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Urea is a weak base and a organic compound with the formula CH4N2O. Urea is also called as carbamide which is white crystalline powder. It is highly soluble in water and non-toxic. Urea reacts with azo and diazo compounds to generate toxic gases, and reacts with strong reducing agents to form flammable gases. Urea should be sealed and stored in cool and dry place.
1. Uses of Urea
Urea is used as a nitrogen-release fertilizer in agriculture. In chemical industry it is a raw material for the manufacture of many important chemicals, such as: various plastics, especially the urea-formaldehyde resins; various adhesives, such as urea-formaldehyde or the urea-melamine-formaldehyde used in marine plywood ; potassium cyanate, another industrial feedstock; Urea nitrate, an explosive. And also Urea is used in topical dermatological products to promote rehydration of the skin. If covered by an occlusive dressing, 40% Urea preparations may also be used for nonsurgical debridement of nails. This Urea is also used as an earwax removal aid.
2. Physical properties about Urea

Name:Urea

EINECS:200-315-5

Molecular Formula:CH4N2O

CAS Registry Number:57-13-6 

Synonyms:Carbamide; Carbonyl diamide; Carbonyldiamine; Diaminomethanal; Diaminomethanone; Prespersion, 75 urea; Urea-13C; Ureacin-20; Urepearl;

InChI:InChI=1/CH4N2O/c2-1(3)4/h(H4,2,3,4)

HS Code:31021010

Appearance:White crystalline powder

Molecular Weight:60.05

Density:1.335

Boiling Point:196.6°C at 760mmHg

Melting Point:131-135°C

Flash Point:72.7°C

Storage Temperature:2-8°C

Refractive index:n20/D 1.40

Solubility:1080 g/L (20°C) in water

Stability:Substances to be avoided include strong oxidizing agents. Protect from moisture.

Usage:Microbiocide, fungicide.

Chemical Properties:White crystalline powder
Usage: Used for the denaturation of proteins and as a mild solubilization agent for insoluble or denatured proteins. Useful for renaturing proteins from samples already denatured with 6 M guanidine chloride such as inclusion bodies. May be used with guanidine hydrochloride and dithiothreitrol (DTT) in the refolding of denatured proteins into their native or active form.
General Description:Solid odorless white crystals or pellets. Density 1.335 g /cc. Noncombustible.
Air & Water Reactions: Water soluble.
Reactivity Profile :Urea is a weak base. Reacts with hypochlorites to form nitrogen trichloride which explodes spontaneously in air . Same is true for phosphorus pentachloride. Urea reacts with azo and diazo compounds to generate toxic gases. Reacts with strong reducing agents to form flammable gases (hydrogen). The heating of improper stoichiometric amounts of Urea and sodium nitrite lead to an explosion. Heated mixtures of oxalic acid and Urea yielded rapid evolution of gases, carbon dioxide, carbon monoxide and ammonia (if hot, can be explosive). Titanium tetrachloride and Urea slowly formed a complex during 6 weeks at 80°C., decomposed violently at 90°C. Urea ignites spontaneously on stirring with nitrosyl perchlorate, (due to the formation of the diazonium perchlorate). Oxalic acid and Urea react at high temperatures to form toxic and flammable ammonia and carbon monoxide gasses, and inert CO2 gas .
Health Hazard: May irritate eyes.
Fire Hazard: Behavior in Fire: Melts and decomposes, generating ammonia.
3. Safety of Urea
When you are using Urea, please be cautious about it: Urea is irritating to eyes, respiratory system and skin. And limited evidence of a carcinogenic effect. In case of contact with eyes, you should rinse immediately with plenty of water and seek medical advice. Moreover, you should wear suitable protective clothing to avoid contact Urea with skin and eyes.

 

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Levetiracetam is used in combination with other medications to treat certain types of seizures in people with epilepsy. Levetiracetam is in a class of medications called anticonvulsants. It works by decreasing abnormal excitement in the brain.

Levetiracetam(CAS.NO:102767-28-2) is used to help control certain types of seizures in the treatment of epilepsy. This medicine cannot cure epilepsy and will only work to control seizures for as long as you continue to use it.

1. Medical uses

Levetiracetam has been approved in the European Union as a monotherapy treatment for epilepsy in the case of partial seizures, or as an adjunctive therapy for partial, myoclonic and tonic-clonic seizures. It is also used in veterinary medicine for similar purposes.
Levetiracetam has potential benefits for other psychiatric and neurologic conditions such as Tourette syndrome, autism, bipolar disorder and anxiety disorder, as well as Alzheimer’s disease.However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.

