Sulindac prevents restenosis after angioplasty in rodents
The Lancet, vol.356, Oct.14, 200, pg.1333
New research in rodents suggests that sulindac, a non-steroidal anti-inflammatory drug, may be effective in preventing vascular restenosis after angioplasty and related procedures.
The research team from the Mount Sinai School of Medicine (New York, NY USA) used a mouse model of arterial injury, recognised to have essential similarities to human cardiovascular disorders, to assess the effects of aspirin and sulindac on neointimal formation. They report that sulindac reduced neointimal formation by as much as 70% in normolipidaemic and hyperlipidaemic mice. Treatment with aspirin did not significantly reduce neointimal formation.
“The clinical implications are that a drug that has proven safe and effective in human beings may have the potential to reduce the rate of restenosis, but this remains to be proven in a clinical trial”, says lead author, Edward Fisher.
Etomoxir: a new approach to treatment of chronic heart failure.
The Lancet, vol.356, Nov.11, 2000, pg.1621.
Etomoxir, a compound once developed for the treatment of diabetes mellitus, has recently been shown to have promise as a novel form of therapy for heart failure.
Etomoxir is an oxirane carboxylic acid derivative that is an inhibitor (Ki of 8mM) of carnitine palmitoyltransferase-I (CPT-1). CPT-1 is a mitochondrial enzyme that plays a key role in the transport of long-chain acyl-CoA compounds into the mitochondria, so etomoxir inhibits fatty-acid metabolism but promotes that of glucose.
Rats made diabetic with streptozotocin develop myocardial molecular or biochemical abnormalities that resemble chronic myocardial failure in human beings. The abnormalities include those of b-receptor signal transduction and induction of the “fetal” gene programme.
The concept of the fetal gene programme is that pathological hypertrophy is produced by both qualitative and quantitative change is to a ventricular expression of genes which contribute to the increase in myocardial mass. The qualitative change is to a ventricular expression pattern ordinarily observed only during fetal life. The fetal gene programme includes atrial natriuretic peptide and brain natriuretic peptide, two counter regulatory proteins considered to be molecular markers of hypertrophy. Other members of the fetal gene programme are the contractile proteins b-myosin heavy chain (b-MyHC), atrial light chain-1, and the a-skeletal actin, all of which demonstrate increased expression in humans and/or rodent models of pathological hypertrophy and myocardial failure. Associated with the increased expression of these contractile protein fetal isoforms, at least in rodent models, is a down-regulation in sarcoplasmic reticulum Ca ATPase (SERCA2), a key enzyme in regulating systolic and diastolic function.
In diabetic rats etomoxir attenuates these molecular abnormalities. Moreover, when rats are subjected to pressure overload, etomoxir also prevents induction of the fetal gene programme, preserves myocardial contractile function and prevents dilatation of the left ventricule.
The observation make it logical to evaluate etomoxir as a treatment for chronic heart failure.
These investigators evaluated the effects of etomoxir on haemodynamics and myocardial function acutely in vitro and in vivo, and chronically (over 3 months) in patients with heart failure. Etomoxir produced no acute effects in isolated preparations of human heart or in patients with heart failure. However, when etomoxir was given over 3 months to patients with Class II or III symptoms , systolic function improved. Evidence of this improvement included substantial increase in stroke volume at rest and improved cardiac output with exercise, a decrease in pulmonary wedge mean pressure and an increase in LVEF. However, a single dose of etomoxir did not decrease systemic vascular resistance over the next 4 h, and the investigators offer the oblique argument that the improvement in myocardial function was due to a direct, time-dependent effect of etomoxir on myocardial gene expression.
They speculate that an up-regulation of SERCA2 accounted for the improvement in myocardial function. If they turn out to be right, etomoxir could be a pharmacological agent for reversing abnormal myocardial gene expression in patients with chronic heart failure. As such, etomoxir would join b-blocking agents as a compound that improves SERCA2 expression and other aspects of fetal gene expression in chronic heart failure, as well as improving myocardial contractile function in a time dependent, biological fashion. b-blocking agents are also CPT-1 inhibitors. However, the precise mechanisms by which etomoxir or b-blockers reverse fetal gene induction is not well understood.
