippocampal synapses by activating CB1Rs, what determines the direction of the modulation? The authors showed that applying a CB1R agonist reduced the efficacy of eSP induced by neuronal depotentiation. This suggests that synapses showing eSP do express CB1Rs but that these receptors are not activated by endocannabinoids released from an activated neuron, perhaps because the endocannabinoids cannot reach them. Indeed, the authors found that DSE occurred at synapses located near the stimulated neuron, whereas eSP was only found at synapses further away. This is in agreement with previous findings that Ca2+ elevation induced in astrocytes by depolarization of a nearby neuron can spread through the cell and thereby have effects at some distance from the stimulated neuron.

This study showed that endocannabinoids released by neurons activate CB1Rs on nearby neurons, with short-range, inhibitory effects, and CB1Rs on astrocytes, which leads to Ca2+ elevation and subsequent astrocytic glutamate release, stimulation of presynaptic glutamate receptors and synaptic potentiation at more distant sites. These findings provide further insight into the role of astrocytes in synaptic plasticity.

source: nature neuroscience

Hyponatremia in Acute Decompensated Heart Failure: Mechanisms, Prognosis, and Treatment Options

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Hyponatremia is common and is increasingly recognized as an independent prognostic marker that adversely affects morbidity and mortality in various disease states, including heart failure. In acute decompensated heart failure (ADHF), the degree of hyponatremia often parallels the severity of cardiac dysfunction and is further exacerbated by any reduction in glomerular filtration rate and arginine vasopressin dysregulation. A recent study showed that even modest improvement of hyponatremia may have survival benefits. Although management of hyponatremia in ADHF has traditionally focused on improving cardiac function and fluid restriction, the magnitude of improvement of serum sodium is fairly slow and unpredictable. In this article, we discuss the mechanisms of hyponatremia in ADHF, review its evolving prognostic significance, and evaluate the efficacy of various treatments for hyponatremia, including the recently approved vasopressin receptor antagonists for managing hyponatremia among patients hospitalized for ADHF. Copyright © 2008 Wiley Periodicals, Inc.

Dr. Jun Chiong is a member of the Speaker’s Bureau of Otsuka Pharmaceutical company. The authors have no additional funding, financial relationships, or conflicts of interest to disclose.

Jump to…Top of pageAbstractIntroductionArginine Vasopressin in Sodium and Water HomeostasisMechanisms of Hyponatremia in Heart FailureClinical PresentationHyponatremia in ADHF: Prognostic SignificanceTreatment of Hyponatremia in ADHFVasopressin Receptor AntagonistsClinical Application of VRAsConclusionAcknowledgementsReferences

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Arginine Vasopressin in Sodium and Water Homeostasis
  5. Mechanisms of Hyponatremia in Heart Failure
  6. Clinical Presentation
  7. Hyponatremia in ADHF: Prognostic Significance
  8. Treatment of Hyponatremia in ADHF
  9. Vasopressin Receptor Antagonists
  10. Clinical Application of VRAs
  11. Conclusion
  12. Acknowledgements
  13. References

Hyponatremia is generally defined as serum sodium (Na) concentration of < 135 mEq/L (1 mEq/L Na = 1 mmol/L Na). Its prevalence in the acute hospital setting ranges from 4% to 45%.1 Nineteen percent to 25% of patients with acute decompensated heart failure (ADHF) have hyponatremia,2–4 which is independently associated with increasing short-term and long-term morbidity and mortality. Even mild hyponatremia among patients with ADHF, regardless of ventricular function, is associated with increased in-hospital and postdischarge mortality, prolonged hospital length of stay, and frequent rehospitalization. This review will focus on the mechanisms, prognostic significance, and treatment considerations of hyponatremia in ADHF.

Jump to…Top of pageAbstractIntroductionArginine Vasopressin in Sodium and Water HomeostasisMechanisms of Hyponatremia in Heart FailureClinical PresentationHyponatremia in ADHF: Prognostic SignificanceTreatment of Hyponatremia in ADHFVasopressin Receptor AntagonistsClinical Application of VRAsConclusionAcknowledgementsReferences

Arginine Vasopressin in Sodium and Water Homeostasis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Arginine Vasopressin in Sodium and Water Homeostasis
  5. Mechanisms of Hyponatremia in Heart Failure
  6. Clinical Presentation
  7. Hyponatremia in ADHF: Prognostic Significance
  8. Treatment of Hyponatremia in ADHF
  9. Vasopressin Receptor Antagonists
  10. Clinical Application of VRAs
  11. Conclusion
  12. Acknowledgements
  13. References

Sodium (Na+) is the major extracellular cation that primarily determines serum osmolality. Under physiologic states, serum osmolality is regulated primarily by arginine vasopressin (AVP), renal responsiveness to AVP, and thirst.5 A 1% to 2% perturbation in serum osmolarity results in accompanying serum AVP changes via a reflex arc designed to maintain fluid and electrolyte homeostasis.6 The baroreceptor-mediated, nonosmotic release of AVP is the predominant mechanism of hyponatremia in adult hospitalized patients and is more potent than the osmotic path of AVP regulation.7–9 Thus, a hypo-osmotic effect to suppress AVP synthesis and release may be overridden by nonosmotic AVP stimulation.

