Photo courtesy of SNAP

Dr. James Weedon, executive director of the Spay Neuter Assistance Program, Inc., (SNAP) in Texas, sterilizes a dog with a shot of zinc gluconate. SNAP neutered 1,738 dogs by injection in 2004-05 when the drug was first available.

An injectable drug that sterilizes male dogs is headed back to the U.S. market seven years after it went out of production due to business missteps and complications associated with its use.

Renamed Zeuterin, the drug once called Neutersol is a solution of zinc gluconate that’s injected directly into the testicles, killing existing sperm and stimulating inflammation that leads to scarring. Scar tissue blocks future sperm from passing through feeder tubes, rendering the patient infertile.

Officials of Ark Sciences, the company that acquired the rights to the prescription drug, anticipate bringing Zeuterin to the market on Dec. 21, pending approval by the U.S. Food and Drug Administration (FDA) of the manufacturing facility in Albuquerque, N.M. The drug currently is in limited use by veterinarians and clients participating in training and review studies.

A successful reintroduction will require overcoming skepticism among the many private practice veterinarians who are accustomed to neutering dogs surgically and consider the existing procedure simple and effective. Success also will require rebooting the drug’s reputation, which was damaged in the bungled debut.

“Neutersol did such a good job advertising, it got people excited, but when it fell on its face, it brought a big backlash,” said Dr. Michael Braun, a veterinarian with Ark Sciences. “That’s tough. It’s a tough way to start a company again.”

Braun, a small animal clinician for more than 30 years, joined the company as a “master trainer” after Ark Sciences identified improper injection technique as the main factor behind adverse effects, which were chiefly severe scrotal ulcers. The company is requiring all veterinarians who wish to use Zeuterin to undergo between four to six hours of in-person training.

Braun said he believes in the product’s safety, efficacy and potential to make a difference in pet overpopulation. “Sometimes you have a chance in life to do something bigger,” he said. “This is (a) chance, once in a lifetime, I can do something that affects more than just my sphere of influence. When millions of animals are being put to sleep just in America, something is wrong.”

Neutersol was approved in 2003 by the FDA as a sterilant for male puppies age 3 months to 10 months. At the time, it was welcomed cautiously by a number of spay-neuter advocacy groups as a potential game-changer: Here was an effective method of neutering dogs that was far less invasive, less expensive and faster than surgical castration, with no need for anesthetics.

Dr. Sarah Brown, a practitioner in North Carolina who works with a national spay-neuter organization, said, “When it first came out, we were very interested in it; we were looking to promote it nationally.”

But before giving an endorsement, the group put the product to the test. (Brown declined to name the organization, noting that she was speaking personally and not for the group.) It injected on the order of 75 to 100 dogs. Brown recalls two, possibly three, developing severe scrotal ulcers. One dog had to undergo a scrotal ablation, a surgical procedure that is more extensive than routine castration. Another was euthanized because he “was getting aggressive,” Brown explained, “— whether ... because (he) was in pain, I don’t know.”

Alarmed by the outcome for these unlucky dogs, the group sought answers from the drug maker to no avail. Two companies were behind Neutersol: Pet Healthcare International, the manufacturer, and Addison Biological Laboratory Inc., which handled marketing.

“They were fighting each other like cats and dogs," Brown said.

Ark Sciences explains on its website: “Addison Labs, the exclusive distributor of Neutersol, overestimated the growth in demand and created too much inventory. The excess inventory expired in two years and the manufacturer went unpaid...”

The contentious environment made for poor product support and training. “It was basically, ‘Yep, here’s how you measure the testicles, here’s how to pull up the drug. Give it to them,’ ” Brown said.

She said a veterinarian involved with another Neutersol project about the same time also reported severe ulceration in 2 to 3 percent of animals injected — higher than the 1.1 percent rate of severe side effects reported in studies conducted as part of the drug approval process.

“When we got the ulcers, we said, ‘OK, we’re done,’ ” Brown said. “ ‘The companies aren’t behaving nicely.’ So that was that.”

That was that for the drug maker, too. Summarizing the missteps by the product’s early promoters, Braun at Ark Sciences recounted:

“They did not realize that this was a disruptive technology that needed a radical change in (the) business models of veterinarians. Nor did they anticipate that an eight-step instruction sheet and sometimes a video, as well, was not enough to get veteran veterinarians comfortable with the procedure. Such training was not sufficient to minimize adverse reactions, either.”