S Gaitonde, VR Joshi
Sarcoidosis : A Needle in the Haystack
JAPI, VOL.49, December 2001, pg. 1143
Sarcoidosis is ususally mistaken for tuberculosis. In addition it causes juvenile chronic arthritis and uveitis. Sarcoidosis primarily affects the lung and lymphatic organs. In addition it mimics autoimmune diseases.
It is not rare although the incidence is much less than that of tuberculosis.
Prazosin Therapy and Scorpion Envenomation
JAPI, Vol.49, December 2001, pg.1213
Dr. Bawaskar’s report has now been accepted by ICMR. However the dosage use of Prazosin is pre-fixed. Bawaskar has not tried different dosage schedules.
To determine the optimum dose, a well planned clinical trial is required.
Scientists suggest a link between rotenone and Parkinson’s disease
The Lancet, vol.356, Nov.11, 2000, pg.1659
Chronic systemic exposure to rotenone, a commonly used pesticide, produces parkinsonian symptoms in rats, according to research presented at the annual society for Neuroscience meeting.
In the 1980s some heroin users developed irreversible symptoms of Parkinson’s disease after injecting themselves with a batch of drug contaminated with MPTP. Rotenone, like MPTP, inhibits complex I (also called the NADH dehydrogenase complex), an enzyme involved in oxidative phosphorylation.
In these new experiments, rotenone was intravenously infused into rats for 1-5 weeks. The researchers observed selective nigrostriatal dopaminergic degeneration, behavioural symptoms of Parkinson’s disease, and structures that closely resembled Lewy bodies something which has never been seen in an animal model of Parkinson’s before.
However, since rotenone is a widely used pesticide these data may go further than simply offering another animal model of Parkinson’s disease. J Timothy Greenamyre, the lead investigator of the study, suggests that there may be a link between chronic exposure to environmental pollutants such as rotenone and the development of Parkinson’s in human beings. The only way we can answer the question, says Greenamyre ” is to carry out prospective epidemiological studies”.
Hiroyuki Komoriyama, Ichiro Tanaka, et al
Continuous Intraarterial Infusion of Protease Inhibitors in Acute Pancreatitis.
Drugs of Today, 2001, 37(3): 151-158
Low-molecular-weight protease inhibitors were synthesized and developed in Japan and are in clinical use there for the treatment of acute pancreatitis. However, protease inhibitors are not acknowledged as drugs for the treatment of pancreatitis in other countries. In a recent study in 30 patients with necrotizing pancreatitis, survival rate was improved (mortality rate 13.3%) by continuous intraarterial administration of low-molecular-weight protease inhibitors as compared to conventional treatment. In Italy it was reported that pancreatic disorder decreased after the administration of low-molecular-weight protease inhibitors before the start of endoscopic retrograde cholangiopancreatography. Low-molecular-weight protease inhibitors may be potential alternative drugs for the treatment and/or prevention of acute pancreatitis and, therefore, warrant further evaluation.
Development of Pancreatic Enzyme Inhibitors
Acute pancreatitis is considered to be due to autodigestion of the pancreas. If the defense mechanism of the pancreas is broken down by physical or chemical invasion, successive activation of pancreatic enzymes occurs, which causes acute pancreatitis. It was suggested that the activation of pancreatic enzymes is started by trypsin. Therefore, a trypsin inhibitor-PI in a narrow sense which suppresses the activity of trypsin would be an important drug for the radical treatment of pancreatitis. The first pancreatic PI was aprotinin, a protein with a molecular weight of 6512, extracted from bovine lungs Based on the effects of aprotinin in experimental models, clinical use was expected. Double-blind clinical trials were performed in 1960s and 1970s. Trapnell et al reported that the mortality rate was reduced by the administration of large doses of aprotinin in the early stage of acute pancreatitis, but many studies demonstrated that the mortality rate and incidence of complications caused by acute pancreatitis were not improved by intravenous administration of aprotinin. Furthermore, since there were side effects because it is a heterologous protein, aprotinin was not accepted as a drug for the treatment of pancreatitis. This led to studies on low-molecular-weight PIs, which can enter cells.