Along with other anticonvulsants like gabapentin, it is also sometimes used to treat neuropathic pain. It has not been found to be useful for essential tremors.

2. Mechanism of action
The exact mechanism by which levetiracetam acts to treat epilepsy is unknown. However, the drug binds to a synaptic vesicle glycoprotein, SV2A, and inhibits presynaptic calcium channels. This is believed to impede impulse conduction across synapses.
3. Adverse effects
Levetiracetam is generally well tolerated, but may cause drowsiness, weakness, unsteady gait, fatigue, coordination problems, headache, pain, forgetfulness, anxiety, irritability or agitation, dizziness, mood changes, nervousness, loss of appetite, vomiting, diarrhea, throat pain, constipation, and changes in skin pigmentation.
Serious side effects may include depression, hallucinations, suicidal thoughts, seizures that are worse or different, fever, sore throat, signs of infection, double vision, itching, rash, swelling of the face. A study published in 2005 suggests that the addition of pyridoxine (vitamin B6) may curtail some of the psychiatric symptoms.
A rare side effect of levetiracitam is a pins and needles sensation in the patient’s legs, similar to neuropathy.
4. Storage and Disposal 
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

 

Cisplatin  is a chemotherapy drug. It was the first member of a class of platinum-containing anti-cancer drugs, which now also includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to and causing crosslinking of DNA, which ultimately triggers apoptosis (programmed cell death).

Cisplatin(CAS.NO:15663-27-1) can cause severe kidney problems or allergic reactions. Hearing problems (more common in children), bone marrow suppression, or severe nausea and vomiting may also occur. The risk of these problems increases as the dose or total amount of cisplatin used over time increases. Notify your doctor immediately if you develop changes in the amount of urine, rash, trouble breathing, swelling of the face, fast heartbeat, dizziness, ringing in the ears or hearing loss, unusual bruising or bleeding, nausea and vomiting, unusual tiredness, or signs of an infection (eg, fever, persistent sore throat).

Possible side effects:

Each person’s reaction to chemotherapy is different. Some people have very few side effects while others may experience more. The side effects described here won’t affect everyone who has cisplatin and may be different if you’re having more than one type of chemotherapy drug.

We have outlined the most common side effects but haven’t included those that are rare and unlikely to affect you. If you notice any effects that are not listed below, discuss them with your doctor or nurse.
Feeling sick (nausea) and being sick (vomiting)

This may begin soon after the treatment is given and can last for a few days. Your doctor can prescribe very effective anti-sickness (anti-emetic) drugs to prevent or greatly reduce nausea and vomiting. If the sickness isn’t controlled, or if it continues, tell your doctor; they can prescribe other anti-sickness drugs that may be more effective.

Some anti-sickness drugs can cause constipation. Let your doctor or nurse know if this is a problem.

Your kidneys may be affected

This doesn’t usually cause any symptoms, and the effect is generally mild. Rarely, cisplatin may cause permanent damage to the kidneys unless treatment with it is stopped.

Before each treatment, your kidneys will be checked with a blood test. You’ll be given fluid through a drip (infusion) before and after the treatment to keep your kidneys working normally. You may be asked to measure and record what you drink and the amount of urine you pass. It’s important to tell your nurse or doctor if you pass less urine than usual.

If necessary, you may be given medicine to help you pass urine. You may be asked to drink extra fluid before and after treatment. It’s important to do this so let your doctor know if this is a problem – for example, if you’re feeling sick.

Numbness or tingling in hands or feet

This is due to the effect cisplatin has on nerves and is known as peripheral neuropathy. You may also notice that you have difficulty doing up buttons or with similar fiddly tasks.

Tell your doctor if you notice any numbness or tingling in your hands or feet. It’s important to report your symptoms to your doctor as they may be controlled by slightly lowering the dose of the drug.

This side effect usually improves slowly for a few months after the treatment has finished. Sometimes symptoms can persist, talk to your doctor if this happens.

Changes in hearing

You may have ringing in the ears (tinnitus), and you may lose the ability to hear some high-pitched sounds. Hearing loss can be more severe with higher doses and longer courses of treatment. Very occasionally, your sense of balance may be affected.

