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Erectile dysfunction is a stumbling block for all couples in the world. It troubles partners unexpectedly and ruins their relations. Men become silent and try to avoid spending time in their women’s company. Women start thinking that something is wrong with their appearance and that men cannot erect because they are not attractive anymore. Cialis is a drug that can make men’s intimate relations not so complicated. Tadalafil brings back erection back to the norm and women start feeling pretty and desired again.

Cialis Can Be Different

It’s a well-known fact that there are two types of drugs according to their origin: brand and generic ones. Many people think that they differ much. They think that only brand-name medicines can produce the best effect and cope with the problem. The truth is that generics are mere analogs. They have the same composition and can treat the same health disorders.

So, what’s the difference? Why does this distinctive feature make people think that brand-name drugs are better than generics? The matter is in their price. Generics are cheaper but a cheap thing doesn’t always mean a bad thing. The research shows that contemporary pharmaceutical companies spend huge sums on research to have the right to sell solid drugs with an excellent reputation. Generics take the formula and rename the medicine. They economize on international fame but reserve the quality. So, there is no need to pay more to get the desired results.

Generic variants of Tadalafil are also of high-quality. They differ in strength, shape, and form. There are six main analogs of Cialis.

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Cialis Soft Tabs

These tablets have a strong effect and improve men’s health. Erectile dysfunction is a delicate problem and it requires a soft solution. Cialis Soft Tabs produce such an effect and help to gain a natural erection.

Generic Cialis

The generic variant of the brand doesn’t differ from the original. Its price is lower and when buying a blister that contains more than 100 pills, a person can save a solid sum.

Female Cialis

This is the only drug variant that can be taken by females. Scientists have found out that women can also lack sexual desire after menopause, childbirth, and surgery. Female Cialis brings back sensitivity of the clitoris. It leads to better lubrication and a woman feels pleasure instead of irritation and burning provoked by the dryness.

Cialis Black 800

Cialis Black 800 is not to be taken by males who have first signs of impotence. Only patients who have serious problems with erection and even neglected impotence take Black Cialis. Doctors prescribe these pills to those who also lack libido and stamina. One pill contains 80mg of the active component. It means that they are strong but can cause severe adverse effects in case of improper intake.

Cialis Professional

Men with impotence need professional help. Cialis Professional has an improved formula. Their aim is to find the reason, delete it and let a person experience a stable erection that promises satisfaction in bed for both partners.

Cialis Super Active+

If a person needs to raise the level of testosterone, improve erection, get rid of premature ejaculation, and experience sexual arousal, then it’s high time to take Cialis Super Active+. Compared to other generic variants, this type starts working in 5-7 minutes. That’s their PLUS.

Where to Get Pills?

Online pharmacies can supply people with the generic every man needs. The online drugstore offers high-quality products, discounts, and bonuses for regular customers and quick service to let everyone get the drugs as soon as possible.

List of verified online pharmacies:

• canadapharmacy.com
• canadadrugsdirect.com
• northwestpharmacy.com
• costco.com
• cvs.pharmacy
• pillpack.com

Erectile dysfunction treatment course usually depends on the severity of the case and the underlying conditions and causes. According to recent statistics, about 50% of men aged between 40 and 70 suffer from some degree of ED. This information may sound terrible to younger men, but good news is that only each 10th is fully unable to reach and maintain erections. ED therapy usually implies taking drugs, although there are a few other methods: from lifestyle changes to surgeries. In this article we are going to consider ED therapy with medications.

Does ED therapy depend of its causes?

It is strongly recommended to consult your physician and pass a few laboratory tests to help identify the reason of ED. There are 5 major health problems that frequently are to blame for erectile dysfunction symptoms. In this article by My Canadian Pharmacy you can learn more about them. In some cases, the erection problems can be caused not by a disease itself, but by medications for its treatment. Important: never interrupt a prescribed treatment course without informing your doctor, even if you found symptoms of ED caused by this drug. A qualified healthcare specialist can offer alternatives or change your treatment plan.

