Tag Archives: Pharmaceuticals

Toxic Indian lake is cost of cheap drugs

A boy prepares to jump off a rock into the waters of the Osman Sagar Lake near the southern Indian city of Hyderabad May 29, 2011. REUTERS/Krishnendu Halder/File Photo

A boy prepares to jump off a rock into the waters of the Osman Sagar Lake near the southern Indian city of Hyderabad May 29, 2011. REUTERS/Krishnendu Halder/File Photo

By Zeba Siddiqui 
Fall, 2016

HYDERABAD, India (Reuters) – Centuries ago, Indian princes would bathe in the cool Kazhipally lake in Medak. Now, even the poorest villagers here in India’s baking south point to the barren banks and frothy water and say they avoid going anywhere near it.

A short drive from the bustling tech hub of Hyderabad, Medak is the heart of India’s antibiotics manufacturing business: a district of about 2.5 million that has become one of the world’s largest suppliers of cheap drugs to most markets, including the United States.

But community activists, researchers and some drug company employees say the presence of more than 300 drug firms, combined with lax oversight and inadequate water treatment, has left lakes and rivers laced with antibiotics, making this a giant Petri dish for anti-microbial resistance.

“Resistant bacteria are breeding here and will affect the whole world,” said Kishan Rao, a doctor and activist who has been working in Patancheru, a Medak industrial zone where many drug manufacturers have bases, for more than two decades.

Drugmakers in Medak, including large Indian firms Dr Reddy’s Laboratories Ltd <REDY.NS>, Aurobindo Pharma Ltd <ARBN.NS> and Hetero Drugs Ltd, and U.S. giant Mylan Inc <MYL.O>, say they comply with local environmental rules and do not discharge effluent into waterways.

National and local government are divided on the scale of the problem.

While the Central Pollution Control Board (PCB) in New Delhi categorizes Medak’s Patancheru area as “critically polluted”, the state PCB says its own monitoring shows the situation has improved.

The rise of drug-resistant “superbugs” is a growing threat to modern medicine, with the emergence in the past year of infections resistant to even last-resort antibiotics.

In the United States alone, antibiotic-resistant bacteria cause 2 million serious infections and 23,000 deaths annually, according to health officials.

Thirteen leading drugmakers promised last week to clean up pollution from factories making antibiotics as part of a drive to fight the rise of drug-resistant superbugs, while United Nations member countries pledged for the first time to take steps to tackle the threat.

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MAJOR EARNER

Patancheru is one of the main pharmaceutical manufacturing hubs in Telangana state, where the sector accounts for around 30 percent of GDP, according to commerce ministry data. Drug exports from state capital Hyderabad are worth around $14 billion annually.

Local doctor Rao pointed to studies by scientists from Sweden’s University of Gothenburg that have found very high levels of pharmaceutical pollution in and around Kazhipally lake, along with the presence of antibiotic-resistant genes.

The scientists have been publishing research on pollution in the area for nearly a decade. Their first study, in 2007, said antibiotic concentrations in effluent from a treatment plant used by drug factories were higher than would be expected in the blood of patients undergoing a course of treatment. That effluent was discharged into local lakes and rivers, they said.

“The polluted lakes harbored considerably higher proportions of ciprofloxacin-resistant and sulfamethoxazole-resistant bacteria than did other Indian and Swedish lakes included for comparison,” said their latest report, in 2015, referring to the generic names of two widely used antibiotics.

Those findings are disputed by local government officials and industry representatives.

The Hyderabad-based Bulk Drug Manufacturers Association of India (BDMAI) said the state pollution control board had found no antibiotics in its own study of water in Kazhipally lake. The state PCB did not provide a copy of this report, despite several requests from Reuters.

“I have not seen any credible report that says that the drugs are no longer there,” Joakim Larsson, a professor of environmental pharmacology at the University of Gothenburg who led the first Swedish study and took part in the others, told Reuters by email.

“There might very well have been improvements, but without data, I do not know.”

 

WATER TREATMENT

Local activists and researchers say the Common Effluent Treatment Plant (CETP) built in Medak in the 1990s was ill-equipped to handle large volumes of pharmaceutical waste.

After protests and court cases brought by local villagers a 20-km (12-mile) pipeline was built to take effluent to another plant near Hyderabad. But activists say that merely diverted the problem – waste sent there, they say, mixes with domestic sewage before the treated effluent is discharged into the Musi river.

A study published this year by researchers from the Indian Institute of Technology, Hyderabad, found very high levels of broad-spectrum antibiotics in the Musi, a tributary of the Krishna, one of India’s longest rivers.

Local government officials responsible for the plants did not respond to Reuters’ requests for comment.

Nearly a dozen current and former officials from companies producing medicines in Patancheru told Reuters that factory staff from various firms often illegally dump untreated chemical effluent into boreholes inside plants, or even directly into local water bodies at night.

All the officials spoke on condition of anonymity and Reuters was unable to independently verify those allegations.

Major manufacturers in the area, including Dr Reddy’s and Mylan, said they operated so-called zero liquid discharge (ZLD) technology and processed waste onsite.

“Mylan is not dumping any effluent into the environment, borewells or the CETP,” said spokeswoman Nina Devlin.

Dr Reddy’s said it recycled water onsite and complied with all environmental regulations.

The same industry officials who spoke to Reuters said the pollution control board rarely checked waste-treatment practices at factories, adding that penalties for breaches were meager.

The Telangana state government did not respond to requests for comment.

“We are aware some companies are releasing more than the allowed effluent, but they are profit-making companies,” said state PCB spokesman N. Raveendher. “We do try and take action against the offenders, but we cannot kill the industry also.”

Many smaller companies also lacked the funds to install expensive machinery for treating waste, he added.

COURT BATTLES

A series of local court cases have been filed stretching back two decades, accusing drug companies of pollution and local authorities of poor checks. In some cases, companies have been ordered to pay annual compensation to villagers, but many are still grinding through India’s tortuous legal system.

Wahab Ahmed, 50, owns five acres of land near the shores of Kazhipally lake, where he grew rice until a decade ago. He says the worsening industrial pollution from several nearby pharmaceutical factories left his land barren.