In 1972, gabexate mesilate (FOY), was developed in Japan as the first low-molecular-weight Pl. Fuji et al developed nafamostat mesilate (FUT). FUT inhibits the activities of trypsin, thrombin, plasmin, kallikrein, complements, activated coagulation factors and a2MG-trypsin complex. These drugs suppress platelet aggregation and are effective in disseminated intravascular coagulation, which is often caused by acute pancreatitis. There have been a number of studies showing that pretreatment with and simultaneous administration of these guanidino compounds are effective in suppressing pancreatitis, and these drugs are widely used as first-line treatment for pancreatitis in Japan. Because acute pancreatitis is caused by activation of the pancreatic enzymes, PIs should theoretically suppress inflammation in the pancreas. However, the clinical effects of PIs are often not so good as expected.
Protease lnhibitors(PIs) for the Prevention of Pancreatitis:
Recently, PIs have drawn attention as drugs for the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). In the early stage of acute pancreatitis, trypsinogen is activated. Because PIs inhibit the activity of the key enzyme, trypsin, they could theoretically suppress pancreatitis and/or inhibit its development before ERCP. It was reported in Japan that administration of PIs before ERCP was effective because subjective symptoms and hyperamylasemia were suppressed.
PIs as drugs for the treatment of acute pancreatitis are not used in countries other than Japan. However, improvements due to the continuous injection of PIs directly into the artery circulating in the pancreas, and the usefulness of PIs as a prophylactic for pancreatitis after ERCP have been reported. Therefore, PIs should be considered as acceptable drugs for the treatment and/or prevention of pancreatitis.
Jinhua Xiang, Sabina Wunschmann, et al
Effect of Coinfection with GB Virus C on Survival Among Patients with HIV Infection
New Eng J Med. Vol.345, Sept. 6, 2001, pg.707-14
Previous studies have suggested that people with human immunodeficiency virus (HIV) infection who are coinfected with GB virus C (GBV-C, or hepatitis G virus) have delayed progression of HIV disease. GBV-C is related to hepatitis C virus but does not appear to cause liver disease.
The effect of coinfection with GBV-C on the survival of patients with HIV infection was examined. The cultures of peripheral-blood mononuclear cells infected with both viruses to determine whether GBV-C infection alters replication in vitro were also evaluated.
Coinfection did not alter the surface expression of HIV cellular receptors on peripheral-blood mononuclear cells, as determined by flow cytometry.
GBV-C infection is common in people with HIV infection and is associated with significantly improved survival. The possible role of GBV-C infection as a treatment for HIV infection remains to be evaluated.
Hans L. Tillmann, Hans Heiken, et al
Infection with GB Virus C and Reduced Mortality Among HIV-Infected Patients
New Eng J Med. Vol.345, Sept. 6, 2001, pg.715-24
Coinfection with GBV-C is associated with a reduced mortality rate in HIV-infected patients. GBV-C is not known to cause any disease, but it is possible that its presence leads to an inhibition of HIV replication.
However, GBV-C infection could also be a marker for the presence of other factors that lead to a favorable HIV response.
Valentina Stosor and Steven Wolinsky
Editorial- GB Virus C and Mortality from HIV Infection
New Eng J Med. Vol.345, Sept. 6, 2001, pg.761-62
It was unexpected when recent reports suggested that patients who were infected with both HIV and GB virus type C (GBV-C) had a more favorable prognosis and delayed development of AIDS, as compared with HIV-infected patients who had never had GBV-C infection. GBV-C was first recovered in 1995 from an archival sample of peripheral blood obtained in the early 1960s from a surgeon with acute non-A-E hepatitis.
A closely related isolate of the same virus was originally designated hepatitis G virus, but these viruses did not appear to replicate primarily in hepatocytes or to cause acute or chronic liver disease. GBV-C is a positive-sense, single-stranded RNA virus of approximately 9400 nucleotides that belongs to the Flaviviridae family; distantly related human viruses are hepatitis C virus, yellow fever virus, and dengue virus. Transmission of GBV-C principally occurs by the parenteral route.