To resume: before choosing tablets for ED treatment (or along with choosing them), healthcare providers recommend health screening for ED causes. In case you take antidepressants or other drugs that may cause troubles with having erection, visit your doctor for a competent advice on drug interaction and necessary therapy adjustments.

Which drug to choose for erectile dysfunction?

The group of medications used for ED treatment is called Phosphodiesterase-5 (PDE-5) inhibitors. They are used worldwide, are very effective and have few side effects. PDE-5 inhibitors work by increasing the blood flow to genitals during arousement. This type of drugs does not work without sexual stimulation.

The most important generic names for PDE5 inhibitors for erectile dysfunction treatment are:

• sildenafil – usually known under the brand name Viagra
• tadalafil – known under the brand name Cialis
• vardenafil – known under the brand name Levitra
• avanafil – known under the brand name Spedra

What is the difference between the abovementioned 4 drugs for erectile dysfunction treatment? Healthcare specialists say that for new patients it requires trying different ones to evaluate their effect.

The first option usually prescribed by the doctor is Sildenafil (Viagra). This medication has longest been on the market; a lot of research is carried out to study the side effects and interactions of Sildenafil. Patients suffering from side effects of Viagra, are usually prescribed Avanafil (Stendra).

Sildenafil, Vardenafil and Avanafil show effectiveness the next 8 hours after administration, while the action of Tadalafil is much longer – patients report about 36 hours. This feature of Tadalafil is the reason why it is also known under the name “weekend pill”.

Depending on the active ingredient of the pill and the dose, it should be administered about 30-60 minutes before the planned intercourse.

Taking an ED medication after a substantial meal may increase the time of absorption, so it may take longer to notice the effect. The most important rule of ED treatment with PDE5 inhibitors is 1 pill per 24 hours.

Which ED medication is best?

Each of abovementioned drugs has its own benefits and disadvantages and its own mechanism of action. The choice should be entrusted to the healthcare provider. The doctor takes this decision, considering you overall sexual activity and previous experience with ED treatment drugs.

Viagra, Levitra, Cialis and Stendra are effective in more than 70% of cases. Lack of effect may happen due to individual insensitivity or due to one of the following reasons:

• the medication hasn’t started working, i.e. you just haven’t waited long enough;
• the medication has already stopped working (the dosage was taken more than 8 hours ago for Viagra and Levitra and more than 36 hours ago for Cialis);
• your case requires a higher dosage;
• it is necessary to have more sexual stimulation for you to get an erection even with the help of medications.

Nevertheless, the main challenge to obtaining the best ED drug may depend on health insurance or costs. Shopping at local pharmacies may be very expensive, the price for ED medications can be as high as $15-20 per pill.

To be able to hit limits and afford really working medications, you may look for a trusted online pharmacy to shop generic medications for erectile dysfunction treatment.

Side effects and precautions

• PDE5 inhibitors have relatively few side effect, but they do have some, and patients diagnosed with ED should be aware of them.
• Tell your doctor, if you have any cardiovascular disease, even suspected. Discuss risks and benefits of regular sexual activity with you GP.
• Peyronie’s disease, any risk or priapism (painful long-lasting erection), taking alpha-blockers – are also a reason to consult your doctor before taking ED medications.

Important: PDE5 inhibitors should not be combined with drugs containing nitrates (also known as “poppers”, often used for heart diseases treatment.) This combination may put your health at risk.

Contraindications to PDE5 inhibitors intake:

1. Low blood pressure;
2. Strokes in the past;
3. Non-arteritic anterior ischaemic optic neuropathy;
4. In case you suffer from unstable angina or are prone to heart attack;

The most common side effects from taking Viagra, Cialis, Levitra or their generics are:

• Headaches (from mild to severe);
• Increased blood flow to the face (flushing);
• Stuffy nose;
• Nausea and vomiting;
• Vision disturbances;
• Muscle and joint pain.

However, the side effects are slightly different for each drug. Muscle and joint pain side effect is more common for Cialis than for other medications from the list. Levitra and Viagra are more likely to provoke temporary blue-tinged or disturbed vision.