Jump to…Top of pageAbstractIntroductionArginine Vasopressin in Sodium and Water HomeostasisMechanisms of Hyponatremia in Heart FailureClinical PresentationHyponatremia in ADHF: Prognostic SignificanceTreatment of Hyponatremia in ADHFVasopressin Receptor AntagonistsClinical Application of VRAsConclusionAcknowledgementsReferences

Mechanisms of Hyponatremia in Heart Failure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Arginine Vasopressin in Sodium and Water Homeostasis
  5. Mechanisms of Hyponatremia in Heart Failure
  6. Clinical Presentation
  7. Hyponatremia in ADHF: Prognostic Significance
  8. Treatment of Hyponatremia in ADHF
  9. Vasopressin Receptor Antagonists
  10. Clinical Application of VRAs
  11. Conclusion
  12. Acknowledgements
  13. References

Ventricular Dysfunction and Neurohormonal Activation

The pathophysiology of the heart failure (HF) syndrome involves the complex interplay between renin-angiotensin-aldosterone system (RAAS) activation, sympathetic nervous system stimulation, and nonosmotic AVP release. Though initially triggered to preserve hemodynamic integrity following cardiac injury, these neurohormonal actions, if uncorrected, lead to progressive cardiac dysfunction and retention of salt (sodium chloride; NaCl) and water.

Hyponatremia in HF often parallels the severity of cardiac dysfunction and is further exaggerated by any reduction in glomerular filtration rate and AVP dysregulation.10 Asymptomatic left ventricular dysfunction is associated with preserved Na balance attributed to activation of the cardiac natriuretic peptides. As ventricular dysfunction progresses and clinically evident HF develops, up-regulation of the maladaptive neurohormonal systems collectively limits distal solute and free water delivery, ensures maximal free water reabsorption, and causes progressive cardiac dysfunction. If uncorrected, this vicious cycle predisposes to hyponatremia.11 RAAS stimulation, primarily through the effect of angiotensin II, increases the resistance of the afferent arterioles, decreases the glomerular filtration rate through reduction of renal perfusion, and increases Na and water reabsorption in the proximal tubule. Sympathetic nervous system activation leads to increased peripheral resistance and heart rate that increase afterload, reduce cardiac output, decrease renal and tissue perfusion, enhance proximal tubular Na reabsorption, and decrease water and Na delivery to the distal diluting segments.12 Circulating levels of AVP are 2× to 3× greater among hyponatremic HF patients compared with normal subjects. The trigger for nonosmotic release of AVP in ADHF remains unclear, but arterial underfilling from reduced cardiac output is the leading hypothesis.13 Both low cardiac output and high angiotensin II levels are also potent thirst stimuli; patients with severe HF may develop hyponatremia with only 1–2 L of water intake per day.11

Diuretic-Induced Hyponatremia

HF patients are at increased risk for diuretic-induced hyponatremia because diuretics activate water-retention pathways similar to those operative in HF. Thiazides are more potent inducers of hyponatremia compared with loop diuretics, because by blocking NaCl cotransport at the distal convoluted duct they increase distal Na delivery and preserve the medullary interstitial gradient, which then effectively prevents the excretion of maximally dilute urine and promotes reabsorption of solute-free water if AVP is acting at the collecting duct.14 In the largest retrospective review on this subject, thiazide and thiazide-type diuretics alone or in combination with potassium-sparing agents were responsible for hyponatremia in 94% of 129 cases. Of note, 97% of the doses were within the limits of pharmacologic recommendations.15 Other proposed mechanisms for diuretic-induced hyponatremia that both classes of diuretics share are: (1) urinary potassium loss, causing the extracellular Na to shift intracellularly; (2) nonosmotic activation of AVP; and (3) excess thirst, causing increased water intake.

Hypotension From HF Therapeutics vs Progressive Ventricular Dysfunction

Patients with advanced HF who are hyponatremic often have lower systemic blood pressures that limit the adherence to current HF treatment guidelines, because evidence-based drug therapies for HF that show survival benefits also lower systemic blood pressure. Hypotension is a potent stimulus for the neurohormonal changes seen in HF that cause hyponatremia and cardiac dysfunction.16 Whether hypotension related to progression of cardiac dysfunction and hypotension caused by medical therapy have different consequences is unknown.

Jump to…Top of pageAbstractIntroductionArginine Vasopressin in Sodium and Water HomeostasisMechanisms of Hyponatremia in Heart FailureClinical PresentationHyponatremia in ADHF: Prognostic SignificanceTreatment of Hyponatremia in ADHFVasopressin Receptor AntagonistsClinical Application of VRAsConclusionAcknowledgementsReferences

Clinical Presentation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Arginine Vasopressin in Sodium and Water Homeostasis
  5. Mechanisms of Hyponatremia in Heart Failure
  6. Clinical Presentation
  7. Hyponatremia in ADHF: Prognostic Significance
  8. Treatment of Hyponatremia in ADHF
  9. Vasopressin Receptor Antagonists
  10. Clinical Application of VRAs
  11. Conclusion
  12. Acknowledgements
  13. References

The manifestations of hyponatremia are largely related to central nervous system dysfunction secondary to cerebral edema.17 Depending on the rapidity and extent of decline of the serum Na concentration, symptoms may range from nonspecific headache, nausea, vomiting, and disorientation to life-threatening seizures, coma, respiratory depression, and death.