Any hearing loss and balance changes, if they occur, may be permanent. However, tinnitus usually improves when treatment ends. Tell your doctor if you notice any loss of hearing or tinnitus.

Taste changes

You may notice that food tastes different. Normal taste usually comes back after treatment finishes. A dietitian or specialist nurse at your hospital can give you advice about ways of coping with this side effect.
Luteolin is a biological substance, generally found in plant tissues that are yellow-green in color. It is one specific member of the much broader category of plant compounds known as flavanoids, whose properties are of interest to science and medicine. It occurs naturally in a variety of foods, and a much broader array of herbs and plants which are edible but rarely consumed. Some scientific studies have attributed a number of health benefits to the consumption of luteolin, specifically, and the entire category of flavanoids more generally. Research on the possible health benefits of these substances is still ongoing, and not yet conclusive, but luteolin supplements are available on the market.

Luteolin has been studied in several preliminary in vitro scientific investigations. Proposed activities include antioxidant activity (ie. scavenging of free radicals), promotion of carbohydrate metabolism, and immune system modulation. Other in vitro studies suggest luteolin has anti-inflammatory activity, and that it acts as a monoamine transporter activator, a phosphodiesterase inhibitor, and an interleukin 6 inhibitor. In vivo studies show luteolin affects xylazine/ketamine-induced anesthesia in mice. In vitro and in vivo experiments also suggest luteolin may inhibit the development of skin cancer. Importantly, the therapeutic value of the above findings is unclear, and will remain so until further detailed in vivo, toxicity, and clinical studies are performed.

Luteolin is an active inhibitor of different hyaluronidases, which modify hyaluronic acid . Hyaluronic acid, a heteropolysaccharide, is one the polymers that accounts for the toughness and flexibility of cartilage and tendon.

Luteolin exhibits spasmolytic effects: Luteolin significantly antagonized acetylcholine- and histamine-induced contraction of smooth muscle in the guinea pig model of modified air overflow , and showed strong anti-histamine properties.

Luteolin displays anti-leishmanial activity.

Luteolin displays strong antinociceptive (against pain originating from peripheral nerves) action in mice . This is in accordance with the fact that Luteolin is an active principle of Brazilian plant Wedelia paludosa, traditionally used against the variety of disorders, including painful conditions.
Ramipril  an angiotensin-converting enzyme inhibitor used in treatment of hypertension and congestive heart failure and the prevention of a major cardiovascular event in high-risk patients.

Ramipril blocks ACE from converting angiotensin I to angiotensin II, a powerful vasoconstrictor, leading to decreased blood pressure, decreased aldosterone secretion, a small increase in serum potassium levels, and sodium and fluid loss; increased prostaglandin synthesis also may be involved in the antihypertensive action.

1. History

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor, used to treat high blood pressure and congestive heart failure. It is marketed as Prilace by Arrow Pharmaceuticals in Australia, Ramipro by Westfield Pharma in the Philippines, Tritace by Sanofi-Aventis in Italy and United States and Altace by King Pharmaceuticals in the United States, Ramitens by PharmaSwiss, Ampril by Krka in Slovenia, Corpril by Cemelog-BRS in Hungary, Piramil and Prilinda by Hemofarm in Serbia, by Lek in Poland and by Novartis and Opsonin Pharma Limited as Ramace in Bangladesh, and in Canada as Altace (Sonfi) and Ramipril (Pharmascience).

2. Medical uses

Indications for its use include:

*Hypertension;

*Congestive heart failure;

*Following heart attack in patients with clinical evidence of heart failure;

*Susceptible patients over 55 years: prevention of heart attack, stroke, cardiovascular death or need of revascularization procedures.

*Diabetic nephropathy (kidney damage due to diabetes) with microalbuminuria (protein in the urine)

3. Side effect

As with any medicine, there are possible side effects with ramipril. Not everyone who takes the drug will experience side effects. When side effects do occur, in most cases they are minor and either require no treatment or can easily be treated by your doctor.

Common ramipril side effects include, but are not limited to:

*low blood sugar (in patients taking medication for diabetes), causing sweating or shakiness

*dry cough

*dizziness and light-headedness due to low blood pressure

*tiredness and fatigue, especially in the early stages

*mouth dryness in the early stages

*nausea, vomiting, diarrhea (persistent in rare cases)

*fainting

*change in amount of urine

*signs of infection (e.g., fever, chills, persistent sore throat)

*yellowing of eyes or skin, dark urine

*stomach or abdominal pain

*neutropenia (low white blood cells)

*impotence (erectile dysfunction)

*Serious allergic reactions to this drug are unlikely, but immediate medical attention must be sought if they occur. Symptoms of a serious allergic reaction include, but are not limited to a rash or swelling of the face, mouth, tongue, or throat.