Common mistake in taking ED medications

There are many patients who report about poor effect of ED drugs or claim they don’t work at all. In some cases, this may happen due to improper use of the medication. The most widespread misconception is that ED drugs work as an on/off button for erections. Of course, they don’t and don’t have to. Sexual stimulation and some foreplay are required. And this makes ED medications safe as the erection is achieved when necessary and customers are not likely to get in awkward situations.

How to cut the costs of ED treatment?

The costs per pill may significantly vary from state to state. They also depend on the dosage, packaging and other aspects. It is well-known that the price for branded Viagra, Levitra and Cialis is much higher than for generics, which can be of excellent quality when purchased at a trusted online-pharmacy.

Here are a few more tips:

• Shop for future use: larger packages allow saving up to 40%!
• Ask your doctor, if it is possible to split pills: you may save on buying higher dose and split the pills.
• Learn more about special offers and promotion of the pharmacy you shop at.
• Compare the prices at online pharmacies and pay attention to delivery terms: some online pharmacies offer free shipping for orders from 50-100 dollars.

How to improve the effect from ED medications?

Here are a few tips of how to help ED pills work better and to improve your health and decrease ED symptoms:

1. Lose weight in case you are overweight. Healthy diet and limiting of fatty foods helps to improve the cardiovascular health and protect blood vessels from clogging – all that leads to better and stronger erections.
2. Give up smoking. Smoking is associated with impaired blood flow due to increased blood viscosity, poor vessel elasticity and, as a result, weak erections.
3. Cut back your alcohol consumption. Most of the ED treatment pills don’t make a good combination with alcohol. Research say that excessive consumption of alcohol leads to decreased sexual activity.
4. Add some physical exercise. Regular movement, walking a few hours per day and exercising improves the blood flow, especially in the pelvis, where the blood can’t move freely as we sit most of the time throughout the day. Besides, exercising decreases risks of heart diseases.
5. Avoid stress. This may sound unreal, but try to replenish your emotional and mental reserves after a stressful day and do not use stimulators, such as drugs, alcohol, smoking or caffeine. Give yourself a peaceful rest, enjoy the silence occasionally. Stress hormones block the mechanisms responsible for sexual activity as the nature decided that stressful time is not suitable for reproduction.

Although, there are no breathtaking research results, proving that healthy lifestyle can beat ED, but it can’t hurt anyway.

Canadian Pharmacy is reinventing the way people shop for generic drugs online – the dark days when getting drugs through the web are coming to an end as the neoteric platform steps in. The brand new project of Online Pharmacy, the aspiring aggregator of online pharmacies is gaining momentum at a railway speed – the lineup of generic drugs represented at the platform has increased by 57% in just 5 months, while the number of pharmacy partners has quadrupled since December, 2015. And what is absolutely important – the platform doesn’t sell drugs, it is primarily aiming at gathering trustworthy, licensed online drugstores with a successful track record, practicing fair offers and transparent terms.

The risks associated with counterfeit products are reduced to nothing as the platform initiates an in-depth scanning of high and low level business activities before issuing an approval. From investigations of the origin of drugs to tests of payment methods and delivery methods, once the drugstore is approved to share its offers within the platform, you almost get a guarantee that the quality of both products and customer service will leave nothing to be desired. And this is how these guys pave the way towards success and help millions of people to access quality drugs at a fair price.

The prices are falling. The quality is the same.

Online Pharmacy primarily bets on those online pharmacies who have managed to establish business communications with manufacturers. In aspiration to encourage more competitive terms among its partners and maintain access to cost-effective meds, the local authorities promise to keep the price range at a reasonable level, excluding any risks associated with upsurges. Therefore, the cost of generic Viagra according to the late March, 2016 offers starts from just $2.00 per pill, and even lower for those buying in bulk. That’s approximately 10 times lower in comparison with branded medications. No hidden fees or extra payments. Everything’s fair and transparent. And that’s not the only advantage Canadian Pharmacy boasts: it leaves its brick and mortar competitors in dust in terms of products selection. What can your local pharmacy offer? A couple of dose modifications of Viagra, Cialis and Levitra… and that’s it. At Canadian Pharmacy https://www.canadianhealthmall.com you can choose from a wealth of dosage, form and even formulations options – Viagra Oral Jelly, 2.5 – 150mg sildenafil citrate pills, multi-component drugs like Viagra Super Active (based on sildenafil citrate and dapoxetine, it helps you effectively deal with premature ejaculation and sexual fatigue)… and that’s just the tip of the iceberg.