The brain’s compensatory response to hyponatremia-induced brain swelling is to lose NaCl from the interstitial fluid and potassium and organic osmolytes from the intracellular space. When hyponatremia develops within 48 hours (acute hyponatremia), or when serum Na concentration falls faster than 0.5 mEq/L/hr, irreversible neurologic damage or death may occur if the condition is not emergently addressed.18 In contrast, chronic hyponatremia (>48 h) presents more subtly. But even apparently asymptomatic, mild chronic hyponatremia causes gait disturbances and altered cognition that predispose to increased risk of falls and fractures.19

Hyponatremic ADHF patients tend to have lower systolic blood pressure and worse renal function, and require intravenous inotropes during hospitalization.3 Although the effect of hyponatremia on symptoms specifically for HF patients is uncertain, the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT) trials have shown significant improved mental component scores of the Short Form-12 Health Survey if hyponatremia improves.20

Jump to…Top of pageAbstractIntroductionArginine Vasopressin in Sodium and Water HomeostasisMechanisms of Hyponatremia in Heart FailureClinical PresentationHyponatremia in ADHF: Prognostic SignificanceTreatment of Hyponatremia in ADHFVasopressin Receptor AntagonistsClinical Application of VRAsConclusionAcknowledgementsReferences

Hyponatremia in ADHF: Prognostic Significance

  1. Top of page
  2. Abstract
  3. Introduction
  4. Arginine Vasopressin in Sodium and Water Homeostasis
  5. Mechanisms of Hyponatremia in Heart Failure
  6. Clinical Presentation
  7. Hyponatremia in ADHF: Prognostic Significance
  8. Treatment of Hyponatremia in ADHF
  9. Vasopressin Receptor Antagonists
  10. Clinical Application of VRAs
  11. Conclusion
  12. Acknowledgements
  13. References

Regardless of the healthcare setting (ie, in-hospital or ambulatory), ventricular function (depressed or preserved), or the timing of blood draw (on admission, predischarge, or at follow-up), hyponatremia in HF is associated with adverse short-term and long-term morbidity and mortality (Table 1).2–4, 21–26 The one exception to this finding is when hyponatremia occurs in the setting of hyperglycemia. Then, serum Na has no prognostic significance.27

Table 1. Prognostic Studies Evaluating Hyponatremia in ADHF
Setting NYHA Class Study Findings

  1. Abbreviations: ACE, angiotensin-converting enzyme; ACTIV in CHF, Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure; ADHF, acute decompensated heart failure; ARB, angiotensin II receptor blocker; BB, β-blocker; EF, ejection fraction; ESCAPE, Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness; HF, heart failure; HFPEF, heart failure with preserved ejection fraction; Na, serum sodium concentration; NR, not reported; NYHA, New York Heart Association; OPTIME-CHF, Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure; OPTIMIZE-HF, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure
Diuretic and digoxin era
Before and after treatment with ACE inhibitors21 IV Prospective cohort (n = 203) Pretreatment Na <138 meq/L was the strongest predictor of cardiovascular mortality.
ACE/ARB, BB, and diuretic era
Newly diagnosed ADHF patients regardless of systolic function (Canada)22 NR Retrospective (n = 4031) Admission Na <136 meq/L predicts 30-d and 1-y mortality
Patients with systolic HF who died23 III-IV before death Retrospective (n = 160) Hyponatremia (mean Na 128 meq/L) was worse in the months preceding death than at the time of death.
ADHF with systolic dysfunction (OPTIME-CHF)24 III-IV Retrospective (n = 949) Admission Na 132–135 meq/L was associated with increased in-hospital and 60-d mortality.
ADHF regardless of onset and ventricular function (OPTIMIZE-HF)2 III-IV Retrospective (n = 47 647) Admission Na <135 meq/L is independently associated with longer hospital stays and higher in-hospital and postdischarge 60-d mortality.
ADHF with systolic dysfunction (ESCAPE)3 IV Retrospective (n = 433) Baseline Na <135 meq/L was associated with 6-mo mortality. Persistent hyponatremia independently predicts mortality, HF hospitalization, and death or rehospitalization despite clinical and hemodynamic improvements similar to normonatremic patients. Patients with corrected Na died more than normonatremic patients but less than persistently hyponatremic patients. The comparison of the latter group is not significant but limited by small number of events.
ADHF with systolic dysfunction (ACTIV in HF)4 III-IV Retrospective (n = 301) Baseline Na <135 meq/L was statistically significant predictor of 60-d mortality. >2 mEq/L increase among hyponatremic patients was associated with improved survival at 60 d.
First hospitalization of patients with HFPEF (EF >50%)25 II-IV Prospective cohort (n = 358) The risk of 7-y overall mortality increased by 6% for each 1-meq/L decrease in baseline serum Na. Patients with normalized Na at discharge had excess 7-y overall mortality compared with the normonatremic group. Patients with persistent hyponatremia (Na <136 meq/L) had the lowest 7-y survival.
First hospitalization for HF26 II-IV Prospective cohort (n = 735) Admission Na <136 meq/L is an independent predictor of 7-y mortality.