*In extreme cases, ramipril may lead to potentially fatal liver problems.

Neomycin sulfate , its cas register number is 1405-10-3. It also can be called Mycifradin sulfate; O-2,6-diamino-2,6-dideoxy-.beta.-L-idopyranosyl-(1.->3)-O-.beta.-D-ribofuranosyl-(1->5)]-O-[2,6-diamino-2,6-dideoxy-.alpha.-D-glucopyranosyl-(1->4)]-2-deoxy sulfate .

1. Chemical Properties

Name:Neomycin sulfate

EINECS:215-773-1

Molecular Formula:C23H46N6O13.3(H2SO4)

CAS Registry Number:1405-10-3

Appearance:Tan powder

Molecular Weight:908.87

Boiling Point:1046.1°C at 760 mmHg

Flash Point:586.5°C

Storage Temperature:2-8°C

Refractive index:56 ° (C=10, H2O)

Solubility:500 g/L (20 C)

Stability:Stable. Incompatible with strong oxidizing agents

Usage:Antibacterial

H-Bond Donor: 19

H-Bond Acceptor: 31

2. Safety Profile

Poison by intramuscular, intravenous, and subcutaneous routes. Human systemic effects by ingestion: somnolence, hallucinations and distorted perceptions, and anorexia. A human skin irritant. When heated to decomposition it emits very toxic fumes of SOx.

3. First aid measures

1)General advice

Consult a physician. Show this safety data sheet to the doctor in attendance.

2)If inhaled

If breathed in, move person into fresh air. If not breathing give artificial respiration Consult a physician.

3)In case of skin contact

Wash off with soap and plenty of water. Consult a physician.

4)In case of eye contact

Rinse thoroughly with plenty of water for at least 15 minutes and consult a physician.

5)If swallowed

Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a physician.

4. Handling and Storage 

1)Precautions for safe handling

Avoid formation of dust and aerosols.

Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.

2)Conditions for safe storage

Store in cool place. Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2 – 8 °C

5. Personal protective equipment 

1)Respiratory protection

Where risk assessment shows air-purifying respirators are appropriate use a dust mask type N95 (US) or type P1 (EN 143) respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

2)Hand protection

The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and the standard EN 374 derived from it. Handle with gloves.
3)Eye protection

Face shield and safety glasses

4)Skin and body protection

Choose body protection according to the amount and concentration of the dangerous substance at the work place.

5)Hygiene measures

Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is (as of 2007) approved for this use in the European Union and Russia. It was designed as a more potent successor to gabapentin. Pregabalin is marketed by Pfizer under the trade name Lyrica. Pfizer described in an SEC filing that the drug could be used to treat epilepsy, post-herpetic neuralgia, diabetic peripheral neuropathy and fibromyalgia.

Gabapentin is a pharmaceutical drug, specifically a GABA analog. It was originally developed to treat epilepsy, and currently is also used to relieve neuropathic pain.

Pregabalin(CAS.NO:148553-50-8) is used to relieve neuropathic pain (pain from damaged nerves) that can occur in your arms, hands, fingers, legs, feet, or toes if you have diabetes or in the area of your rash if you have had shingles (a painful rash that occurs after infection with herpes zoster). It is also used to treat fibromyalgia (a long-lasting condition that may cause pain, muscle stiffness and tenderness, tiredness, and difficulty falling asleep or staying asleep). Pregabalin is used with other medications to treat certain types of seizures in people with epilepsy. Pregabalin is in a class of medications called anticonvulsants. It works by decreasing the number of pain signals that are sent out by damaged nerves in the body.

Pregabalin, like gabapentin, is an amino acid derivative of gamma-amino butyric acid (GABA analogue). Pregabalin is the pharmacologically active S-enantiomer of 3-aminomethyl-5-methyl-hexanoic acid, and has a similar pharmacological profile to gabapentin. These agents are part of a unique class that have a high affinity to the alpha-2-delta protein in the CNS. Both agents have been shown to be effective for neuropathic pain disorders, however, only prebabalin has been FDA approved for both the management of diabetic peripheral neuropathy and post herpetic neuralgia.