The juicy benefits of staying with Online Pharmacy

Basically, Canadian Pharmacy is a one way stop for efficient erectile dysfunction treatment – not only you can choose some cheap drugs here. If you are beating your brains about finding an optimal way to recover your sexual function, ask the experts with solid medicinal background – the helpful stuff will assist you with your questions in a timely fashion. Make use of piles of articles, reviews, notes and statistics gathered under one roof – everything you should know about erectile dysfunction and effective remedies is gathered at one place for your convenience. Just drop in at the platform and give it a try – you will love the way it works for sure.

Our everyday goal is to provide you with affordable medicines for fast and efficient ED treatment. And though there are numerous resources available for those, who need to know more about male impotence, some questions still remain.

We really want you to learn more about Generic Viagra and its effects. We need you to have enough information to feel safe while taking it. So, here are top FAQs and physician’s answers to them.

Brand vs. Generic Viagra. Is there any difference?
Actually, there is no. People believe that anything that has generic in its name is of bad quality. We still don’t understand where this idea came from. Today we are trying to convince our patients of the false of this opinion. Ingredients and elements in both drug types are identical. So are the effects.

People call it aphrodisiac. Can Viagra be regarded as such?
You may say it for fun. But don’t take it seriously, because these pills never increase the sexual need as aphrodisiacs do. Generic Viagra only helps those, who are sexually inspired. When relationship crisis is the reason for impotence, no blue pill can cure it.

Can Generic Viagra cure ED?
Unfortunately, it can’t. In fact, neither of existing drugs can. We call them dysfunction treatment medicines, yet they all are only permanent solutions. Recently there has appeared a theory that these pills can be taken regularly to help men be ready whenever needed.

Is it safe to take pills daily?
If a man consults his physician, this variant may be suggested. Though cases are rare. Besides, to escape side effects and ensure best results a proper dose should be chosen. That may be tough, so only a few doctors do that.

You’ve mentioned the dosage. Could you tell what the recommended dose is?
As I’ve mentioned, it’s the physician who can decide what doses are suitable in different cases. The prescription will depend on numerous factors. However, 50mg are regarded as the most frequent and suitable choice. The pill is taken 40-60 minutes before the intercourse. The time difference depends on toleration and efficacy. Sometimes the dose either decreases to 25mg or increases to 100mg.

And for how long does the pill work?
It depends. On average, it functions during 5 hours. The first two hours are characterized by a very high plasma concentration. Then the action subsides, but gradually. Some men state that the effect wasn’t as great as they expected (2-3 hours). I have an answer to that too. And it sounds like much alcohol and fattening foods. Don’t expect pills to work for more than six hours. If they do, don’t get too excited. It’s the first symptom of the problem that requires medical examination.

One may read much about Viagra interaction with other pills. So, should one refuse from other treatment courses and medicines, while he’s trying to manage his ED problems?
Refusing from serious treatment courses to give way to Viagra is surely not the way out. And you are right: Generic Viagra interacts with many various drugs. However, this isn’t necessary the interaction that leads to lethal outcomes. It should never be mixed with medicines that include nitroglycerin as the combination of this sort will surely lead to blood flow problems or even a heart attack.

What about other medicines?
Professional examination and consultation will help dot the i’s and cross the t’s.

Are there any foods that these pills should not be mixed with?
Yes, there are. Though their list is short. I’ve mentioned fattening foods and alcohol. You can drink some wine and eat fries or steak, of course. But in moderation. Too much alcohol will lead to vision changes and even dizziness. Too much fattening foods will increase the time amount required for pills’ effective work. What I want to add to the list is grapefruit juice.

Really? Never though it could cause any problems…
No one did. FYI, grapefruit juice prevents Viagra from absorbing into the system. Generic Viagra can increase in man’s blood and lead to side effects. Some of them are really dangerous.