The first study to establish the prognostic significance of hyponatremia in HF involved 203 New York Heart Association class IV systolic HF patients. In total, 30 clinical, hemodynamic, and biochemical variables were evaluated before and after treatment with vasodilators. Pretreatment hyponatremia was found to be the most powerful predictor of cardiovascular mortality, and this prognostic relationship was modified by use of angiotensin-converting enzyme inhibitors.21 But despite contemporary, optimal, evidence-based medical therapy, hyponatremia (when detected) still predicts increased mortality.

The strongest evidence associating hyponatremia in ADHF to long-term mortality to date is a cohort study that evaluated the relation of serum Na level to 7-year overall mortality after first hospitalization for HF with preserved ejection fraction.26 Mortality seems to be highest among patents with persistent hyponatremia, lower in those with improved hyponatremia, and lowest in those who maintain normonatremia.

Jump to…Top of pageAbstractIntroductionArginine Vasopressin in Sodium and Water HomeostasisMechanisms of Hyponatremia in Heart FailureClinical PresentationHyponatremia in ADHF: Prognostic SignificanceTreatment of Hyponatremia in ADHFVasopressin Receptor AntagonistsClinical Application of VRAsConclusionAcknowledgementsReferences

Treatment of Hyponatremia in ADHF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Arginine Vasopressin in Sodium and Water Homeostasis
  5. Mechanisms of Hyponatremia in Heart Failure
  6. Clinical Presentation
  7. Hyponatremia in ADHF: Prognostic Significance
  8. Treatment of Hyponatremia in ADHF
  9. Vasopressin Receptor Antagonists
  10. Clinical Application of VRAs
  11. Conclusion
  12. Acknowledgements
  13. References

Several factors need to be taken into consideration when choosing the most appropriate treatment for hyponatremia: (1) clinical manifestation, (2) volume status, (3) severity of hyponatremia, (4) rapidity of onset, (5) comorbid illnesses, and (6) rate of correction. The challenge is balancing between the risk of permanent and lethal complications if hyponatremia is treated incorrectly vs the risk of iatrogenic brain injury from overly rapid correction of hyponatremia (>12 mEq/L/d or > 18 mEq/L/48 h). Acute, symptomatic, severe hyponatremia is a medical emergency that demands prompt intervention with hypertonic saline solution (HSS). In this setting, the risk of persistent marked hyponatremia far exceeds any risk from correction of serum Na.28 Conversely, overly rapid correction of chronic hyponatremia causes pontine and extrapontine myelinolysis, the osmotic demyelination syndrome (ODS).29

Hyponatremia among patients with ADHF is usually chronic, rarely overtly symptomatic, or present with serum Na < 120 mEq/L. Administering HSS to this patient subgroup with congestive symptoms and expanded extracellular fluid volume is, therefore, often unnecessary. In the rare event that treatment for acute symptomatic hyponatremia in HF patients is needed, a small, randomized, single-blind study involving 107 refractory HF patients did show that low-dose HSS plus a high-dose loop diuretic (vs high-dose loop diuretics alone) was safely tolerated, improved hyponatremia, overcame diuretic resistance, and relieved congestive signs and symptoms. Although all patients clinically improved, those on high-dose diuretics alone had worsening hyponatremia and renal function.30 This study should be interpreted cautiously, because only 10 patients in each arm were hyponatremic.

The management of hyponatremia in ADHF has traditionally focused on improving cardiac function while at the same time restricting fluid intake. Water restriction alone, however, will increase serum Na by only approximately 1–2 mEq/L/day and is poorly tolerated.28 Correction of hypokalemia can improve hyponatremia. Use of lithium and demeclocycline in HF patients is limited by serious renal and/or cardiovascular side effects.11 Vasopressin receptor antagonists (VRAs) are new pharmacologic agents that have been shown to safely and effectively increase serum Na concentration. We shall focus our discussion on tolvaptan and conivaptan, the only VRAs that are approved by the US Food and Drug Administration to treat both euvolemic and hypervolemic hyponatremia.

Jump to…Top of pageAbstractIntroductionArginine Vasopressin in Sodium and Water HomeostasisMechanisms of Hyponatremia in Heart FailureClinical PresentationHyponatremia in ADHF: Prognostic SignificanceTreatment of Hyponatremia in ADHFVasopressin Receptor AntagonistsClinical Application of VRAsConclusionAcknowledgementsReferences

Vasopressin Receptor Antagonists

  1. Top of page
  2. Abstract
  3. Introduction
  4. Arginine Vasopressin in Sodium and Water Homeostasis
  5. Mechanisms of Hyponatremia in Heart Failure
  6. Clinical Presentation
  7. Hyponatremia in ADHF: Prognostic Significance
  8. Treatment of Hyponatremia in ADHF
  9. Vasopressin Receptor Antagonists
  10. Clinical Application of VRAs
  11. Conclusion
  12. Acknowledgements
  13. References

AVP release is almost always either increased or inadequately suppressed in persistent hypotonic hyponatremia (once psychogenic polydipsia and pseudohyponatremia are excluded).28 To correct euvolemic and hypervolemic hyponatremia, therefore, AVP synthesis can either be switched off or the site of its action can be blocked. There are 2 major subtypes of vasopressin receptors: V1A and V2. The V1A receptors are found on vascular smooth muscles and cardiomyocytes, affecting vascular tone and myocardial function. V2 receptors are principally located on the basolateral membrane of the cortical and medullary collecting duct, the blockade of which leads to aquaresis, the excretion of electrolyte-free water.