What with the unsold inventory and the manufacturer going unpaid, the business partnership collapsed, Braun said. At the same time, “Rumors spread that the product was bad. It hurt dogs. It killed dogs. Hence," he said, "it was pulled from the market.” That was 2005.

But some believers in Neutersol hadn’t lost faith. Joe Tosini, a minor investor in Pet Healthcare, picked up the international distribution rights. He founded Ark Sciences, becoming its CEO, and received approval in Colombia, Bolivia, Panama and Mexico, where it is marketed as Esterilsol. The activity abroad paved the path to the drug’s resurrection in the United States.

Injection should be given slowly

The revived product, Zeuterin, is identical to Neutersol. It consists of a zinc compound (zinc is a mineral that occurs naturally in the body) and L-arginine, an amino acid that serves to neutralize zinc gluconate, which otherwise is acidic.

What’s different is the new owner’s emphasis on injection technique. The right way to inject the solution into a testicle, Braun said, is very, very slowly, using a 28-gauge needle, which is finer than needles typically used for vaccinations.

Proper administration means taking at least five seconds and as many as 12 seconds to gently introduce between 0.2 and 1 cc of liquid into each testis, according to the Zeuterin training manual. (The dosage per side depends upon the maximum width of each testis.)

Photos courtesy of Ark Sciences

Testes typically swell in the first few days following treatment, as seen in the photo at left of a dog one day after his injection. Ultimately, the testes tend to atrophy. The dog in the photo at right is shown three months after his treatment.

Except for the mild prick as the needle enters the skin, an injection should cause no pain, the product makers maintain, because the testicles themselves have no pain sensors; only pressure sensors.

The training manual cautions that injecting too rapidly may stimulate contraction of the seminiferous tubules, causing pressure pain and leakage of the drug from the injection site. Leakage may lead to infection and ulceration.

The whole procedure may be completed in a matter of moments. “I can do 30, 40, 50 dogs before I even think about a coffee break because all I’m doing is injecting,” said Braun. “We don’t shave, we don’t surgically prep, we just clean with chlorhexidine.”

Ark Sciences recommends lightly sedating dogs to keep them still and relaxed but Braun said some dogs, if simply steadied by their owners, may be calm enough for an experienced veterinarian to inject without sedation.

Patients benefit from monitoring in the days immediately following the injection, as some may try to lick or chew on their testicles, which typically swell before beginning to atrophy. Treated dogs usually end up with smaller testicles, although one study referenced in a document provided to the FDA noted “a large amount of variability in individual dog testicle size, with some dogs showing larger testicles ... and other dogs with testicles so small they could not be measured at one year post-injection.”

While the injection itself is said to be virtually painless if done correctly, dogs may feel mild to moderate pain during the week following treatment. Some dogs may vomit within the first four hours, as well. In rare cases, treated dogs have developed necrosis of scrotal tissue.

Intact look appeals to certain owners

In its quest to revive the drug, Ark Sciences contacted Brown, the North Carolina veterinarian who had tried Neutersol and found it wanting. Persuading her to take another look took some effort.

“I was very reluctant,” Brown said. Company representatives persisted. “I’d say, ‘Yeah, but ...’ and they’d come up with a good answer.”

So Brown agreed to attend a training session in August in Kansas City, where she was already headed for a veterinary conference. That experience turned around her poor opinion of the drug.

She was impressed by the company’s commitment to training and the quality of the training. “They seem really genuine in making this as safe as they can and as consistent,” she said. She added that it makes “logical sense” that the scrotal ulcers resulted from improper injection technique rather than an inherent flaw in the product.

Brown has decided to make the product available in her private practice in select instances. “When somebody shows any hesitation about traditional castration, I make the offer,” she said.

As an example, Brown said that during a recent Saturday rabies clinic, the owner of a Doberman puppy told her, “I’m supposed to get him neutered, and I don’t feel comfortable changing him like that.”

“When I really listen to my clients, that’s what I’m hearing,” Brown said. “There is a percentage who aren’t comfortable and are a little embarrassed that they’re uncomfortable.”