What minor or serious side effects are the commonest? And what is more important: can males escape them all?
Any drug can cause side effects. Frankly speaking, it is even normal to experience side effects, because they always come with positive ones. Consumption of the generic product is not an exception. The severity or mildness depends on the dose being taken. Mild ones can include head- or stomach ache, dizziness or nausea. They are absolutely harmless, so there’s nothing to get worried about.

What about severe cases?
These are rarely reported. They develop after the combination of pills with the foods and beverages mentioned above. If there is an abnormal heart rate or chest pain, a man should rush to the hospital.

Is there any advice for those, who faced ED?
Well, the only tip I can give is not to hesitate over professional examination. The sooner you go to your physician, the faster your sexual life gets back to norm.

Thanks for tips and recommendations. We hope they will be handy for millions of ED sufferers.
It was a pleasure to share some important facts.

Probably the most disturbing issue of each citizen nowadays is his/her health. In search of the best place to buy drugs we pay attention to the smallest detail. Local drugstores do not always offer cheap and quality medications, that is why more and more often customers are resorting to online ones. Low prices and a wide range of drugs are the main attraction of the pharmacies found on the Internet. However, opting for any medication, one should check the company carefully and purchase only from a reliable one.

Canadian Health&Care Mall can boast of years of international recognition and successful cooperation with customers all around the globe. All the attention of pharmacy’s staff is focused on satisfying the clients’ consuming desires. The diversity of medications, their prices, customer support and policies offered are among those beneficial options that incline people to make a purchase here.

Correlation of Price and Quality

Antibiotics, eye and skin care, blood pressure, antibiotics, men’s and women’s health and many other medications are displayed at the online Canadian Pharmacy. The variety consists of qualitative medications, tested and approved on the highest pharmaceutical levels. Due to the fact that not only brand, but generic drugs are offered, the prices are rather competitive. The most dependable manufacturers provide the pharmacy with the best medicines at the most acceptable cost. The vast majority of medications does not bear brand names, though includes the same active ingredients as their expensive counterparts. So, here you have a perfect opportunity to get the same effective medication at a much lower price.

Time-Tested Services of CHCM

Apart from great quality exceeding the price, the services offered by Canadian Health&Care Pharmacy www.canadianhealthcaremalll.com are doubtlessly the key advantages of the online drugstore. First of all, the website is simple to use, easy to navigate and find the necessary treatment. Besides, in case of any issues appeared you will be offered help from the customer support service. It is available 24 hours a day, 7 days a week and ready to solve all the problems and help you with the tiniest misunderstandings.

A team of professional doctors is also ready to assist you in choosing the medication. You can get online consultations of an experienced physician who will recommend you the necessary dosage, pill type and strength. The privacy policy provided by the online pharmacy will keep your personal information confidential and it will not be passed to the third party. Your private data, tests results and condition, as well as the drugs bought, will be only between you and the drugstore. Easy purchasing process and fast delivery will make you appreciate the platform even more. Order relevant medications and receive them right at the door, enjoy the quality, price and services offered by Canadian online Pharmacy and you will never regret your choice.

Sooner or later each of us comes to the necessity of buying medicines. According to the statistics, the age of those who begin taking medicines regularly is much lower than ever before. This is the sad statistics. Illnesses do not make good to our organisms and they do not prolong our ability to live. They cut it down greatly. So, it is advisable to keep to healthy habits and do much sport.

The advice is wonderful but it turns out to be absolutely impossible with today’s daily routines. People have to work much and, thus, they lack time to cook healthy food and stay in their stuffy offices for hours. Moreover, they sometimes even lack time to go out to the local pharmacy and buy pills for health improvement.

I am one of those extremely busy personalities that literally live in the Internet. I work here, socialize, find friends, take part in different sorts of things and even do shopping. I do not have enough time for walking to the markets and cafes, let alone sport gyms. That is why it is so important for me to be able to do shopping at a pharmacy through the Internet as well. Recently I noticed certain disorders in functioning of some of my most important organ. You know what… Well, I do understand that drugs are usually bought at pharmacies.