Tolvapatan

Tolvaptan is the first FDA-approved oral selective V2 receptor blocker to treat hyponatremia associated with ADHF, liver cirrhosis with ascites, and the syndrome of inappropriate antidiuretic hormone hypersecretion. It was shown in randomized, double-blind, placebo-controlled studies to safely and effectively raise serum Na concentration in the short term among patients with euvolemic and hypervolemic hyponatremia.21 A prespecified post hoc analysis of the SALT trials also showed significantly improved mental component scores on the Short Form-12 Health Survey.

The effects of tolvaptan on ADHF were investigated much earlier by well-designed clinical trials that showed that tolvaptan was safely tolerated and superior to placebo in reducing body weight and edema and normalizing Na.31 A post hoc analysis of the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) trial, which analyzed the effects of changes in serum Na with treatment on the 60-day mortality among ADHF patients, showed that even modest improvement of hyponatremia may have survival benefits.4 Of the 68 hyponatremic patients, 45 patients whose serum Na improved by ≥ 2 mEq/L were more likely to be alive at 60 days compared with placebo. These findings suggested that treatment of hyponatremia might alter the natural history of HF and provided the rationale for a larger, more definitive investigation.

The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trials consisted of 2 multicenter, randomized, double-blind, placebo-controlled studies that investigated the effects of tolvaptan on clinical signs and symptoms of HF and an outcome study that combined all patients from the clinical status trials.32 Overall, 4133 patients were randomized to receive tolvaptan 30 mg/day or placebo, plus standard HF treatment, for a minimum of 60 days.33 The mean follow-up time was 9.9 months. There was an equivalent dropout rate in both arms (20%), attributed to patient request to withdraw from the study and adverse events (mostly dry mouth and thirst) that were similar in both groups. Tolvaptan plus standard HF treatment quickly improved many HF signs and symptoms without serious adverse events. However, there was no difference in the primary endpoints of all-cause mortality, the composite of cardiovascular death and HF hospitalization, or overall quality of life scores between the groups. It is noteworthy that only 8% of the ADHF patients in this study were hyponatremic, possibly reflecting exclusion of refractory end-stage HF patients. The findings from EVEREST therefore cannot be generalized to include this subgroup that should theoretically gain the most benefit from treatment with VRAs.

A prespecified post hoc analysis of the EVEREST trials suggested that addition of tolvaptan to standard HF treatment modestly improves dyspnea, whether given early or relatively late after hospitalization.34 Its effects are greatest within 12 hours of the first dose, and although patients continue to report dyspnea improvement up to 60 hours after admission, the magnitude of benefit diminishes with time. Although dyspnea improved regardless of the severity of the patient’s baseline dyspnea, the greatest treatment differences were seen in patients with continuous dyspnea at baseline. This study also found a linear correlation between improvement in patient-assessed dyspnea and reductions in body weight (Figure 1). Whereas weight gain after hospitalization for ADHF strongly predicts HF rehospitalizations, a reduction in body weight as a result of a specific intervention may not necessarily prevent readmissions.35

Figure 1. Relationship of patient-assessed dyspnea to body weight

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The hemodynamic effects of tolvaptan in ADHF patients provide a potential mechanistic explanation for the short-term favorable effects of tolvaptan on dyspnea and sustained body weight reduction. Tolvaptan resulted in modest changes in filling pressures, a dose-dependent increase in urine output, and increase in free water clearance with no short-term changes in potassium or renal function. Its ability to achieve these changes while maintaining blood pressure and heart rate (without activating the RAAS) suggests that significant aquaresis may occur primarily by removing excess extravascular volume with minimal reduction in intravascular volume.36

Conivaptan

Conivaptan is the first intravenous nonpeptide VRA that blocks both V1A and V2 receptors and is FDA-approved for short-term treatment of euvolemic and hypervolemic hyponatremia. In a randomized, placebo-controlled trial involving 84 hospitalized patients, conivaptan 40 mg/day was superior to placebo in improving euvolemic or hypervolemic hyponatremia and increased serum Na by ≥ 4 mEq/L in 24 hours; a 6- mEq/L increase with normalization of serum Na was achieved in 69% of patients after 4 days.37

In the first randomized, placebo-controlled study investigating the utility of conivaptan exclusively among New York Heart Association class III or IV HF patients, 142 patients were randomized to receive a single intravenous dose of conivaptan (10, 20, or 40 mg) or placebo.38 Conivaptan in the 20-mg and 40-mg groups led to dose-dependent decrease in pulmonary capillary wedge and right atrial pressures, along with a dose-dependent increase in urine output compared to placebo. Changes in cardiac index, systemic/pulmonary vascular resistance, blood pressure, or heart rate were similar to placebo.