“We have protested, sued, and done all sorts of things over the years … that’s how some of us are now getting around 1,700 rupees (roughly $20) a year from the companies,” he said.

“But what can you do with that small sum today?”

More than 200 companies were named as respondents in the case he was referring to, filed by a non-profit organization on behalf of villagers.

While pollution of farmland is a serious problem for villagers who depend on it for their livelihood, the potential incubation of “superbugs” in Medak’s waterways has wider implications.

The issue is particularly worrisome in India, where many waterways also contain harmful bacteria from human sewage. The more such bacteria are exposed to antibiotics, the greater the chances they will mutate and render such drugs ineffective against them.

The risk is that resistant bacteria would then infect people and be spread by travel.

So far, most of the focus worldwide on antimicrobial resistance has been on over-use of drugs in human medicine and farming.

“Pollution from antibiotic factories is a third big factor in causing antimicrobial resistance,” the chairman of one of the world’s largest drugmakers told Reuters. “But it is largely overlooked.”

Copyright Reuters 2016

(Additional reporting by Ben Hirschler in LONDON; Editing by Clara Ferreira Marques and Alex Richardson)

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Pharmaceuticals in pregnancy are untested. How safe are they?

Most Drugs Aren’t Tested on Pregnant Women. This Anti-nausea Cure Shows Why That’s a Problem

by Nina Martin, ProPublica
May 28, 2016

Marquita Smiley’s first surprise was discovering she was pregnant. Her second was how miserable being pregnant felt. With her older daughter, she had experienced some mild queasiness. This time, the nausea and vomiting were so bad, “I would be calling off work and not wanting to get out of bed.” As a single mom in Birmingham, Alabama, and a social worker who investigated horrific cases of child abuse, she didn’t have that option. Her ob/gyn wrote a prescription for Zofran, generic name ondansetron, which had been developed for cancer patients ravaged by radiation and chemotherapy but had become the preferred treatment for extreme morning sickness. The pills melted in Smiley’s mouth, dissolving the nausea with them. “I felt so much better,” she said. “So we just kept kinda going with it.”

Marquita Smiley and her son, Zaidan. (Bob Miller for ProPublica)

Marquita Smiley and her son, Zaidan. Photo by Bob Miller for ProPublica

Fifty to 90 percent of women spend some part of their early pregnancies sick to their stomachs, and what begins as simple nausea can become dangerously debilitating. Some expectant women use ondansetron for only a few days; Smiley took it two or three times a week into her second trimester. In her fifth month, an ultrasound showed that the left side of her baby’s heart was critically underdeveloped. Three days after her son, Zaidan, was born in April 2014, cardiologists at the University of Alabama Hospital in Birmingham performed open-heart surgery, but a blood clot caused the baby to have a heart attack and his kidneys began to fail. Somehow Zaidan hung on: At two months, he had a heart transplant; at four months, he went home.

Smiley was torn between feeling extraordinarily lucky — Zaidan was her “miracle baby” — and blaming herself for his suffering. As his first birthday neared, one of her coworkers mentioned she’d seen TV commercials by a law firm claiming that Zofran might cause serious congenital heart problems and other birth defects.

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Smiley began doing her own research. She had assumed that medications prescribed in pregnancy are tested and monitored for prenatal use, perhaps even more carefully than other drugs. But ondansetron, for years the most widely used drug to treat the most common complication of pregnancy, was never approved in the U.S. or anywhere for use in pregnancy. The pharmaceutical giant GlaxoSmithKline vigorously denies Zofran causes birth defects, and most research so far seems to support that claim. Smiley acknowledges she can’t be certain what caused Zaidan’s problems. But if she’d known the drug hadn’t been approved for prenatal use, she said one morning in her lawyer’s office, distracting her squirmy toddler with Goldfish crackers, “I would not have placed him at risk.”

Women, Drugs and Devices: 5 cases that shook America’s FDA

Thalidomide

How it was used: As a sedative and sleeping pill, off-label for morning sickness

What happened: Developed in West Germany in the 1950s, the drug was soon linked to miscarriages and devastating birth defects, including limb deformities. At least 10,000 “thalidomide babies” were born around the world before the drug was banned in the early 1960s. The US escaped largely unscathed thanks to FDA medical officer Dr. Frances Oldham Kelsey, who refused to approve the drug without sufficient safety information.

The aftermath: Spurred by the crisis, the US government passed amendments in 1962 that require drug manufacturers to prove their products not only safe but effective, too. Thalidomide later re-emerged as a treatment for leprosy.

Diethylstilbestrol (DES)

How it was used: Introduced in 1938 as the first synthetic form of estrogen, it was prescribed to prevent miscarriage, premature labor and related pregnancy complications—even though clinical trials in the 1950s showed it was ineffective.

What happened: In 1971, medical studies found that women exposed to DES in utero (“DES daughters”) were at heightened risk for developing clear cell ardenocarcinoma, a rare vaginal cancer. The FDA warned against its use, but by then, up to 10 million women and children had been exposed.

The aftermath: Women who took the drug have a heightened risk of breast cancer, as do their daughters (who also have higher rates of infertility, pregnancy complications and reproductive abnormalities). DES sons are at higher risk for non-cancerous testicular growths. Thousands of lawsuits have been filed, totaling billions of dollars.

Bendectin

How it was used: A combination of the antihistamine doxylamine and vitamin B6, it was approved to treat morning sickness in 1956

What happened: Close to 33 million women worldwide took Bendectin over nearly three decades. But after families started suing for alleged birth defects in the 1970s, the manufacturer’s insurance premiums soared, and Merrell Dow voluntarily withdrew the drug in 1983.

The aftermath: In the wake of the lawsuits, Bendectin became one of the most-studied drugs in pregnancy. The combination of doxylamine/vitamin B6 was found to be safe, and in 2013, the same basic formula, renamed Diclegis, won FDA approval once more. Bendectin’s most important impact, though, may be in the courtroom: In 1993, in a case called Daubert v. Merrell Dow, the U.S. Supreme Court issued sweeping limits on expert witnesses and “junk science” that affected many areas of the law.

