February 2008 Archives

Speaking of 1956 black-and-white heist movies...this week, the Pathophilia blog recommends Rififi ("Trouble" en français). The magnetically reticent Jean Servais stars as a seasoned thief who attempts to pull off one last, great jewel robbery. Particularly delightful is the ensemble break-in, with its silent (literally), low-tech ingeniousness. According to the imdb, Al Pacino has signed up for a 2009 remake.

In its continuing coverage of the criminal case against transplant surgeon Hootan Roozrokh, MD, the San Luis Obispo Tribune reports on the second day of testimony from Laura Lubarsky, MD, at a preliminary hearing. Lubarsky is the critical-care specialist who served as Ruben Navarro's attending physician at the Sierra Vista Medical Center on the night of February 3, 2006, when Navarro's organs were to be harvested during cardiac-death donation.

Lubarsky, who has received immunity from prosecution, reportedly described her role on the night in question in conflicting terms: although an "independent observer" of the organ-donation process, she admitted to also having "an ethical and legal obligation to protect [Navarro] from harm." The reported facts of the case suggest that Lubarsky acted more consistently (and regrettably) as a spectator in Navarro's end-of-life care, while the patient was given massive doses of morphine and lorazepam, which were ordered by Roozrokh.

Lubarsky admitted yesterday on the stand that Navarro, once his mechanical ventilation was removed, did not exhibit the signs of pain or distress that would warrant such large doses of analgesic or sedating medication. Lubarsky also implied either ignorance or confusion regarding her role as attending physician in the process of cardiac-death donation.

Information to date suggests that the final events of Ruben Navarro's life are a consequence of the unhappy meeting of extreme passivity and aggressiveness in Lubarsky and Roozrokh, respectively.

For what it's worth, a newly available, heavily redacted inspection form details observations made by FDA investigator Regina T. Brown and chemist Zi-Qiang Gu regarding Changzhou SPL Company Ltd, the Chinese facility that supplied some of the main ingredient in Baxter's now-recalled heparin products.

The general impression, after attempting to read through the "whiteout," is one of shoddy documentation and execution of heparin processing (particularly concerning the removal of impurities) and quality control at the Chinese plant.

One itemized deficiency relates to the "description of manual manipulations of the [Redacted] during processing steps." The description continues, "[T]hey do not include the actual, manually entered [Redacted] set temperatures and times and, operator observations such as level measurements, used in calculations, during the [Redacted] step are not recorded." Given the reference to "manually entered...set temperatures and times," this notation may well relate to a poorly documented autoclave depyrogenation step.

A letter in the latest issue of the NEJM indicates that the number of neonates identified with cystic fibrosis (CF) through neonatal screening declined substantially during the 4-year period from 2003 to 2006 in Massachusetts and was associated with a significant decrease in the number of infants with the most common CF-related genotype, ∆F508/∆F508.

The authors, from the New England Newborn Screening Program, observed an expected number of infants with CF from 1999 to 2002; however, in 2003, infants identified with the ∆F508/∆F508 genotype declined significantly, and this decline was maintained during the next 4 years.

The authors conjecture that the gradual uptake of preconception and prenatal screening to identify CF carriers among the general population since 2001 has resulted in fewer births of children with recognized CF-related genotypes. But they advise that the reduced incidence of known CF genotypes will lower the predictive value of newborn screening for CF.

Photo: iStockPhoto

Printing its first non-AP blurb on the subject, the NYT today features the criminal proceedings against California transplant surgeon Hootan Roozrokh, MD—a story that has heretofore received considerable attention in the West Coast press and elsewhere. Prompting the NYT's attention now is evidently the fact that a preliminary hearing in the case begins today in the San Luis Obispo County Superior Court. Roozrokh is charged with three felony counts related to the 2006 death of potential organ donor Ruben Navarro at the Sierra Vista Regional Medical Center.

 

Some of the best coverage to date on this story (and available through the oh-so-terrific Google News archive feature) can be found in a-little-paper-that-could, the San Luis Obispo Tribune, with the bulk of its reporting on this story by Sarah Arnquist. Particularly informative are reports of unsealed court documents from the AP, by way of the Tribune. These documents, coupled with complementary news stories, enable the construction of the following rough timeline of the attempt to harvest Navarro's organs during his unfortunate last hours and the ensuing events.

 

• 01/29/06: Navarro, a 25-year-old man debilitated by adrenoleukodystrophy, is found in respiratory arrest at the Casa de Vida adult-care facility and is taken to Sierra Vista (which, according to Google Maps, is right across the street), where he is revived but remains comatose and on life support.

 

• 01/29/06-02/03/06: At some time during this period, Navarro's family agrees to remove the patient from mechanical ventilation and to donate his organs (however, this claim is challenged later by the patient's mother, Rosa Navarro, who says her consent was not informed). Navarro reportedly has minimal brain function but is not brain dead, and at least one of his Sierra Vista physicians allegedly writes in medical records that Navarro would not make a good candidate for a procedure known as cardiac-death donation—which requires organ harvesting within 30 minutes of death—because Navarro's "drive to breathe was still intact."