But how can I stand in a line with people that buy medicines for their headaches, coughs and painkillers, and I suddenly pronounce ‘Viagra, please…’ or ‘Something to treat hemorrhoids, please…’ I already hear them giggling behind my back and a young drugstore assistant-girl trying to behave naturally. That is awfully embarrassing! That is why I sat about finding an online pharmacy which could deliver the drugs I need right to my house (because at the post office they can read the name of the parcel and it is not going to be pleasant as well). I thought I could bear the expression of the courier’s face at my doorstep. How happy I was when I noticed neither of any possible reaction on his face when he actually delivered my parcel. Thanks Goodness, I found the way out with online Canadian pharmacy.

I Became Regular of the Online Canadian Health&Care Mall

They offer so many advantages in comparison with shopping at land based drugstores that it becomes just nonsense to go on attending the latter ones. You switch on your PC or laptop or tablet whenever you can do it (independently of working hours because online stores do not have those) and look for the medicines you need. My only advice would be to read the instructions to make sure that the chosen medicine is really the one you need and then you are free to make an order with a single click.

When It Comes to Pricing Policy…

The prices are low. To be more precise, they are even lower than you think. You can check out that fact without going too far. Just visit several other online drugstores, open webpages containing information on the certain drug and look through the prices of the same medicines. A pleasant surprise, isn’t it? This online pharmacy has a transparent policy so that the clients could know what they pay for and how much.

Privacy Guaranteed? I Swear It Is!

This feature is extremely important when you are trying to purchase one of those medicines mentioned above. Viagra-like drugs will be delivered right to your house. The couriers are very polite and the delivery is really fast. So, you’ve got my recommendations and now can feel absolutely comfortable to order from Canadian Health and Care Mall – http://www.canadianhealthcaremalll.com.

Music, in the physical world, is needed for organizing the disorganized matter. The physical world is disorganized. Through music matter vibrates harmoniously.

Music is a Divine way for success in the world. Through music higher beings reach us. You, if you sing, will contribute for more advanced creatures to come and help you. If you do not sing, they will not be interested in you.

Occult science recommends singing as a method for converting the negative energies into positive.

Music organizes the body and from there – the thought. It organizes the thought and from there – all cells. Music raises the vibrations of the organism.

Music is used from long ago as a method for transforming of the energies and for treatment.

Singing is an appeal of the human soul to Nature. Being responsive, it sends its reasonable building powers toward a person to help him recover sooner.

Today music can be harnessed as a method of treatment Ed Viagra Australia. If you make somebody, who is ill, sing a little every day, he will soon recover. On the other hand, if one, who is healthy, stops singing, he will easily fall ill. Music is the boundary between the physical and spiritual worlds. Through it, man can transform his energies. Through a song, a particular vital energy flows into the human body. If you are nervous, indisposed, start singing. Your condition will change right away. By singing such abilities are developed, which may not develop in another way.

In order one to be healthy and develop normally, he should gain an inner balance between the powers of the matter, of which his body is made, as well as between his thoughts and feelings. Music is one of the means for maintaining that balance. One, who knows the laws of natural music, can stop the destructive activity of the parasites in his body and improve his condition.

Singing is not entertainment, it is a means of toning up the energies. You shall sing to gain certain energies. If a patient does not sing, he will die prematurely. He should sing to provide the lost energy to his organism.

When one sings, he has to put in the song his soul and his spirit. They change the vibrations, raise them, and each increase of the vibrations has a healthy effect on the organism.

When you sing, Love, Wisdom and Truth must take part in your singing to express everything that God has put in you.

Many of the modern doctors, particularly in the West, treat patients by music. Bulgarians are pessimist by nature, that is why they have created horo-songs to take treatments for their pessimism. Joyful music has a healthy effect. There are sad songs that may make even a healthy person ill. Bulgarian horo-songs are healing.

At each pain capillaries contract. When you start singing, expansion happens and that contraction of capillaries stops, pains stop.

Music is a way for transforming human conditions. There are conditions that cannot be changed without music.