The etiologic role of GBV-C infection in human disease and the long-term consequences of persistent GBV-C infection have not been established. Notably, GBV-C infection does not affect the severity of chronic liver disease caused by hepatitis C virus.
Any suggestion that the intentional infection of persons with GBV-C be explored as a therapeutic approach for HIV infection is premature. Moreover, given that GBV-C frequently coexists with other pathogens, intentional infection by inoculation with peripheral blood from GBV-C was only recently discovered, and the potential long-term consequences of persistent infection, especially in persons with weakened immune systems, will not be known for some time.
Jefferson V. Proano, Ignacio Madrazo, et al
Medical Treatment for Neurocysticercosis Characterized by Giant Subarachnoid Cysts
New Eng J Med. Vol.345, Sept. 20, 2001, pg.879-85
Surgical removal of cysts has been the accepted treatment for neurocysticercosis characterized by giant cysts when there is associated intracranial hypertension.
Patients received 15 mg of albendazole per kilogram of body weight per day for four weeks. Ten patients were also treated with 100 mg of praziquantel per kilogram per day for four weeks. Seventeen patients received a second course of albendazole, three received a third course, and one received a fourth course. During the first cycle of treatment, all patients also received dexamethasone. Five patients had previously undergone neurosurgery for giant cysts.
After a median of 59 months of follow-up (range, 7 to 102), the condition of all 33 patients had improved, and the cysts had disappeared or become calcified. Of the 22 patients with a history of seizures, only 11 continued to receive antiseizure medications.
Intensive medical treatment can be effective in patients with neurocysticercosis characterized by giant cysts. Neurosurgery may be required only when there is an imminent risk of death.
Thomas H. Hostetter
Editorial: Prevention of End-Stage Renal Disease Due to Type 2 Diabetes
New Eng J Med. Vol.345, Sept. 6, 2001, pg.910-11
Three articles provide additional evidence with regard to this question. Parving and his coinvestigators administered an angiotensin-receptor blocker to patients with type 2 diabetes and hypertension who had normal glomerular filtration rates but early renal damage as manifested by low-grade proteinuria (so-called microalbuminuria).
The drug was associated with lower levels of proteinuria than the placebo. Initially, the glomerular filtration rate fell slightly, probably because of hemodynamic actions of the angiotensin-receptor blocker, but the long-term trends did not differ among the groups.
However, the diminution of proteinuria indicates protection from ongoing kidney damage that would probably translate into the preservation of the glomerular rate in the longer term. Also, the study demonstrates a satisfying dose-response effect of the angiotensin-receptor blocker.
Therefore, as compared with the other drugs, those that block the renin-angiotensin-aldosterone system probably led to greater decreases in the glomerular capillary pressure, greater reductions in the fibroproliferative actions of aldosterone and angiotensin, or both.
Testing multiple agents also increases the difficulty of identifying clear differences among them. If ACE inhibitors and angiotensin-receptor blockers are indistinguishable with respect to efficacy, as many previous data predict, decisions about which type of drug to prescribe should be based on side effects and cost.
ACE inhibitors provoke a troubling cough in 5 to 20 percent of patients; for them, the angiotensin-receptor blockers have an advantage. Whether dangerous hyperkalemia occurs more frequently with one class than the other is not known; it can occur with either class. Experience indicates that ACE inhibitors, when used with reasonable caution, are safe in this regard. The same caution applies to angiotensin-receptor blockers.
Regis Bedry, Isabelle Baudrimont, et al
Wild-Mushroom Intoxication as a Cause of Rhabdomyolysis
New Eng J Med. Vol.345, Sept. 13, 2001, pg.798-802
Most fatalities are due to amatoxin-containing species, which cause fulminant hepatocytolysis, and to cortinarius species, which lead to acute renal damage.
Since 1992, 12 cases of delayed rhabdomyolysis have occurred in France after meals that included large quantities of the edible wild mushroom Tricholoma equestre. Three of the 12 patients died.