In another randomized, double-blind, placebo-controlled trial, 170 patients with ADHF received conivaptan (a 20-mg loading dose followed by continuous infusion of 40, 80, or 120 mg/d for 2 d) or placebo, plus standard therapy.39 Conivaptan significantly increased urine output (1–1.5 L/d), was hemodynamically well tolerated, and had minimal side effects, but it did not improve respiratory symptoms.

Jump to…Top of pageAbstractIntroductionArginine Vasopressin in Sodium and Water HomeostasisMechanisms of Hyponatremia in Heart FailureClinical PresentationHyponatremia in ADHF: Prognostic SignificanceTreatment of Hyponatremia in ADHFVasopressin Receptor AntagonistsClinical Application of VRAsConclusionAcknowledgementsReferences

Clinical Application of VRAs

  1. Top of page
  2. Abstract
  3. Introduction
  4. Arginine Vasopressin in Sodium and Water Homeostasis
  5. Mechanisms of Hyponatremia in Heart Failure
  6. Clinical Presentation
  7. Hyponatremia in ADHF: Prognostic Significance
  8. Treatment of Hyponatremia in ADHF
  9. Vasopressin Receptor Antagonists
  10. Clinical Application of VRAs
  11. Conclusion
  12. Acknowledgements
  13. References

VRAs were proven safe and effective in correcting euvolemic and hypervolemic hyponatremia in properly selected patients who were closely followed up. The rate of change in serum Na concentration seems to be greatest during the first 24 hours after drug administration; therefore, fluid restriction should be avoided during this time. After all, thirst, dry mouth, and polyuria are among the most commonly encountered adverse effects of VRAs. Because they can cause brisk and prolonged diuresis, VRAs are contraindicated in hypovolemic hyponatremia and should be initiated or reinitiated only in the hospital setting, where serum Na can be closely monitored. The risk of overly rapid correction of chronic hyponatremia causing ODS is a concern, but no cases of ODS have been reported to date.

There is no evidence to date that supports the use of VRAs in patients with acutely symptomatic severe hyponatremia, serum creatinine > 3.5 mg/dL, end-stage renal disease, and refractory end-stage HF. The SALT trials did show that serum Na may drop within a week after tolvaptan is discontinued; therefore, optimal treatment of the underlying cause(s) of hyponatremia is recommended prior to discontinuing this drug. The serum Na should be closely followed thereafter.

Jump to…Top of pageAbstractIntroductionArginine Vasopressin in Sodium and Water HomeostasisMechanisms of Hyponatremia in Heart FailureClinical PresentationHyponatremia in ADHF: Prognostic SignificanceTreatment of Hyponatremia in ADHFVasopressin Receptor AntagonistsClinical Application of VRAsConclusionAcknowledgementsReferences

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Arginine Vasopressin in Sodium and Water Homeostasis
  5. Mechanisms of Hyponatremia in Heart Failure
  6. Clinical Presentation
  7. Hyponatremia in ADHF: Prognostic Significance
  8. Treatment of Hyponatremia in ADHF
  9. Vasopressin Receptor Antagonists
  10. Clinical Application of VRAs
  11. Conclusion
  12. Acknowledgements
  13. References

Hyponatremia in ADHF is a marker of advanced disease severity and predicts increased morbidity and mortality. The currently available VRAs safely and effectively improve hyponatremia, increase urine output, modestly improve dyspnea, and sustain weight loss while preserving hemodynamic status, electrolyte homeostasis, and renal function among patients with ADHF. Although current evidence shows that addition of VRAs to a standard HF regimen does not confer additional survival benefits, further prospective studies are needed to determine whether this holds true for the hyponatremic HF population. Meanwhile, careful adherence to evidence-based dosing and close follow-up is needed when administering VRAs to prevent the theoretical but potentially catastrophic risk of ODS.

Acetaminophen Not Linked to Liver Damage in Kids

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Risk of Liver Damage in Children Is Very Low When Taking Dosages Within
acetaminophen pill

Nov. 22, 2010 — A review of the medical literature indicates that despite a reported association between liver toxicity and acetaminophen use, the risk of children developing any kind of liver damage after taking the everyday painkiller at recommended dosing is less than 0.01%.

Acetaminophen overdosing is associated with liver toxicity in children and adults, but in this study, researchers led by Eric J. Lavonas, MD, from the Rocky Mountain Poison and Drug Center in Denver, wanted to evaluate the risk of standard acetaminophen doses. Looking at data on 32,414 children, from newborns to young adults, they found that not a single child who took acetaminophen therapeutically showed signs of liver disease, received antidotes or transplantation, or died.

Combing the Medical Literature

Using medical data sources dating back to 1950, Lavonas and his team included 62 clinical studies and case reports in their analysis. The trials occurred in both the industrialized and developing worlds, and children treated in private practices, hospitals, intensive care units, and clinics. The children were treated with a standard dose of acetaminophen that  did not exceed 4 grams during a 24-hour period — a dose that is in line with FDA recommendations for children. In most cases, acetaminophen was used to treat pain, such as postoperative pain or infection. Children received acetaminophen orally, by intravenous infusion, as a suppository, and by feeding tube.