Gabapentin and pregabalin are structurally related compounds with recognized efficacy in the treatment of both epilepsy and neuropathic pain. The pharmacological mechanisms by which these agents exert their clinical effects have, until recently, remained unclear. The interaction of gabapentin and pregabalin with conventional antiepileptic and analgesic drug targets is likely to be modest, at best, and has been largely dismissed in favour of a selective inhibitory effect on voltage-gated calcium channels containing the α2δ-1 subunit. This mechanism is consistently observed in both rodent- and human-based experimental paradigms and may be sufficiently robust to account for much of the clinical activity of these compounds.

Pregabalin has been shown in studies to provide equivalent efficacy to gabapentin, however, at much lower doses. Because lower dosages can be used to treat neuropathic pain, it is likely that pregabalin will be associated with fewer dose-related adverse events. Part of the reason why pregabalin requires lower dosages is that it has a much higher bioavailability (90% versus 33-66%) and is rapidly absorbed (peak: 1 hr). Also, plasma concentrations increase linearly with increasing dose.This is not true with gabapentin. Gabapentin is slowly absorbed (peak: 3 to 4 hours post-dose) and more importantly, plasma concentrations have been found to have a non-linear relationship to increasing doses. Pregabalin has been found to have distinct pharmacokinetic advantages over gabapentin.

Pregabalin has shown greater potency than gabapentin in pain and seizure disorders.J. Fehrenbacher et al stated that pregabalin has been shown to have greater analgesic activity in rodent models of neuropathic pain.Further, D. Wesche et al noted that pregabalin is approximately 2.5 times more potent than gabapentin based on plasma concentrations.

Gabapentin and pregabalin are efficacious treatments for neuropathic and postsurgical pain. Future research addressing several specific questions would serve to better delineate their optimal roles in treating these and other pain conditions.

Rifampicin , its cas register number is 13292-46-1. It also can be called Rifampin ; Rimactane ; Rifadin ; Rimactan ; and 3-[[(4-methyl-1-piperazinyl)imino]methyl]-rifamycin . It is a bactericidal antibiotic drug of the rifamycin group, and is a semisynthetic compound derived from Amycolatopsis rifamycinica. There are various types of rifamycins from which this is derived, but this particular form is by far the most clinically effective. It inhibits DNA-dependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA and subsequent translation to proteins.

1. History

In 1957, a sample of soil coming from a pine wood on the French Riviera was brought for analysis to the Lepetit Pharmaceuticals research lab in Milan, Italy. There, a research group headed by Prof. Piero Sensi (1920-) discovered a new bacterium. This new species appeared immediately of great scientific interest since it was producing a new class of molecules with antibiotic activity. Rifampicin was introduced in 1967, as a major addition to the cocktail-drug treatment of tuberculosis and inactive meningitis, along with isoniazid, ethambutol, pyrazinamide and streptomycin. Because Prof. Sensi and some of his fellow researchers were particularly fond of the French crime story Rififi (about a jewel heist and rival gangs), they decided to call these compounds “Rifamycins”. After two years of attempts in order to obtain more stable semi-synthetic products, in 1959 a new molecule with high efficacy and good tolerability was produced and was named “Rifampicin”.

2. Chemical Information

Name:Rifampicin

Molecular Formula:C43H58N4O12

CAS Registry Number:13292-46-1

Appearance:Red to orange crystalline solid

Molecular Weight:822.95

Density:1.34 g/cm3

Boiling Point:1004.42 °C at 760 mmHg

Melting Point:183°C (dec.)

Flash Point:561.253 °C

Storage Temperature:2-8°C

3. Application

Rifampicin is used to treat tuberculosis and infections, and should be used in combination with other antibiotics. In combination with fusidic acid, it is used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection.

4. Mechanism of action

Binding of rifampicin in the active site of RNA polymerase. Mutation of amino acids shown in red are involved in resistance to the antibiotic.

Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.

Crystal structure data and biochemical data indicate that rifampicin binds to RNA polymerase at a site adjacent to the RNA polymerase active center and blocks RNA synthesis by physically preventing extension of RNA products beyond a length of 2-3 nucleotides (“steric-occlusion” mechanism).

Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin.Resistant mutations map to the rpoB gene, encoding RNA polymerase beta subunit.