She continued, “I don’t think (injectable sterilant) will replace surgical castration anytime soon, but I think it’s a realistic option we should make available to people.”

Brown said she’s talking with a local shelter about switching from surgical castration to the chemical sterilant. They’re hesitant, she said, worried that the method is so different that using it may “look like we’re experimenting with dogs.”

Photo courtesy of SNAP

The offer of free neutering via zinc gluconate injection drew a crowd of pet owners with their dogs to an event in Galveston, Texas, in 2004.

One spay-neuter organization with extensive experience using zinc gluconate solution is the Spay Neuter Assistance Program, Inc. (SNAP), based in Houston. Between August 2004 and April 2005, SNAP injected 1,738 male dogs with Neutersol, mostly during one-day events around New Mexico and Texas.

Corporate and foundation donations enabled SNAP to offer the injections for free, and the events were popular, in some venues drawing long lines of participants, said Dr. James Weedon, executive director of SNAP.

One such event, dubbed Hooters for Neuters, was hosted by the chain restaurant known for its busty waitresses. “We got a lot of bikers in there with their big, macho dogs and their macho bikes, and it went really well,” Weedon remembered with a chuckle.

He said the injection method appeals to dogs owners who want their dogs intact not for the biological function but for appearance’s sake.

SNAP tracked results in the dogs it injected. Weedon reported the details in a presentation at the 2009 North American Veterinary Conference.

Of 1,738 participating dogs, 12 required follow-up veterinary care. Among those, seven needed minor care, such as pain medication. The other five underwent surgical castration or scrotal ablation. SNAP provided or paid for all after-care services.

SNAP ended its Neutersol events when the product went off the market. Now that it’s on the way back, Weedon is asked frequently whether his organization will resume its use. He hasn’t decided.

It’s not that he’s lost confidence. “I’m not afraid of the product,” Weedon said. “It’s an OK product.”

His hesitation is for practical reasons. For one, male dogs aren’t the clinic’s main patient population. “The public is much more likely to bring you females. After all, that’s who delivers the unwanted puppies and kittens,” Weedon said. “And I get a lot more male cats probably than male dogs because living with a male cat in your home is pretty unacceptable,” he said, alluding to tomcats’ penchant for spraying.

Secondly, SNAP is comfortable and efficient with surgical spaying and neutering. “My team is so geared right now doing true spays and neuters that it would be almost an interruption to do something different,” Weedon explained.

Behavioral, medical side effects debated

Many veterinarians in private practice are reluctant to adopt what they view as a generally unknown agent with possible disadvantages compared with castration.

In South Carolina, Dr. Jennifer Ng works in a clinic that used Neutersol when it was available. Though Ng wasn’t there at the time, she has seen several zinc-neutered patients in the years since.

One is a beagle mix who had been chemically sterilized at 6 months of age. Two years later, his owner brought the dog to the veterinarian complaining of a sudden increase in marking behavior (urinating as a way of claiming territory), indoors and out. Laboratory analysis showed that although he was sterile, the dog still had the testosterone levels of an intact male, Ng said. She castrated him surgically, and the owner reported that dog stopped marking.

A second patient, a West Highland terrier who had been injected with Neutersol when 9 months old, was found six years later to have developed prostatitis — inflammation of the prostate gland, a condition fueled by testosterone. Following surgical castration, the problems with his prostate resolved, Ng reported.

Ng doesn’t know how many dogs in total were sterilized with Neutersol at the clinic but found records for at least 26. The beagle mix and Westie are the only two she’s aware of who developed hormone-related problems.

All the same, Ng said she’s disinclined to use the injectable sterilant. “Most people who want their dog neutered also want the behavioral and medical benefits that come along with it,” she said. “I don’t feel you necessarily get these with Zeuterin. I’m also not convinced that it’s any less painful than a surgical neuter.”

Questions of behavioral and medical side effects of castration versus chemical sterilization are contentious.

According to Ark Sciences, zinc sterilization reduces testosterone levels to about half that of an intact dog. By comparison, surgical castration reduces it to almost none. Which state is better for dogs is debatable.

Potential health consequences are associated with both normal and very low testosterone levels. Normal levels are likely to fuel prostate enlargement in older dogs, predisposing them to chronic bacterial infection and inflammation. Very low levels have been found to raise the risk of prostate cancer, although the condition is much less common than prostate enlargement. The health effects of reducing testosterone levels by half remains to be seen.