Rhabdomyolysis is a rare but potentially fatal condition. Muscle compression is the most common cause. Experiments in animals confirmed the involvement of T. equestre in the etiology of rhabdomyolysis. Mice receiving T. equestre extract had increased creatine kinase levels, whereas those receiving P. ostreatus extract did not.
Since all extracts of T. equestre were toxic to mice, inducing increases in creatine kinase levels, the toxic compound appears to be extracted equally well by water and chloroform-methanol. It remains to be identified.
Jack E. Ansell
Air Travel and Venous Thromboembolism – Is the Evidence in ?
New Eng J Med. Vol.345, Sept. 13, 2001, pg.828-29
Although immobility leading to venous stasis may be the principal precipitating factor, there might be additional factors associated with air travel in particular that further predispose travelers to thrombosis.
These include dehydration, leading to hemoconcentration, decreased oxygen tension and ambient pressure, impairing fibrinolysis and including the activation of coagulation, increased fluid retention, causing swelling in the legs; and increased erythropoietin levels. Many of these factors are not likely to be present in persons traveling by other means, so the risk of venous thromboembolism may be greater with air travel.
Lapostolle et al have made an important contribution to the understanding of this problem by providing a yardstick for the objective quantification of the risk of pulmonary embolism during air travel.
What the authors have clearly shown is that air travel is a risk factor for pulmonary embolism and that there is a progressive and significant increase in the incidence of severe pulmonary embolism per 1 million passengers per 2500 km traveled.
The frequency of pulmonary embolism among those who traveled more than 5000 km (approximately 3100 mi) was 150 times as high as the frequency among those who traveled less than 5000 km. More than one severe pulmonary embolism occurred every other month during the seven-year period of observation.
The investigators limited their definition of case subjects to persons who had symptoms within one hour of landing; symptoms of deep venous thrombosis were not sought; and events that might have occurred hours, days, or weeks later were not tracked. Because they used symptoms as the criterion for determining the presence of pulmonary embolism, they could have missed a large number of emboli that were asymptomatic or that caused only minor symptoms.
Several studies have found that 70 to 90 percent of those in whom venous thromboembolism develops have associated risk factors such as cancer, obesity, or thrombophilic conditions (including hereditary thrombophilias such as factor V Leiden). There is also clear evidence, however, that thrombosis may develop in persons without associated risk factors. Until nonpharmacologic approaches such as leg exercises, increased water consumption, and limitation of alcohol consumption have been fully promoted, it may be premature and even dangerous to recommend aspirin or low-molecular-weight heparin to persons who are considered to be at high risk. The use of compression stockings may be helpful in preventing deep venous thrombosis, but possibly at the risk of inducing superficial venous thrombosis.
Michael S. Lauer
Aspirin for Primary Prevention of Coronary Events
New Eng J Med. Vol.346, May 9, 2002, pg.1468-74
Suggested Algorithm for Making Decisions about the Use of Aspirin for Primary Prevention of Coronary Heart Disease
Aspirin use probably reduces the risk of myocardial infarction in men over the age of 50 years. For individual patients, the decision to initiate aspirin therapy should be based on a careful assessment of absolute risk. The absolute risk of major coronary events should be calculated as the Framingham risk score.
This can easily be done in the physician’s office with the use of an on-line or downloaded version of the scoring system (for example, that available at http://www.nhlbi.nih.gov/atpiii/calculator.asp? usertype=prof). A suggested algorithm for making decisions about the use of aspirin therapy on the basis of predictions of absolute risk is presented in the figure.
Nicholas I Paton, Jamila Aboulhab, et al
Hydroxychloroquine, Hydroxycarbamide, and Didanosine As Economic Treatment for HIV-1
Lancet Vol.359, May 11, 2002, pg.1667-68
Most people who have HIV-1 and live in less-developed countries cannot afford standard combination antiretroviral therapy, and more economical approaches to treatment are therefore needed.
The authors treated 22 patients who were infected with HIV-1, with hydroxychloroquine (200 mg), hydroxycarbamide (hydroxyurea) (500 mg), and didanosine (125-200 mg), taken twice daily.