Butylated hydroxytoluene (BHT), also known as butylhydroxytoluene, is a lipophilic organic compound, chemically a derivative of phenol, that is useful for its antioxidant properties. European and U.S. regulations allow small percentages to be used as a food additive. While there may be some dispute in BHT’s use in the human diet, the chemical is widely used in industry wherever oxidation in fluids (e.g. fuel, oil) and other materials must be treated, and free radicals must be kept in check.

1. Applications

Butylated hydroxytoluene is primarily used as a food additive that exploits its antioxidant properties. It is approved for use in European Union under E321 and in the U.S. by the Food and Drug Administration via regulation.

Antioxidant BHT is also documented as an antioxidant additive in such diverse products as cosmetics, pharmaceuticals, rubber, electrical transformer oil (at 0.35%), and embalming fluid. In the petroleum industry, where BHT is known as the fuel additive AO-29, it also finds uses in hydraulic fluids, turbine and gear oils, and jet fuels, among other applications. BHT is also used to prevent peroxide formation in diethyl ether and other laboratory chemicals.

Some additive products contain BHT as their primary ingredient, while others contain the chemical merely as a component of their formulation, sometimes alongside butylated hydroxyanisole (BHA).

2. How does it work?

BHT is an antioxidant. It may damage the protective outer layer of viral cells. This may keep the viruses from multiplying and/or doing more damage.

3. Reactions

The species behaves as a synthetic analogue of vitamin E, primarily acting as a terminating agent that suppresses autoxidation, a process whereby unsaturated (usually) organic compounds are attacked by atmospheric oxygen. BHT stops this autocatalytic reaction by converting peroxy radicals to hydroperoxides. It affects this function by donating a hydrogen atom:

RO2. + ArOH → ROOH + ArO.

RO2. + ArO. → nonradical products

where R is alkyl or aryl, and where ArOH is BHT or related phenolic antioxidants. Each BHT consumes two peroxy radicals.

4. Safety

Antioxidant BHT is safe in the amounts found in processed foods. But there isn’t enough information to know if it is safe to take BHT in medicinal doses, which are typically higher. There also isn’t enough information to know whether BHT can be safely used on the skin.

BHT is safe when eaten as food, but there’s not enough information to know if it’s safe in the larger amounts that are used as medicine. If you are pregnant or breast-feeding, stick with food amounts until more is known.

1.Introduction

Stroke is the second leading cause of death in the world and of disability in developed countries. In North America, 550 000 new strokes occur each year and there are approximately five million people who have had a stroke, 60% of whom have some residual disability.  Stroke is also responsible for a substantial proportion of deaths and disability in developing countries.Strokes can be prevented by lowering blood pressure in people with hypertension and by the use of antiplatelet agents in people with vascular disease.  Although a person’s risk of stroke increases with blood pressure, the population attributable risk of stroke is greatest at pressures that would not currently be treated with drugs.9 We therefore need additional strategies that lower the risk of stroke across a broad range of patients at high risk.

Angiotensin converting enzyme inhibitors have been shown to block the activation of the renin-angiotensin system in the plasma as well as in the vascular wall. Recent experimental and human data suggest that angiotensin converting enzyme inhibitors reduce proliferation of vascular smooth muscle; enhance endogenous fibrinolysis; have the potential to stabilise plaques; and decrease angiotensin II mediated atherosclerosis, plaque rupture, and vascular occlusion. Angiotensin converting enzyme inhibitors therefore have the potential to lower the risk of ischaemic vascular events, including strokes, through mechanisms that are independent of lowering blood pressure.

We provide a detailed analysis of the impact of ramipril, an angiotensin converting enzyme inhibitor, on stroke, its subtypes, and the related disability and report the effects in various subgroups of patients in the heart outcomes prevention evaluation (HOPE) study.

2. Design and methods

The HOPE study was a double blind randomised trial with a two by two factorial design, in which participants were randomised to receive up to 10 mg of ramipril, 400 IU of vitamin E, both, or matching placebos. We provide a brief outline here.

3.Participants

Participants were aged 55 or over and were at high risk of cardiovascular events because of previous coronary artery disease, cerebrovascular disease, or peripheral arterial disease or diabetes plus one additional risk factor. Patients were excluded if they were taking either an angiotensin converting enzyme inhibitor or vitamin E; had heart failure or a known left ventricular ejection fraction of less than 0.40, known proteinuria, or uncontrolled hypertension; or had had a previous stroke or a myocardial infarction less than one month before enrolment in the study. Informed consent was obtained from all participants before enrolment in the study, and the study was approved by the ethics committee at each centre.