Dalkon Shield

How it was used: Long-acting, reversible birth control that was supposed to be safer than the Pill

What happened: Introduced in 1971, the intrauterine device was used by more than 2 million women in the US and 4.5 million worldwide. But design flaws made its users susceptible to acute pelvic infections and spontaneous abortions, leading to hysterectomies and at least 18 reported deaths.

The aftermath: Manufacturer A.H. Robins suspended sales in 1974 under pressure from the FDA, but didn’t recall the device, leaving thousands of women at risk. Robins eventually declared bankruptcy, 300,000 women filed claims, and lawyers hammered out a $3 billion settlement. The disaster fueled efforts to better regulate the medical device industry. It also discouraged a generation of women from using IUDs.

Terbutaline

How it was used: Approved by the FDA to treat asthma, bronchitis and other lung diseases, it was used off-label to stop premature labor, even though studies eventually concluded it was ineffective.

What happened: In 2011, the FDA warned there was a risk of heart problems and even death for pregnant patients who were administered certain forms of terbutaline over an extended period (longer than two to three days). The agency said it had received reports of 16 deaths and 12 serious heart issues associated with prolonged use of the drug.

The aftermath: It’s still being used for to prevent preterm birth, but in much more controlled settings (i.e., not at home).

Source: Delphine D’Amora, Mother Jones

Photo by Bob Miller for ProPublica

Photo by Bob Miller for ProPublica

A healthy baby is the universal goal of pregnancy, shared by women and doctors, researchers and regulators alike. The nine months from conception to birth are extraordinarily dynamic and complex, and the complications that arise can have lifelong effects. There’s a critical need for knowledge about almost everything, from environmental causes of birth defects to how the mother’s preexisting medical conditions can affect her baby’s well-being.

Yet the same desire to protect the fetus often deters scientists and drug makers from studying the expectant mother. When it comes to drug safety, pregnancy is a largely research-free zone, women’s health experts say. The consequence? Treatment that often is based on informed guesswork rather than solid evidence, in which medications that have never been approved for use during pregnancy, and whose long-term dangers may not be known, become the standard of care. Zofran is a case study in just how problematic this system has become.

Zofran is far from unique — almost every drug prescribed during pregnancy in the U.S. is “off label,” meaning it hasn’t gone through the clinical trials required by the Food and Drug Administration before approving a drug for a specific use in a specific population. Only eight medications are currently approved by the FDA for prenatal use; from 1995 to 2011, the agency OK’d only one pregnancy-related drug. (By contrast, 29 drugs to treat cardiovascular-related conditions have won approval just since 2010.) Pregnant women have become what researchers and ethicists call“therapeutic orphans,” reliant on drugs of uncertain risk, sometimes during the earliest and most vulnerable stages of fetal development.

The problem goes back to efforts to protect women and babies from the kind of severe birth defects and other harm caused by thalidomide and other drugs in the 1960s and ‘70s — and pharmaceutical companies from legal liability for those injuries. Decades later, “pregnant women may be the most underrepresented group in the entire clinical research process,” a 2011 report by the National Institutes of Health’s Office of Research on Women’s Health declared. In a 2013 analysis, 95 percent of industry-sponsored clinical drug trials excluded expectant mothers; a mere 1 percent were designed specifically to study them.

Yet according to the Centers for Disease Control, as many as 9 in 10 expectant mothers use medications — for ailments that occur before they even realize they’re pregnant; for complications such as morning sickness, early labor, or gestational diabetes; for chronic conditions such as epilepsy, high blood pressure, or depression that often become more challenging to manage as the months pass. Hampered by a lack of peer-reviewed evidence and hard data, ob/gyns find themselves in the dark about some basic best practices: How does a drug work in an expectant woman’s body? What’s the right dose to take and the right time to take it? What are the true risks to the fetus (or lack thereof)?”Pregnant women are not like non-pregnant people,” observed Susan Wood, director of the FDA’s Office of Women’s Health from 2000 to 2005 and now an associate professor of health policy at George Washington University. “They have a different fluid volume ratio, a different metabolism … all sorts of [physiological] changes that could affect how well a drug works.”

Fewer than 10 percent of medications have enough information to determine their safety for prenatal use, the CDC notes. Off-label use of a drug during pregnancy thus becomes a kind of unregulated, unmonitored clinical trial. “We learn on the backs of [pregnant] women while pretending we don’t experiment on pregnant women,” said Ruth Faden, director of the Johns Hopkins Berman Institute of Bioethics. “But in fact, we do.” By the time the real risks become apparent, several decades may pass. The watchdog group Public Citizen analyzed how long it can take the FDA to issue a “black box” warning after problems surface with a drug. The average: 27 years after the drug was approved.

In the absence of reliable information, sometimes mothers-to-be and their physicians conclude the risks are too great and stop a medication that’s really needed, triggering an avoidable medical emergency that can do more harm than the drug itself. “If research is important to tell us when medications are unsafe, it is also important to reassure us when drugs are safe,” Faden and a group of women’s health advocates calling themselves the Second Wave Initiative argued in a recent manifesto.

The question of how to improve research on pregnant women has greater urgency as new threats such as the opioid epidemic and the Zika virus have emerged. As policy makers, medical organizations and women’s health experts grapple for a solution, the most intractable problem may be a deep-rooted cultural bias that elevates the fetus above all else. “There’s been a dogma in which pregnant women come last,” Faden said. “Always last.”

Meanwhile, Marquita Smiley and other women are often left with no clear options or answers — and little or no recourse if something goes very wrong. It’s an awful position to be in, Smiley said. “I’m trying to find the words.”

Not so long ago, doctors viewed nausea and vomiting of pregnancy (the medical term for morning sickness, abbreviated as NVP) as largely a psychological problem, at its worst a sign that a woman was so unhappy being pregnant she literally wanted to throw up her fetus. Now, the key culprit is believed to be the hormone human chorionic gonadotropin, which is produced in the placenta and surges through a woman’s body as the embryo begins its rapid growth. Studies suggest that some nausea is actually a healthy sign, with mothers who suffer from it less likely to miscarry or go into premature labor. But up to 2 percent of pregnant women develop hyperemesis gravidarum (HG), nausea and vomiting so serious it can require hospitalization — Charlotte Bronte is believed to have died from it. As with so much else about pregnancy, the long-term effects of hyperemesis are mostly unknown: “Because they see HG as a maternal disorder that lasts three months, they don’t fund the research for it,” said Kimber MacGibbon, founder of the HER Foundation, a patient advocacy group.