You have not used music yet as a means for healing and developing of your abilities. Through music you can produce power in yourself, remove discouragement, or remove your pains. You will sing one, two, three, four, five times a tone or the entire scale and you will see how your situation will improve.

In recent decades, clinical and public health efforts to reduce the burden of cardiovascular disease have emphasized the importance of calculating global, short-term (generally 10-year) risk estimates. However, the majority of adults in the United States who are considered to be at low risk for cardiovascular disease in the short term are actually at high risk across their remaining lifespan. Estimates of the lifetime risk of cardiovascular disease provide a more comprehensive assessment of the overall burden of the disease in the general population, now and in the future, because they take into account both the risk of cardiovascular disease and competing risks (e.g., death from cancer) until participants reach an advanced age. Such estimates can help guide public health policy, allowing projections of the overall burden of cardiovascular disease in the population.

Most estimates of the lifetime risk of cardiovascular disease have been derived from analyses restricted to risk factors measured at a single age in a predominantly white population.6,7 These estimates do not account for the potential effects of birth cohort that may arise from secular changes in risk-factor levels8,9 or for the widespread use of medical treatment, which has translated into marked reductions in rates of cardiovascular events in the United States.10

The Cardiovascular Lifetime Risk Pooling Project was designed to collect and pool data from numerous longitudinal epidemiologic cohort studies conducted in the United States over the past 50 years. This pooling approach provides an opportunity to calculate estimates of the lifetime risk of cardiovascular events according to age, sex, race, and other risk factors across multiple birth cohorts that would not be feasible within any one data set alone.

Study Sample

We included data sets in the Cardiovascular Lifetime Risk Pooling Project if they met the following criteria: they represented either community-based or population-based samples or large volunteer cohorts, they included at least one baseline examination with direct measurement of physiological and anthropometric (e.g., weight) variables, and they included 10 or more years of follow-up for fatal or nonfatal cardiovascular events or both. Data from 18 unique cohorts were included in the study, 17 of which were included in the pooled analysis. Because of the large size of one study, the Multiple Risk Factor Intervention Trial (MRFIT), relative to the other 17 studies, this cohort was analyzed separately. All data were appropriately de-identified, and all study protocols and procedures were approved by the institutional review board at Northwestern University.

Ascertainment of Baseline Measures and Follow-up Events

The protocols used to obtain data on demographic characteristics, personal and medical history, physical examination, laboratory results, and follow-up procedures for ascertainment of vital status and events for all cohorts included in the study have been published elsewhere. Blood pressure and serum cholesterol levels were measured directly in all participants; data on smoking status were self-reported, as were data on diabetes status, the latter derived from records of self-report, use of medication for diabetes, or both. Events were ascertained with the use of strategies selected by each cohort’s investigator group and included death from cardiovascular disease, from coronary heart disease, or from any cause and nonfatal events of interest, including myocardial infarction and stroke.

Preliminary data on correlates of protection against HSV-1 are available. Antibody, but not cellular immunity, was correlated with protection against HSV-1. Among the HSV vaccinees tested in the immunogenicity cohort, 8 were subsequently infected by HSV-1 and 10 by HSV-2. Subjects with HSV-1 infection had significantly lower gD-2 ELISA antibody titers at month 7 (mean titer, 3561) than subjects who remained uninfected (mean titer, 6875; P=0.04). This was not the case for subjects with HSV-2 infection (mean titer, 6339; P=0.78). Cellular immune responses at month 2 or month 7 did not differ significantly between subjects who subsequently became infected with HSV-1 or HSV-2 and vaccinees who remained uninfected (see the Supplementary Appendix for details).

The efficacy of the gD-2 candidate vaccine against HSV-1 is important because epidemiologic studies suggest that sexual transmission of HSV-1 is increasing in the United States,1 although its prevalence among U.S. children is decreasing.11 Among control subjects in the present study, 60% of the cases of genital disease and two thirds of the infections (with or without disease) were caused by HSV-1. These data are similar to the finding that HSV-1 is the most common cause of genital herpes in college students and young heterosexual women, and similar trends are reported in other countries. HSV-1 now rivals HSV-2 as a cause of neonatal herpes disease. Public health officials and researchers will need to closely monitor seroprevalence trends as future herpes vaccines are developed and assessed.