4.Intervention

Eligible patients entered a run-in phase in which they received 2.5 mg ramipril daily for 7-10 days, after which serum creatinine and potassium levels were measured. Participants then started a 10-14 day course of placebo. Those who tolerated and adhered to this regimen were then randomised to receive either placebo or 2.5 mg ramipril daily for one week, followed by placebo or 5.0 mg ramipril for a further three weeks. One month after randomisation the patient’s serum creatinine and potassium were measured; if these were satisfactory the patient continued on either placebo or 10 mg ramipril for the remainder of the study. Participants were seen after six months and then every six months until the end of the study, with an average follow up of 4.5 years.

Of the 10 576 patients who entered the run-in phase, 1035 were not randomised because of non-adherence, side effects, or withdrawal of consent; 244 patients were entered into a substudy of 2.5 mg ramipril and are not included in this paper. Outcome results were available on 9539 (99.9%) of the 9541 patients randomised. The first participant was recruited in December 1993. The originally scheduled completion date was November 1999, but the ramipril arm of the study was terminated early (April 1999) because of clear benefit.

5.Outcome measures

The primary outcome was the composite end point of myocardial infarction, stroke, or cardiovascular death.12 The individual components of this composite end point were analysed separately. All outcomes were adjudicated by a central committee. This analysis focuses on stroke.

Investigators reported the occurrences of stroke or transient ischaemic attack at follow up visits. For every stroke reported, information on the stroke, including symptoms and functional impairment, was documented. The investigators used a simple six point scale to record if there was full recovery, persistent symptoms, some functional impairment, functional impairment necessitating the assistance of others to perform activities of daily living, or inability to perform activities of daily living even with help at seven days or at discharge if earlier. Discharge summaries, consultation notes, and results of computed tomography or magnetic resonance imaging were documented. A central committee adjudicated all strokes on the basis of predetermined definitions. Classification of a stroke as either ischaemic or haemorrhagic was confirmed by computed tomography or magnetic resonance imaging within 14 days of onset or by autopsy. All other strokes were classified as being of uncertain aetiology. Computed tomography, magnetic resonance imaging, or autopsy results were obtained for 84% of strokes.

Blood pressure was measured at entry to the study, after two years, and at the end of the study. Two measurements were taken on each arm after the patient had been supine for five minutes. The lowest measurements on each arm were averaged to obtain the systolic and diastolic values that were recorded.

6.Statistical analysis

The study had 90% power to detect a 13.5% reduction in relative risk for the primary outcome, with an annual event rate of 4% in 9000 patients studied for five years. Assuming a stroke rate of 1.2% per year in the control group for five years, the study had 80% power to detect a 22.0% reduction in the relative risk of stroke with a two sided Embedded Imagelevel of 0.05 in an intention to treat analysis. We estimated survival curves according to the Kaplan-Meier procedure and compared treatments by using the log rank test.13 Because of the factorial design, we stratified all analyses for the randomisation to vitamin E or placebo. We conducted subgroup analyses by using tests for interactions in the Cox regression model. We used this model to estimate the reduction in relative risk and the 95% confidence intervals associated with ramipril treatment in unadjusted analyses and after controlling for changes in blood pressure.

The data and safety monitoring board monitored the study. Monitoring boundaries for the study were four standard deviations between the two groups in terms of benefit of ramipril in the first half of the study and three standard deviations in the second half. For harm, the boundaries were three standard deviations in the first half of the study and two standard deviations in the second half. Because of clear benefit, the study was terminated on 22 March 1999.

7. Study organisation

The study was conducted in 267 hospital clinics in 19 countries. It was coordinated by the Canadian Cardiovascular Collaboration in Hamilton, Canada.

8.Results

Reduction in blood pressure was modest (3.8 mm Hg systolic and 2.8 mm Hg diastolic). The relative risk of any stroke was reduced by 32% (156 v 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61% (17 v 44). Benefits were consistent across baseline blood pressures, drugs used, and subgroups defined by the presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes, or hypertension. Significantly fewer patients on ramipril had cognitive or functional impairment.

9.Conclusion

Ramipril reduces the incidence of stroke in patients at high risk, despite a modest reduction in blood pressure.