Liver complications were reported in 10 children out of the entire study population. Among this group, two children who discontinued acetaminophen use were found to have had acute viral hepatitis. The findings were published in the December issue of Pediatrics.

Question of Cause and Effect Remains

Acetaminophen is, for many people, a medicine cabinet staple. The drug has been available over-the-counter in pediatric formulations since 1959. According to the authors, it is the most common pain reliever administered to American children. Every week, an estimated 11.1% of the 73.7 million children in the U.S. receive acetaminophen.

The authors note that the question of causality, particularly with greater doses of acetaminophen, remains unclear. However, the overall risk of liver toxicity to children who take doses that fall within FDA recommendations appears quite low. “Few reports contain sufficient data to support a probable causal relationship,” the researchers write.

Azacitidine for Myelodysplasia

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Responses were seen in 43% of patients.

Myelodysplasia is a chronic disorder of marrow stem cells that is associated with ineffective hematopoiesis, peripheral blood cytopenias, and a variable risk for transformation into acute leukemia. In addition to supportive therapy with transfusions and stimulating factors, drugs that affect stem-cell proliferation are often given to restore marrow function. Azacitidine, a hypomethylating agent, is one of the oldest drugs used for this purpose.

Now, investigators in France report on the disease outcomes of 282 patients with myelodysplastic syndrome (median age, 71; 61% men) who received azacitidine (75 mg/m2/day for 7 days every 28 days). Patients received a median 6 cycles of therapy; 28% received a reduced dose, mainly to avoid weekend injections. Most patients had refractory anemia: 20% had refractory anemia with excess blasts type 1 (RAEB-1), 54% had RAEB-2, and 22% had RAEB in transformation to acute myeloid leukemia (RAEB-T). Almost all patients were anemic and transfusion dependent; half had absolute neutrophil counts <1000/µL or platelet counts <100,000/µL.

During a median 9.5 months, responses were observed in 43% of patients, including complete responses in 14%, partial remissions in 3%, and stable disease in 15%. Marrow examinations showed complete responses in 11%. The median duration of responses ranged from 7.9 to 10.4 months. Progressive disease was noted in 18%. The factors predicting poor response were blasts >15% (P=0.004), abnormal karyotype (P=0.03), and prior therapy with cytosine arabinoside (P=0.009). The median overall survival was 13.5 months. A prognostic score based on the performance score, peripheral blast count, red cell transfusion dependency, and cytogenetics identified patients with low (6.1 months), intermediate (15 months), and high (>30 months) overall survival. If patients had an improvement in red blood cell count, survival improved (P=0.004), even if adverse prognostic risk factors were present.

Comment: This study indicates that azacitidine is partially effective for patients with myelodysplastic syndrome who have not been previously treated with an anthracycline and who have a low peripheral blast count and a normal karyotype. Unfortunately, these represent less than half of the higher-risk patients with this disease. The development of newer agents with greater efficacy and safety is clearly needed.

— David Green, MD, PhD

Published in Journal Watch Oncology and Hematology November 23, 2010

Oral Preexposure Prophylaxis for HIV

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Despite the growing global access to life-extending antiretroviral drugs for the more than 33 million persons living with human immunodeficiency virus (HIV) infection, approximately 7000 new infections occur daily. This alarming number speaks to the critical need for effective approaches to HIV prevention.1 Early approaches to prevention were limited to the consistent use of barrier methods during sex,2 a reduction in the prevalence of HIV in the blood supply, behavior modification, postexposure prophylaxis, and awareness of HIV-infection status. Antiretroviral drugs that were provided to pregnant women with HIV infection were shown to dramatically reduce the risk of perinatal transmission,3 with added protection to treated breast-fed infants of HIV-infected mothers.4 A single study suggested that treatment of intercurrent sexually transmitted infections could decrease the susceptibility to HIV.5

However, continually impressive advances in the effectiveness of potent antiretroviral therapy to treat chronic HIV infection from 1995 to the present were not matched with concomitant improvements in methods for HIV prevention until relatively recently. For quite some time, the HIV-prevention quiver held precious few arrows. This began to change in the period from 2005 through 2007, when studies showed that adult male circumcision, vaccination, or the use of a vaginal microbicide could variably reduce the risk of HIV infection.6-10 However, the need for more and better preventive treatments remains.

In this issue of the Journal, Grant and colleagues11 report evidence that antiretroviral medications, specifically the combination of emtricitabine and tenofovir disoproxil fumarate (FTC–TDF), taken orally on a daily basis by men and transgender women (born male) who have sex with men, can provide partial protection from HIV infection. The trial, called the Preexposure Prophylaxis Initiative (iPrEx) study (ClinicalTrials.gov number, NCT00458393), was a placebo-controlled, double-blind, randomized trial involving 2499 subjects in the Americas, South Africa, and Thailand. Of the 100 incident infections, 64 occurred in the placebo group and 36 in the FTC–TDF group, for an estimated efficacy of 44% with a 95% confidence interval of 15 to 63. In the FTC–TDF group, the study drug was pharmacologically detected in 51% of subjects who remained free of HIV infection but in only 9% of those who became infected. Thus, exposure to FTC–TDF was associated with a reduction in HIV acquisition, which supports the biologic plausibility of the primary result.