Treatment was well tolerated, with few serious adverse events. Viral load showed a sustained decrease of 1.3 log, and CD4 count was maintained (percentage increase; 2.9%) over 48 weeks in the 16 evaluable patients. This new combination of drugs could be suitable for countries that have restricted resources, but should first be further investigated.
Servier’s Dual Approach to Osteoporosis
Scrip May 17th, 2002, pg. 26
Servier’s novel osteoporosis product, Protos (strontium ranelate), has a dual action in prevention and treatment of osteoporosis. Protos stimulates bone formation (osteoblast action) and inhibits bone absorption (osteoclast action).
The sum total is increased bone density. Clinical trials have demonstrated this effect.
Adefovir Set to Shake up Hepatitis B Market
Scrip No. 2742, May 1st, 2002 Pg. 26
Gilead Sciences’ once-daily oral nucleotide analogue, adefovir dipivoxil has significant advantages over lamivudine for the treatment of hepatitis B infections.
Untreated hepatitis B leads to severe liver damage, cirrhosis and liver cancer in 1/3rd of patients. Lamivudine is very effective in treatment of hepatitis B to very low levels but resistance develops in 2 years. Adefovir is likely to be free from these disadvantages.
Early NICE Draft Rejects Glivec
Scrip No. 2736, April 10th, 2002 Pg. 5
National Institute for Clinical Excellence (NICE) has rejected the product Glivec for the treatment of myeloid leukemia.
Glivec has been approved in many countries. However, the British Society of Haematology says that to prove any improvement in survival rate with Glivec will take some time.
ReQuip Slows Parkinson’s Progression
Scrip No. 2739, April 19th, 2002 Pg. 25
GlaxoSmithKline’s dopamine agonist (D2/D3) also known as ReQuip (ropinirole) has been shown to slow down the progression of Parkinson’s disease as compared to the standard therapy.
The classical treatment of Parkinson’s disease is levodopa. There are at least 5 or 6 dopamine agonists, which are marginally or doubtfully superior to levodopa.
NICE Backs TNF-Alpha Blockers for Rheumatoid Arthritis
Scrip No. 2732, March 27th, 2002 Pg. 4
The UK National Institute for Clinical Excellence has given the NHS the go-ahead to fund two expensive treatments for rheumatoid arthritis – the anti-TNF-alpha products, infliximab (Centocor/Schering-Plough’s Remicade) and etanercept (Wyeth/Immunex’s Enbrel) – which have long been subject to postcode prescribing.
Nimesulide Suspended in Finland
Scrip No. 2732, March 27th, 2002 Pg. 19
In most countries nimesulide has not been approved because of its hepatotoxic effect. Known amongst the few countries, which approve nimesulide, Finland has banned nimesulide.
Pfizer’s Vfend Approved in EC
Scrip No. 2732, March 27th, 2002 Pg. 21
Fungal infections in immunocompromised patients due to rapid progression of infections usually leading to death.
This is particularly common with Aspergillas, Candida, Scedosporium, and Fusarium.
Fluconazole has been used until now. Pfizer’s novel antifungal voriconazole (Vfend) has been approved for the treatment of such potentially fatal fungal infections.
US Reports Link Vioxx to Meningitis
Scrip No. 2733, March 29th, 2002 Pg. 29
5 serious cases of aseptic meningitis associated with rofecoxib (Vioxx) have been reported by the FDA.
David N. Herndon, David W. Hart, et al
Reversal of Catabolism by Beta-Blockade After Severe Burns
New Eng J Med. Vol.345, Oct.25, 2001, pg.1223-9
Catecholamine-mediated hypermetabolic response to severe burns causes increased energy expenditure and muscle-protein catabolism. Authors hypothesized that blockade of b-adrenergic stimulation with propranolol would increase resting energy expenditure and muscle catabolism in patients with severe burns.
Twenty-five children with acute and severe burns (more than 40 percent of total body-surface area) were studied in a randomized trial. Thirteen received oral propranolol for at least two weeks, and 12 served as untreated controls. The dose of propranolol was adjusted to decrease the resting heart rate by 20 percent from each patient’s base-line value.