Three decades before Zofran arrived on the scene, thalidomide seemed like an answer. The German drug was marketed as a sedative and sleeping pill. But it also eased nausea and was believed to pose no dangers to human fetuses — until women began giving birth to babies with severely deformed limbs. After thalidomide was banned in the early 1960s, doctors and women relied on a drug called Bendectin that had received FDA approval in the 1950s specifically for morning sickness and had a long track record for safety; still, lawsuits eventually blamed it for fetal harm, ranging from skeletal malformations to blood disorders and cancer. The claims proved to be unfounded, but in 1983, the litigation-weary manufacturer voluntarily yanked it from the market. For the next 30 years, there was no FDA-approved treatment for NVP.

Other reproductive-health scandals erupted over the cancer-causing synthetic estrogen DES, which was prescribed to prevent miscarriages, and the potentially deadly Dalkon Shield intrauterine device, used to prevent pregnancy. In their aftermath, the ethical and scientific pendulum swung in the direction of extreme caution.

Pharmaceutical companies and regulators concluded that the best way to avoid injuring women and their offspring — and the resulting crush of lawsuits — was to stop doing research on all women. “The fear of bad outcomes in pregnancy led to this sort of general exclusion,” said Wood, the former FDA official. In 1977, the FDA issued formal guidelines stating that women of “childbearing potential” — i.e., anyone who had not gone through menopause or been surgically sterilized — could only be included in late-stage clinical trials, after the safety and effectiveness of a drug had already been established (a rule widely interpreted as “never”).

Thanks in large part to the furious lobbying of feminists and anti-AIDS activists, the FDA finally reversed its stance against most women in research in 1993. But pregnancy remained a conundrum. The influential Institute of Medicine argued in a report co-edited by Faden, that “If a drug is going to be used in pregnant women, then the availability of safety and effectiveness information” is critical, including “adequate information about the risks and benefits.” Moreover, pregnant women should be “treated as competent adults capable of making their own decisions.”

Over the next two decades, the FDA encouraged the pharmaceutical industry in numerous ways. It ran a series of meetings and drafted a “guidance” on how to ethically determine the biochemical and physiological effects of drugs on the pregnant body. It spent years revising labeling rules on drug safety during pregnancy (the final version was issued in 2014) and pressed companies to establish pregnancy registries to simplify tracking adverse outcomes in drugs.

Yet, widespread aversion to prenatal research persisted. The National Institutes of Health continued to categorize pregnant women as “vulnerable,” with a “questionable” capacity to give informed consent — in the same category as kids, prisoners, and the mentally disabled. Conducting research on mothers-to-be was complicated and costly, and women themselves were often hesitant to sign on. “We honestly haven’t really addressed the issue of actively trying to recruit pregnant women into clinical trials,” a research expert for the drug industry said in a recent interview, speaking on the condition of anonymity. A 52-page document by the Pharmaceutical Research and Manufacturers of America, outlining principles for conducting clinical trials and revised in 2015, doesn’t contain a single reference to pregnancy.

Physicians responded by doing what they have always done: They prescribed drugs to pregnant patients “off label,” and shared the benefits and potential risks in medical journals and at conferences. The scientific establishment and the FDA consider this part of the basic practice of medicine, beyond the scope of regulators. The result was something of a vicious cycle, Faden said. “If your product eventually will be used in this population anyway, off label, what’s your incentive for testing the drug in pregnant women before it’s approved?”

Zofran’s introduction in 1991 occurred in the midst of this research vacuum. The drug worked by blocking the action of the chemical serotonin in the brain’s so-called vomiting center. It had been extensively tested on cancer and surgical patients, and on pregnant rats and rabbits. These studies showed “no evidence of impaired fertility or harm to the fetus,” the FDA-approved package insert said. But because animal studies are imperfect predictors of human toxicity and there were “no adequate and well-controlled studies in pregnant women,” the drug “should be used during pregnancy only if clearly needed,” the label added.

Plenty of ob/gyns believed it was needed — desperately. The journal Lancet soon published letters from doctors in Greece and Britain who had used Zofran on patients with severe hyperemesis. Physicians in Hong Kong described a patient so weak that she had considered having an abortion — until the drug turned her pregnancy around. The HER Foundation’s MacGibbon had HG with both her kids, and the drug was such a salvation that she and her husband joked about naming their daughter “Zofrana.” As a registered nurse, she understood the off-label dilemma, “but I knew that if I didn’t [take it], literally, I would just sit there and puke until I couldn’t breath.”

By the time Marquita Smiley was pregnant with Zaidan in 2013, Zofran/ondansetron was available in both liquid and pill form and as a generic from 30 or so manufacturers. The online price for 30 pills had plummeted from nearly $800 to $26. Last year, more than 21 million prescriptions were filled in the U.S. for all uses of the drug, according to an analysis by IMS Health — 10 times as many as in 2006. Doctors were no longer reserving the drug for only the most difficult cases, said Smiley’s lawyer, Don McKenna of the Birmingham law firm Hare Wynn. “It got to the point where if anyone complained of an upset stomach, they would get a prescription.”

Although doctors may decide to prescribe a medication for unapproved uses, it’s illegal for drug companies to encourage them to do it. In 2012, the U.S. Justice Department announced that GlaxoSmithKline had crossed the line.

The allegations originated with ex-Glaxo marketing execs turned whistleblowers. The DOJ accused the company of engaging in all kinds of banned behavior to drive up sales — plying doctors with Caribbean vacations and hunting trips, misreporting clinical trial findings to a medical journal, withholding safety data from the FDA. The most serious, criminal charges covered the antidepressants Paxil and Wellbutrin and the diabetes drug Avandia. But in a civil settlement, DOJ said Glaxo had also spread “unsubstantiated and/or false representations” about Zofran’s use for morning sickness and “paid illegal remuneration” to doctors to promote and prescribe the drug, in violation of federal anti-kickback laws. Glaxo didn’t admit any wrongdoing where Zofran was concerned, but it pleaded guilty to fraud in connection with other drugs and paid a $3 billion fine, the largest ever levied against a drug maker. (Read ProPublica’s reporting about another drug in the civil case, the asthma medication Advair, here.)