Although the development of a vaccine that provides protection against HSV-1 genital disease is a substantial step forward, additional progress is needed before a herpes vaccine is likely to be approved for general use. Any candidate vaccine will probably have to have proven efficacy against both HSV-1 and HSV-2 disease. Prevention of infection (with or without disease) is also an important goal, because asymptomatic genital shedding of HSV may lead to the spread of the virus to newborns or sexual partners. This is a more difficult goal to achieve and may require approaches such as live attenuated vaccines or vaccine vectors to generate protection.

Solicited reports of adverse events included redness, swelling, and pain at the injection site, as well as fatigue, fever, headache, and malaise. The HSV vaccine was more reactogenic and was associated with local pain, redness, and swelling more often than was the control vaccine. There was a small but significant increase in systemic symptoms, including fatigue, fever, headache, and malaise, in the HSV-vaccine group (Table 3). Dose 2 and dose 3 of the HSV vaccine were not associated with increased reports of adverse events; in contrast, reactogenicity decreased slightly with additional vaccination.

Immunogenicity

The HSV vaccine was immunogenic and stimulated ELISA and neutralizing antibodies. As expected, control subjects did not have antibody to gD-2 on ELISA or neutralization of HSV-2. Geometric mean gD-2 ELISA titers were 21 at baseline and 6809 at month 7 after three doses of HSV vaccine; ELISA titers waned to 769 by month 20. HSV-2 neutralizing antibodies developed after two doses of HSV vaccine, but the median value fell to an undetectable level by study month 6 (see the Supplementary Appendix for details). After dose 3, HSV-2 neutralizing antibodies were again above the limit of detection (the mean titer at month 7 was 29) but fell to a median value that was undetectable by study month 16.

Discussion

Our findings of vaccine efficacy against HSV-1 and lack of efficacy against HSV-2 are puzzling in view of the previous two studies involving discordant couples that showed efficacy of this gD-2 vaccine against HSV-2.4 The difference in efficacy is likely to be due to some factor in the two populations studied. The distinguishing feature of discordant couples is that they are a highly selected group in which the uninfected partner is potentially repeatedly exposed to HSV by the infected partner. Attack rates of HSV-2 genital disease in the prior studies of gD-2 vaccine were high among uninfected women in discordant couples (13.9% for 19 months or 8.4% per year) and were reduced significantly by the vaccine (efficacy, 73% and 74% in the two trials; P=0.01 and P=0.02, respectively).4 Too few cases of HSV-1 genital disease occurred in women in the two previous studies to assess efficacy against HSV-1 (one case in each study among women who were seronegative at study entry).4 Potential reasons for vaccine efficacy in the discordant-couple population include selection bias for a population of women with relative resistance to HSV-2, with added benefits from a subunit vaccine; an undefined immunologic priming event from chronic sexual exposure to HSV-2 viral antigens from the infected partner; and less frequent sexual activity due to the long-term nature of the relationship as compared with sexual activity by couples in new relationships.

It is not apparent why the biologic characteristics of HSV-1 are different from those of HSV-2; the gD-2 vaccine induces significant protection against genital HSV-1 disease as well as HSV-1 infection, but not against disease or infection caused by HSV-2. Genital HSV-1 may be acquired primarily through oral–genital sex (although a history of oral sex was not a risk factor for HSV-1 acquisition in our study); a lower inoculum, an oral–genital route (possibly less traumatic sex), and a less suitable environment for HSV-1 replication are all possible explanations for protection by the vaccine against HSV-1 but not HSV-2. The gD-2 antigen is derived from HSV-2, but 89% amino acid homology is shared with gD-2 from HSV-1, which may explain the protection against HSV-1. Type-specific immune responses to vaccine antigen may reveal differences in antibody activity against HSV-1 and HSV-2. Whether HSV-1 is more easily neutralized by vaccine-induced antibodies must be determined by further laboratory studies.