Resting energy expenditure and skeletal-muscle protein kinetics were measured before and after two weeks of beta-blockade (or no therapy, in controls). Body composition was measured serially throughout hospitalization.
The net muscle-protein balance increased by 82 percent over base-line values in the propranolol group.
In children with burns, treatment with propranolol during hospitalization attenuates hypermetabolism and reverses muscle-protein catabolism.
Christine M. Albert, Hannia Campos, et al
Blood Levels of Long-Chain n-3 Fatty Acids and the Risk of Sudden Death
New Eng J Med. Vol.346, April 11, 2002, pg.1113-8
Experimental data suggest that long-chain n-3 polyunsaturated fatty acids found in fish have antiarrhythmic properties, and a randomized trial suggested that dietary supplements of n-3 fatty acids may reduce the risk of sudden death among survivors of myocardial infarction. Whether long-chain n-3 fatty acids are also associated with the risk of sudden death in those without a history of cardiovascular disease is unknown.
The authors conducted a prospective, nested case-control analysis among apparently healthy men who were followed for up to 17 years in the Physicians’ Health Study. The fatty-acid composition of previously collected blood was analyzed by gas-liquid chromatography for 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease and for 184 controls matched with them for age and smoking status.
The n-3 fatty acids found in fish are strongly associated with a reduced risk of sudden death among men without evidence of prior cardiovascular disease.
Irwin H. Rosenberg
Fish – Food to Calm the Heart
New Eng J Med. Vol.346, April 11, 2002, pg.1102-03
By 1930, it was clear that some fatty acids not only were sources of energy (as a result of oxidation), but also were essential in the diet – thus, the term “essential fatty acids.”
The author’s focus is on long-chain n-3 fatty acids, which are characterized by the presence of a double bond three carbons from the n end of the molecule. Two such acids – docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – derived largely from marine species, especially fatty fish (salmon, bluefish, mackerel, arctic char, and sword- fish), are mainly responsible for the protective effects of this group of substances, although they can be made from shorter-chain a-linolenic acid, which is present in some vegetable oils, nuts, and seeds.
The result of the protective action of n-3 fatty acids in blood (these substances are really markers of dietary patterns, as the authors point out), but rather the effect of diet on the fatty-acid content of phospholipids in heart-cell membranes in the functionally critical SN2 position.
In the event of severe physiological stress, such as that caused by the loss of blood supply to a portion of the heart early in an ischemic attack, the DHA or EPA occupying the SN2 position in phospholipids is released and protects the heart cell locally participating in the genesis and propagation of ventricular tachycardia, which can result in cardiac arrest and sudden death.
This protective effect, which is absent if other fatty acids derived from the diet occupy the SN2 position, depends on the unique ability of these n-3 fatty acids to stabilize all contractile heart cells electrically and thus protect against sudden death from arrhythmias.
The mechanism underlying the prevention of sudden death from cardiac causes differs from that of prevention of atherosclerotic heart disease, and n-3 fatty acids play a critical part. It is both safe and prudent to eat, as recommended by the American Heart Association, at least two servings of fish per week, especially fatty fish. There are also likely to be other beneficial effects of the intake of n-3 fatty acids including those on blood triglyceride levels, the immune system, the developing central nervous system (by the transmission of fatty acids through breast milk).
Jonathan Pinkney, Gareth Williams
Commentary: Ghrelin Gets hungry
Lancet Vol. 359, April 20, 2002, Pg. 1360-61
Ghrelin also functions as blood-borne orexigenic (appetite-stimulating) signal from the gut to the brain, possibly its most exciting function. Ghrelin is expressed mainly in the stomach, by neuroendocrine cells in the fundus.
Inhibitory signals seem to include leptin, interleukin-1b, growth hormone itself, and a high-fat diet, whereas a low-protein diet leads to increased plasma concentrations of ghrelin.
What are implications of these findings? Could obesity be caused by overproduction of ghrelin, and could the disease be treated with ghrelin antagonists? Furthermore, could the hormone be used to treat cancer cachexia?