The results of the iPrEx study also reveal real challenges. First, the association between self-reported drug adherence and pharmacologic detection of the study drug was very poor, which underscores the need for better reporting tools to predict drug adherence. Second, although renal insufficiency was seen in a relatively small fraction of subjects and was reversible on drug discontinuation, this finding raises both safety and monitoring concerns regarding possibly cumulative toxic effects associated with large-scale exposure of at-risk persons to daily FTC–TDF therapy for an extended period. The side-effect profile for FTC–TDF was probably diluted, given the reported medication-compliance issues, and thus would probably be more substantial with full compliance. Third, and most worrisome, viral resistance to FTC was documented in both of the subjects who were found to have had acute HIV infection at enrollment. Secondary FTC resistance after exposure to the drug clearly developed in one of these subjects, and the second subject had indeterminate resistance on baseline testing but showed FTC resistance 4 weeks after enrollment. This raises very serious concern about the deployment of oral FTC–TDF in populations of men who have sex with men and who are at greatest risk for HIV acquisition and thus have an increased risk of undiagnosed acute HIV infection. In addition, persons who have other chronic viral infections, such as hepatitis B virus (HBV) infection, may have intermittent antiviral exposure as well, which could lead to the emergence of resistance or HBV rebound with the cessation of prophylactic FTC–TDF therapy. We await the follow-up data from subjects with chronic HBV infection in the iPrEx study to provide some insight here.

The results of the iPrEx study represent a significant advance in HIV-prevention research in providing the proof of concept that a combination antiretroviral drug in widespread clinical use in the treatment of chronic HIV infection reduces the risk of HIV acquisition in men who have sex with men. What will be the public health effect of these results? The overall reduction in HIV incidence in the FTC–TDF group was less than 50%. Although increased medication adherence would raise this degree of protection (along with the risk of potential side effects), what is the likelihood that such a regimen could be accomplished in an implementation program that lacks the intense reinforcement of adherence counseling provided in the context of a clinical trial? How can medication-use fatigue be mitigated over potentially many years of daily therapy? What are the potential long-term safety issues for healthy persons, as well as those with coexisting illnesses, such as diabetes or hypertension? What will the iPrEx results mean for other populations with a lower risk of HIV acquisition? What would be the effect of open-label FTC–TDF use on the prophylactic use of condoms, on knowledge of HIV-infection status (both for subjects and their partners), and on the frequency of casual sex?

The risks of daily FTC–TDF use include the troubling development of secondary antiretroviral resistance in treated persons with undiagnosed acute HIV infection and a low but measurable degree of renal toxicity. Adherence to a daily regimen was low, nondurable, and difficult to assess without pharmacologic testing, which has substantial implications for research that uses this measure of behavior for medication compliance. Thus, the potential implementation of preexposure prophylaxis with FTC–TDF will probably be considered for men who have sex with men and who are at very high risk for HIV infection. In such men, the benefits of preexposure prophylaxis would be maximized and the costs of screening for acute HIV infection and monitoring of renal function and antiretroviral-drug adherence would be best justified.

Because of these considerations, the implementation of FTC–TDF therapy will be especially challenging in resource-limited health care settings. New information on the use of intermittent antiretroviral prophylaxis before risk exposure in men who have sex with men and in other high-risk groups will be coming from ongoing clinical trials. Taken together with the results of the iPrEx study, these data are likely to place another arrow in the quiver for HIV prevention.

source: NEJM

Proteinuria and Glomerular Filtration Rate: Risk Factors for Acute Kidney Injury

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Proteinuria and low estimated glomerular filtration rate (eGFR) should both be considered when assessing a patient’s risk for — and prognosis after — acute kidney injury, according to a large study presented at the American Society of Nephrology’s annual meeting and published online in the Lancet.

Among more than 900,000 adults in Canada tracked for some 35 months, risk for acute kidney injury requiring hospital admission or dialysis increased with increases in proteinuria alone and with decreases in eGFR alone; heavy proteinuria plus low eGFR conferred the highest risk. In turn, acute kidney injury was associated with increased mortality at all levels of proteinuria and eGFR, but particularly in patients with heavy proteinuria and normal eGFR.

Commentators conclude that “urine dipsticks … might just be what the doctor ordered for starting to reverse worldwide trends in acute kidney injury.”

 

Family intervention for schizophrenia

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People with schizophrenia are more likely to experience a relapse within family groups when there are high levels of expressed emotion (hostility, criticism or over involvement) within the family, compared to families who tend to be less expressive of their emotions. There are several psychosocial interventions available involving education, support and management to reduce expressed emotion within families. In this review we compare the effects of family psychosocial interventions in community settings for the care of people with schizophrenia or schizophrenia-like illnesses.

Studies were conducted in Europe, Asia and North America with packages of family intervention varying among studies, although there were no clear differences in study design. Results indicated that family intervention may reduce the risk of relapse and improve compliance with medication. However data were often inadequately reported and therefore unusable. As this package of care is widely employed, there should be further research to properly clarify several of the short-term and long-term outcomes.