The DOJ case hit the news at a delicate moment. For years, reports in medical journals raised few concerns about the Zofran’s use in pregnancy, but they were small and frequently observational — hardly the scientific gold standard. By 2012, however, large-enough numbers of pregnant mothers had used the drug to conduct more meaningful analyses. Researchers associated with the National Birth Defects Prevention Study found an increased risk of cleft palate in infants whose mothers had used ondansetron (a separate, unpublished analysis detected a “modest increased risk” of the type of heart problem suffered by Marquita Smiley’s son). Next came studies based on medical registries in Denmark and Sweden that tracked every pregnancy in those countries going back to the 1990s. One found no difference in birth defects between the Zofran-exposed and unexposed babies; another found an elevated risk — up to twice as high — of hole-in-the-heart defects.

Among scientists, the inconsistent studies triggered calls for more research but no major alarms. Birth defects afflict 3 percent of babies, and heart defects are the most common among them. If ondansetron does harm the fetus, “It absolutely can’t be anything huge or we would have already seen it,” said Christina Chambers, a professor at the University of California, San Diego School of Medicine who is a leading expert on environmental exposures and pregnancy.

Plaintiffs lawyers, though, thought they saw plenty of red flags. Over the next couple of years, they hired their own experts and began digging through everything from adverse-event reports filed with the FDA (more than 450 involving prenatal exposures), to the LinkedIn profiles of Zofran sales people, to obscure Japanese medical journals in which scientists working for Glaxo had published animal studies in the early 1990s.

By this spring, parents had filed more than 200 lawsuits, alleging that Zofran caused heart defects, cleft palates, and kidney problems in babies exposed to the drug in utero; in a few instances, the babies died. Lawyers contended there might be many more cases but for recent U.S. Supreme Court rulings that make it almost impossible for consumers in all but a few states to sue for injuries if the medication at issue was a generic version of a brand-name pill, as ondansetron is for Zofran. One state whose courts did allow such lawsuits was Alabama — until legislators there rewrote the law in 2015. Marquita Smiley, who took generic ondansetron, filed her lawsuit last fall, just before the courtroom doors slammed shut.

In a written statement, Glaxo said the allegations linking Zofran to birth defects are “entirely unfounded,” and pointed to the FDA’s rejection last fall of a citizen’s petition that had sought stronger pregnancy warnings on the label. The company said doctors have a right to “assess the health care needs of their patients and apply their own knowledge, training, and experience in deciding whether the therapeutic benefits of a medicine outweigh the potential risks in each patient.”

But plaintiffs’ lawyers argue that drug makers have a heightened responsibility to assure that medications likely to be used in pregnancy are safe — especially if they are used to treat a condition as common as morning sickness, and if they are marketed off-label.

“When you throw a stone in the water, you have to expect there will be ripples,” said Tobias Millrood, a Philadelphia lawyer who is one of the lead counsels. “It’s really quite that simple.”

Under Alabama law, a woman who uses illicit drugs while pregnant can be arrested, prosecuted and stripped of her parental rights — even if she was just using marijuana to treat her morning sickness. Smiley’s agency, the state Department of Human Resources, is the one often called upon to investigate allegations that pregnant women and new mothers have chemically endangered their babies. Smiley doesn’t handle those kinds of cases, but she knows irony when she sees it: A woman could face 10 years in prison for endangering her unborn child with drugs, while a huge corporation could put children at risk with a drug that’s never been approved for use in pregnancy.”It’s crazy,” she said.

In her lawyers’ office one late winter morning, Zaidan was sweet-tempered and surprisingly sturdy, exploring the unfamiliar environment with sippy cup in hand. But his skin was blotchy and his hair had been falling out. The transplant drugs have wreaked havoc on his immune system, and he spent most of March in the hospital with breathing and other problems. As much as Smiley worries about his physical health, she’s just as concerned about his cognitive and emotional development. “He had a lot of loss of oxygen to his brain early on,” she said. She has to protect him from infections, which means keeping him way from a lot of people, “and I know that’s bad because he needs social skills.” Thanks to her job, she knows where to get help: “The social worker in me had him sign up for early intervention….I’m on the receiving end of the services now.”

With so much to worry about, she hasn’t been paying much attention to the lawsuit. Glaxo lost a bid earlier this year to have the cases dismissed, and now the litigation is in its discovery phase: “GSK has to put all its cards on the table and say … ‘This is everything we knew,'” attorney Don McKenna said. The latest research has not gone in the plaintiffs’ favor: A new study looking at birth outcomes in more than 1,000 women who took Zofran or ondansetron for hyperemesis suggested that HG itself, and not the drug, might be to blame for birth defects.

Back in Washington, D.C., there has been quiet movement on the larger issue of research and pregnancy. Bipartisan bills introduced this spring in the Senate and the House of Representatives would establish a task force on research specific to pregnant women and (in the case of the House legislation) require annual updates from the FDA. The FDA is scheduled to issue its own draft guidance entitled “Pregnant Women in Clinical Trials — Scientific and Ethical Considerations” later in the year.

The agency also has approved a new drug for morning sickness called Diclegis — basically, the long-abandoned Bendectin under a new name. Last year the American College of Obstetricians and Gynecologists revised its practice bulletin, urging doctors to prescribe Diclegis as the first line of defense against NVP and ondansetron only after weighing the benefits against the risks. But Diclegis is less powerful, more costly, and Smiley and her lawyers believe women are still being given ondansetron out of habit.

Recently, she saw an old friend at church who happened to be pregnant. “She said, ‘I’m having these really bad spells with nausea. It’s hard for me to get out of bed. It’s hard for me to go to work.'”

Smiley told her friend about Zaidan and everything her family had been through. “I was like, ‘Hey, whatever you do, I don’t know if there’s any truth to this, but please find something else to take.'”