As for behavior, it’s commonly believed that castrated dogs are less aggressive, less prone to mounting and less apt to mark inappropriately. But to what extent that’s true is uncertain.

“The problem is, we don’t have any good studies on that,” said Brown, the veterinarian in North Carolina. “How many dogs have we euthanized for aggression that were neutered versus intact? After 30 years of practice, I don’t see any difference.”

Whether chemical sterilization affects male dog behavior long-term is even less known. Veterinarians Without Borders - Canada is in the midst of a study in Chile examining the question. The work is supported by the Alliance for Contraception in Cats & Dogs, a non-profit organization in Oregon that has tracked the history of the product in detail and written a profile and position paper on it.

Another factor working against chemical sterilization is the aversion that some people feel at the thought of piercing a testicle with a needle. On a message board of the Veterinary Information Network (VIN), an online community for the profession, the injection method is described variously as “barbaric” and “cringe-worthy.”

Brown said when Neutersol first came out, she gave a presentation to a small gathering of her state veterinary medical association. As she explained that the zinc solution is injected into the testicles, one of the veterinarians in the audience yelped and jumped in his seat, knocking his chair backwards.

“We all looked at him like he had three heads,” Brown recalled. He was embarrassed and later apologized.

Brown asked the doctor: “How many testicles have you cut off dogs?”

“Thousands,” he replied, sheepishly explaining that his response was a pure knee-jerk reaction.

Although women, too, may be squeamish, they tend to be less so than men, Braun said. At training sessions, he said, “Their hands shake a little less.”

High-volume spay-neuter programs seen as niche

Chemical neutering reportedly has been welcomed in developing countries where stray or marginally owned dogs are a problem. Dr. Ben Leavens, a Missouri practitioner who traveled to Samoa in 2010 to assist with a spay-neuter project that employed the injectable sterilant, reported on a VIN message board: “It has been going well, getting dogs neutered that otherwise would not be due to lack of surgical facilities.”

Leavens also has met veterinarians from parts of Africa, Central America and South America who speak well of the product. “It may not be all that popular in the U.S. but will probably have its place,” Leavens said.

Although sterilizing by injection rather than surgery is simpler, some advocacy groups working in foreign countries are mindful that proper training is essential to minimizing complications, since treated dogs may not have access to follow-up care. Friends of the Humane Society of Tijuana, for example, is familiar with zinc neutering but has not deployed it in street clinics the group holds in the Mexican border town.

Photo courtesy of Ark Sciences

Unlike dogs that are surgically neutered, dogs sterilized by injection of zinc gluconate still have testicles. A “Z” tattoo identifies them as chemically neutered.

“We have discussed using it at our clinics, but we would have to make sure that all of our vets are very well trained prior to using it on our clinic animals,” said Nicole Riley, the group’s board secretary. “Our fear is that the animal will not get treatment if there is a reaction or infection at the injection site. Most of our clinic animals have never and likely will never see a vet again after they come to a clinic so we need to make sure that they leave us in good condition.”

Ark Sciences executive team member Sandeep Manchanda estimates that at least 20,000 dogs around the world have been sterilized with zinc gluconate to date.

In the United States, Braun said, the company sees Zeuterin’s niche in large high-volume spay-neuter clinics. “We don’t have the time, expertise and money to go out to every veterinarian in the private sector and face-to-face teach this technique,” he said. (The price of training officially is $500, Braun said, but veterinarians undergoing training before the product is reintroduced formally aren’t being charged, nor are owners of dogs given the injection.)

At the same time, Ark Sciences is trying to reach out to all veterinarians for one important reason: Doctors need to be able to recognize dogs that have been neutered by injection.

Besides the physiological signs — atrophied testes that feel harder than normal due to scar tissue — Ark Sciences suggests that veterinarians using the product tattoo a small green “Z” by the patient’s groin. (Weedon, the veterinarian in Texas, said he found the tattoo process more apt to cause a pain response in dogs than the injections.)

The dog also is supposed to be given an identification tag for his collar and a notation in his microchip record if he is microchipped. Finally, his owner gets a “certification of sterilization” as written documentation.