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Dementia epidemic may not actually be getting worse

By Yu-Tzu Wu and Carol Brayne, University of Cambridge 
August, 2015

The notion of a dementia epidemic has been a big concern in ageing societies across the globe for some time. With the extension of life expectancy it seems to be an inevitable disaster – one of the “greatest enemies of humanity”, according to UK prime minister David Cameron.

Many shocking figures have been published pointing to dramatic increases in dementia prevalence and massive predicted costs and burdens. Yet new evidence seems to suggest otherwise. In a review of dementia occurrence in five studies in the UK, Sweden, Spain and the Netherlands between 2007 and 2013 that used consistent research methods and diagnostic criteria, we found none that supported headlines about dramatic increases in dementia. They report stable or reduced prevalence at specific ages over the past few decades – despite ageing populations.

How to reconcile this relatively optimistic picture with what looks like panic on the part of governments, charities and the mainstream media? One reason is that they fail to recognise the complexity of dementia diagnosis. The main criteria for diagnosing dementia hinge on cognitive decline and an associated deterioration in a person’s ability to carry out day-to-day activities. If there are variations in the recognised boundaries of these criteria either in different countries or during different time periods, this can affect occurrence estimates without changing the fundamentals of the dementia syndrome itself.

Over the past few decades, the diagnostic criteria have indeed changed across the world in parallel with public awareness and perceptions. More people are now diagnosed with very early dementia, for example, though it may or may not progress into more severe forms. The introduction of biomarkers for diagnosis is likely to further expand prevalence by identifying large sections of populations at risk – and is already in its early stages. Such changes will affect different groups of people in different contexts in different ways, but basically we might be counting more people as having dementia due to the use of more inclusive diagnostic criteria.

Having said that, there might be more than careless use of research evidence at play. The worsening epidemic message also fits well with consumer psychology and the recent history of over-medicalisation: fear, demand for a solution, and salvation. The world is looking for a silver bullet. Since the G8 summit of 2013, the hunt for “a dementia cure or disease-modifying therapy by 2025” has become a global target. We have seen major investment from public and private funding bodies alike, stimulating national and even global collaborations. Current research has focused on drug interventions and clinical trials, as well as relevant biomarkers including novel imaging for assumed brain pathology.

The progress to date has not been promising, but the reality is that healthcare and pharmaceutical companies are looking at large potential profits from future dementia interventions. It makes sense for them to play up the possibility of avoiding conditions associated with ageing, both now and in future. It would be particularly lucrative for them to be able to recommend specific medications for younger people who had been found to have a higher risk of developing dementia later in life. Such treatments could enjoy far wider demand than a specific targeted cure for the smaller group who are already developing the condition.

But if dementia prevalence is indeed stable or even declining, might past policies provide a better answer? Remember we are talking about a generation which experienced substantial post-war investments in education and socialised healthcare, and a partial reduction in social inequalities as a result. If it has worked thus far, the same kind of approach might be the best way forward for the future. Adopting a drug-only approach is likely to lead to widening inequalities of access and problems with affordability, as we learned with HIV/AIDS, cancer and other diseases.

The current dementia prevention advice focuses on what people can do in terms of healthy behaviour and lifestyle: exercise, diet and so forth. Yet our lifestyles and health are considerably influenced by factors in our wider social environment over which we have limited control. For the sake of future populations, this is why responsibility for dementia prevention should be seen as a matter for society and the world as a whole.

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The Conversation

Yu-Tzu Wu is Epidemiology at University of Cambridge and Carol Brayne is Professor of Public Health Medicine at University of Cambridge. This article was originally published on The Conversation. Read the original article.

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Facts and Opinions is a boutique journal, of reporting and analysis in words and images, without borders. Independent, non-partisan and employee-owned, F&O is funded by you, our readers. We do not carry advertising or “branded content,” or solicit donations from foundations or causes. Please support us, with a subscription (click here for our subscribe page) or a donation, and/or by spreading the word.

 

 

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Science seeks solutions for drug-tainted waterways

 By Elizabeth Grossman, Ensia
August, 2015

Photo by Iqbal Osman via Flickr, Creative Commons, Drugs, Pharmaceuticals, water pollution

Photo by Iqbal Osman via Flickr, Creative Commons

There’s no way around it, the headlines are disturbing. And they come, not from tabloids or click-bait blogs, but from papers published in scientific journals. They describe fish and birds responding with altered behavior and reproductive systems to antidepressants, diabetes medication, and other psychoactive or hormonally active drugs at concentrations found in the environment. They report on opiods, amphetamines and other pharmaceuticals found in treated drinking water; antibiotics in groundwater capable of altering naturally occurring bacterial communities; and over-the-counter and prescription drugs found in water leaching from municipal landfills. And these are just some of many recent studies examining the countless pharmaceuticals that are now being found just about everywhere scientists have looked for them in the environment.

Exactly how many drugs are in use and how many may be detectable in the environment is difficult to pinpoint. But according to the U.S. Centers for Disease Control and Prevention, U.S. healthcare providers order or provide millions of drugs each year. In 2002, the U.S. General Accountability Office estimated that more than 13 million pounds of active pharmaceutical ingredients were sold for animal use alone. And according to one analysis, the U.S. Food and Drug Administration has approved about 1,500 drugs since it was established in 1938. Recent studies by the U.S. Geological Survey have found dozens of different pharmaceuticals in surface water sampling, and the USGS is now testing water from 38 streams in 24 states plus Puerto Rico for the presence of about 200 different pharmaceuticals or their metabolites (compounds drugs morph into as they pass through the body).

Regulatory and health authorities, including the U.S. Environmental Protection Agency, the FDA and the World Health Organization, note that levels of individual pharmaceutical compounds being measured environmentally — typically in water — have not been shown to harm human health. But many individual scientists, as well as the European Commission and other groups, have expressed concern about potential effects of the mixture of pharmaceutical chemicals present in the environment. Others, including researchers at the USGS who have been studying pharmaceuticals since the 1990s, also express concern about the consequences — for plants, animals and naturally occurring bacteria as well as human health — of long-term, low-level exposure to the various types of compounds being detected.

About 90 percent of pharmaceuticals found in the environment arrive there after being excreted.Where are these compounds coming from? How do we know if they pose hazards to people or the natural systems on which we depend? And what’s being done to address concerns about the ubiquitous presence of so many drugs in the environment?

Prescribing Trouble

About 90 percent of pharmaceuticals found in the environment arrive there after being excreted. Of these, antibiotics are a particular source of growing concern given the rise of antibiotic resistance, says Anna Zorzet, coordinator for ReAct Europe, an antibiotic resistance awareness and advocacy group hosted by Uppsala University in Sweden. The recent rapid increase in antibiotic use in humans and on livestock has reduced these drugs’ effectiveness as bacteria evolve to tolerate frequently used antibiotics, a problem that can be compounded by their presence in the environment.

The rest of the pharmaceuticals in the environment come from discarded medicine and effluent releases at pharmaceutical manufacturing sites, explains Dan Caldwell, toxicology fellow with Johnson & Johnson Environment, Health, Safety, and Sustainability. Many of those discards and much of that effluent also ends up in water — either as runoff from landfill or discharge from factories.

That treatment plants don’t target drugs is actually not surprising in the United States, where there are no drinking water quality standards for pharmaceuticals. While most of the world’s urban wastewater goes to treatment plants, typical waste- and drinking-water treatment methods are not designed to remove pharmaceuticals. In a 2011 report, WHO estimated that depending on the method, conventional water treatment plants might remove anywhere from less than 20 to more than 90 percent of the pharmaceuticals compounds present.

That treatment plants don’t target drugs is actually not surprising in the United States, where there are no drinking water quality standards for pharmaceuticals. About 10 drugs are now included on the EPA’s “contaminant candidate” list of pollutants being considered for possible regulation. But none is yet regulated, meaning there are no set limits on what’s considered a safe level in drinking water. This makes it very hard when local water utilities report on pharmaceuticals they find in their systems — as many do — to know what the reporting actually means or what (if anything) to do about it.

Sophisticated Testing

With use of pharmaceuticals growing worldwide, it’s no surprise that we’re finding more and more of them in the environment. But increased usage is not the only reason detection is on the rise. As increasingly sophisticated environmental testing methods have become available in recent years, what have come to be called micro-pollutants and emerging contaminants — a category that includes pharmaceuticals — have started to be detected with greater precision.

“Analytical chemistry has progressed from being able to detect parts per million to parts per billion to parts per quadrillion,” says Caldwell. USGS research hydrologist Dana Kolpin, who’s been studying pharmaceuticals in the environment for more than 15 years, explains that early on, scientists could only measure about 19 pharmaceuticals in a one liter water sample. Today, he says, “we use a 15-milliliter vial in which we can now measure 110 pharmaceuticals at much more sensitive levels.”

McGill University associate professor of chemical engineering Viviane Yargeau and colleagues have found “illicit drugs” — including amphetamines, methamphetamine, cocaine and prescription opiods — in Canadian drinking water sources at nanograms per liter (parts per trillion) levels. These concentrations are “really small,” says Yargeau, and the impacts of these particular compounds on wildlife and other biota have yet to be determined.

Pharmaceuticals being measured in the environment in small concentrations can produce biological effects when those levels are tested in controlled experiments. 

“The fact they are there, shouldn’t be cause for alarm,” says Caldwell of pharmaceuticals being found in various water sources at this range of levels.

Yet impacts at infinitesimal levels are increasingly what studies are finding. Pharmaceuticals being measured in the environment in small concentrations can produce biological effects when those levels are tested in controlled experiments. For example, University of Wisconsin researchers recently discovered that levels of the antidiabetic drug metformin comparable to those found environmentally caused male fathead minnows to develop intersex gonads. Scientists in the U.K. have found that concentrations of the antidepressant fluoxetine (sold under various names, including Prozac) found in environmental samples altered behavior of starlings in an experimental study. Others in Sweden found similar results when fish were exposed to levels of another psychoactive drug, oxazepam, at levels found in wastewater samples.

While regulators stress the lack of evidence that such levels are harming human health on an acute basis — a point J&J’s Caldwell also made — some scientists, including Kolpin and Yargeau, note that monitoring drugs at low levels is important for understanding possible long-term effects.

“We want to go as low as we can go in measurement as this is important in understanding long-term trends of exposure,” says Kolpin. Even though organisms may look healthy, he explains, when you start to examine their tissues and behavior, “more subtle effects” of chemical exposure may become apparent. Having as much detailed data as possible will help scientists figure out what might be happening at a population level, rather than only to isolated individuals.

This type of detailed information about individual drugs will also help pinpoint which pharmaceuticals to target for removal, says Yargeau. Additional studies are needed to guide regulators toward improving monitoring and treatment, she explains. “If we don’t do something, it might get worse,” she says.

How Big of a Problem?

Part of what’s needed is a more comprehensive grasp of exactly what’s out there and how big of a problem various pharmaceuticals pose in terms of When it comes to assessing a drug’s environmental impacts, things can get very complicated.human and environmental health impacts. As the Natural Resources Defense Council noted in a 2009 white paper, there are large data gaps in this domain — exact volumes of drugs used, relative contributions from humans and livestock, and a full accounting of what drugs are in the environment. Many studies document the presence of drugs, but thus far in the U.S. no data yet yield an overall picture. New studies forthcoming from USGS and the EPA may start to fill in those blanks.

When it comes to assessing a drug’s environmental impacts, things can get very complicated. To understand what the environmental and health ramifications of a particular pharmaceutical may be, regulatory agencies in both the U.S. and Europe rely on information that comes from manufacturers. In the U.S., pharmaceutical manufacturers must submit this information to the FDA as part of the drug registration process, explains Raanan Bloom, senior toxicologist with the FDA’s Center for Drug Evaluation and Research.

This environmental assessment — in Europe called an environmental risk assessment — includes information about the drug’s ecotoxicity at various concentrations and about its effects on various aquatic organisms. The information is then correlated with manufacturers’ projections of production, sales and use volume to estimate what potential environmental impacts will be.

Drug categories now receiving particular attention from the FDA are hormonally active compounds, antibiotics and what the FDA calls “high volume” drugs — those used frequently.A study by a group of Swedish and U.K. researchers found 83 percent of ERAs produced in 2011 and 2012 to be either lacking in data or incomplete. And a report just released by the Swedish Foundation for Strategic Environmental Research is extremely critical of the environmental risk assessments pharmaceutical manufacturers submit to European Union authorities. The report also criticizes claims in these assessments of a need to keep certain information confidential ­— something that is also a feature of the environmental assessments drug manufacturers submit to the FDA — and calls for making the assessments available to the public. To improve efficiency in understanding and heading off potential problems, the study also suggests grouping risk assessment for similar compounds rather than relying on the current compound-by-compound approach. Among its other recommendations is the inclusion of information about a drug’s potential contribution to antibiotic resistance.

Drug categories now receiving particular attention from the FDA are hormonally active compounds, antibiotics and what the FDA calls “high volume” drugs — those used frequently. In April the FDA proposed guidelines about whether manufacturers will have to submit environmental assessments with applications for new drugs with hormonal effects. This, said Bloom, “points out our concern with hormonally active drugs.” But what’s being proposed wouldn’t necessarily prevent such compounds or their breakdown products from ending up in local water sources.

What Can We Do?

Given the demonstrated and potential impacts, what can we do about drugs in the environment?

Unused and unneeded drugs can go into take-back programs. In the EU, take-back and collection programs are required by law. Most collections there are handled by pharmacies, and much of what’s collected is incinerated. In the U.S., the Drug Enforcement Administration has, in many states, offered twice-yearly collections that since 2010 have collected more than 4.8 million pounds of prescription drugs. Some U.S. states and other local governments have drug take-back programs as well. But there are logistical challenges for both recipients and contributors: Collectors of unwanted drugs — typically healthcare facilities, pharmacies and law enforcement offices — must be authorized by the DEA and arrange for proper handling of the unwanted drugs, and such facilities may not be conveniently located for drop-off.

Drug manufacturing offers another opportunity for reducing release of pharmaceuticals to the environment. Although manufacturing’s contribution to pharmaceutical pollution is comparatively small, it can create “hot spots” of pollution. For example, near Hyderabad, India, which has been a major production site for generic drugs, researchers testing wastewater treatment plant effluent found levels of several antibiotics that Zorzet describes as being comparable to those that would be prescribed for treatment.

Pharmaceutical companies are also working to improve their manufacturing processes’ environmental footprint, not just at the end of the pipe but also by moving to “green chemistry solutions.To reduce such emissions, the industry is working to develop and implement what are being called “Ecopharmacostewardship” guidelines. The goal, Caldwell explains, is to work with facilities and suppliers around the world to, as he and colleagues wrote in a recent paper, “achieve the general standard of ‘no discharge of APIs [active pharmaceutical ingredients] in toxic amounts.’”

Both Caldwell and the FDA note that pharmaceutical companies are also working to improve their manufacturing processes’ environmental footprint, not just at the end of the pipe but also by moving to “green chemistry” solutions. Those include both more efficient drug production and designing drugs that will biodegrade more efficiently or that are effective as intended but minimize by-products that will be excreted and end up in the environment.

Wastewater treatment plants, meanwhile, are exploring possibilities for boosting their ability to remove pharmaceuticals from sewage.There is also concerted and substantial work underway in the pharmaceutical industry — including in India — to make manufacturing processes more efficient given that, historically, the industry was known for inputs — raw materials and energy — at volumes that dwarfed the volume of the finished product. Several pharmaceutical manufacturers, including  Bristol-Myers Squibb, Eli Lilly, Merck & Co. and Pfizer, have won U.S. Presidential Green Chemistry Challenge awards for these efforts.

Wastewater treatment plants, meanwhile, are exploring possibilities for boosting their ability to remove pharmaceuticals from sewage. Options range from treating water with ozone to enlisting the assistance of microbes. But, as the 2011 WHO report cautions, “Advanced and costly water treatment technology will not be able to completely remove all pharmaceuticals to concentrations less than the detection limits of the most sensitive analytical procedures at all times.”

Just Beginning

All indications are that we’re just at the beginning when it comes to understanding the presence and importance of pharmaceuticals in the environment, let alone what to do about them. Even as scientists investigate what’s actually out there, pharmaceutical companies work to make drugs and drug production more environmentally benign, wastewater treatment professionals develop better ways to remove pharmaceuticals, and environmental and public health advocates work on campaigns to change practices, studies finding pharmaceuticals in the environment keep coming.

In fact, Kolpin says, hundreds are published each year. And although the amounts of pharmaceuticals being measured are exceptionally small, he says this information is important because it provides a base line for future comparison.

“What we think today is safe, we may find 10 years from now there is some effect, that we didn’t realize at the time was important,” he says. “We’re not trying to say the sky is falling. We’re trying to put out the science saying there are some things that are of concern.”   View Ensia homepage

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Related on F&O:

Boys will be girls: “zombie” chemicals are pervasive, by Natural Security columnist Chris Wood, October, 2014 (subscription needed*)

In Alberta rivers downstream from certain Intensive Livestock Operations – better-known as feedlots, where hundreds and even thousands of cattle are crowded together in foetid paddocks of manure and urine the more economically to supply North America’s steak and burger-loving consumers – almost all the males have disappeared from key minnow populations.The suspected cause: the buildup in the water of chemicals that mimic hormones, the molecules that signal most life forms how to develop and function. The water-borne mimics originate in steroids and other drugs that agribusinesses pump into feedlot cattle to speed weight gain, and counter the spread of disease among animals close-packed in compounds paved with excrement.

 

 

Elizabeth Grossman is an author and journalist.Elizabeth Grossman is an author and journalist.

Visit her web site here: http://www.elizabethgrossman.com/Elizabeth_Grossman/Home.html

 

 

 

 

 

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*Facts and Opinions is a boutique journal, of reporting and analysis in words and images, without borders. Independent, non-partisan and employee-owned, F&O is funded by you, our readers. Some of our work is behind a paywall because we do not carry advertising or “branded content,” or solicit donations from foundations or causes. Please support us, with a subscription (click here for our subscribe page) or a donation, and/or by spreading the word.

 

 

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