 

• Friday, 02/03/06, evening: A dispatched team from the California Transplant Donor Network, which includes Roozrokh, another surgeon Arturo Martinez, and nurse coordinator Carla Albright, arrive at Sierra Vista. Roozrokh and Martinez examine Navarro in the ICU, a clear violation of organ-donation law, which prohibits contact between transplant surgeons and potential donors during life. This contact is also in violation of Sierra Vista policy.

 

• 02/03/06, 11 pm and after: In preparation for a cardiac-death donation (reportedly the first ever performed at Sierra Vista), Navarro is transferred from the ICU to an operating room, where mechanical ventilation is to be disconnected and his organs harvested within a 30-minute window of time after death. The transplant physicians are evidently in the OR at this time, another clear violation of transplant law and hospital policy. Also allegedly present are at least six staff members, including critical-care specialist Laura Lubarsky, MD, a respiratory therapist, and several nurses. According to reports of unsealed records, at 11:10 pm, a transplant surgeon (presumably Roozrokh) orders 100 mg of morphine and 40 mg of lorazepam (Ativan) to be given to Navarro, despite the fact that the doctor does not have hospital privileges at Sierra Vista. Shortly thereafter, Roozrokh allegedly directs the respiratory therapist to remove Navarro’s ventilatory assistance, and Lubarsky tacitly agrees (per the respiratory therapist). However, once off the respirator, Navarro does not die. What apparently follows is a disagreement between Roozrokh and nurse coordinator Albright as to whether Navarro has a pulse: Roozrokh believes there is none, while Albright claims that she can see Navarro’s heartbeat through his emaciated chest (Navarro apparently weighed about 80 pounds; also, there is confusion in the press reports as to whether Navarro is hooked up to a heart monitor at this time). Allegedly frustrated with Albright, Roozrokh orders another large dose of morphine and lorazepam to be given to Navarro and is quoted as uttering the unfortunate phrase, "Let's just give him some more candy." (Reports indicate that astonishing doses of both medications are ultimately given to Navarro—200 mg of morphine and 80 mg of lorazepam.) Also at some point in time, Roozrokh suggests that the neuromuscular blocker vecuronium be given to Navarro; however, Albright objects. Roozrokh does administer Betadine through Navarro's feeding tube, presumably as a sterilization maneuver—which should be performed after death but before organ harvesting. From reports, it can be concluded that Roozrokh (possibly along with the rest of the transplant team) leaves Sierra Vista at approximately midnight. Navarro, still alive, is transferred back to the ICU at Sierra Vista.

 

• 02/04/06, ~8 am: Ruben Navarro dies at Sierra Vista, and his death certificate is reportedly signed by Lubarsky. Navarro's cause of death is originally listed as cerebral anoxia with the contributing factor of respiratory arrest. Navarro’s organs are never harvested, there is no autopsy, and his body is cremated. Sometime later, Navarro’s cause of death is revised to "pending investigation."

 

• Monday, 2/06/06: A Sierra Vista employee informs hospital administrators of the transplant-policy violation, and they contact the San Luis Obispo county coroner, the Medical Board of California, the California Department of Health Services, and the Joint Commission (the hospital-accrediting association). The medical board and county law enforcement officials begin their investigations.

 

• 05/18/06: Roozrokh is placed on administrative leave from Kaiser Permanente, after learning of allegations against the physician.

 

• 01/07: Roozrokh is reinstated by Kaiser Permanente, after "no new developments" in the investigations.

 

• 03/07: The San Luis Obispo police turn their investigation of the Navarro case over to the county DA's office.

 

• 06/29/07: Rosa Navarro, the patient's mother, files a civil suit against Sierra Vista, the California Transplant Donor Network, physicians Roozrokh and Martinez, and their employer, Kaiser Permanente Medical Group for assault, battery, fraud, civil conspiracy, negligence, medical malpractice, and intentional infliction of emotional distress. Reports also indicate that Ms. Navarro is suing her son's "primary care doctors" (naming Lubarsky, among others), as well as ResCare (a provider of disability services) and Casa de Vida. 

 

• 07/30/07: San Luis Obispo county prosecutors charge Roozrokh with three felony counts: dependent-adult abuse, administering a harmful substance (Betadine), and the unlawful prescription of a controlled substance. If convicted, Roozrokh could face up to 8 years in jail and $20,000 in fines. Roozrokh is again placed on administrative leave from Kaiser Permanente.

 

• 07/31/07: Roozrokh is booked at the San Luis Obispo county jail and is freed after posting a $10,000 bond.

 

• 09/12/07: Roozrokh pleads not guilty to two counts, and his lawyer, M. Gerald Schwartzbach (who successfully defended actor Robert Blake), requests that the second count (administering a harmful substance) be dismissed.

 

• 11/07: Ms. Navarro's civil suit against Sierra Vista and its parent company is settled for $250,000. Sierra Vista acknowledges no wrongdoing in the settlement, which covers all hospital employees who cared for Ruben Navarro on the night in question. (A disclaimer at Sierra Vista's website indicates, "Physicians performing services at Sierra Vista Regional Medical Center are independent contractors and not employees, agents or representatives of Sierra Vista Regional Medical Center," suggesting that physicians who cared for Navarro at Sierra Vista are still defendants in Ms. Navarro's civil suit.)

 

• 11/07/07: A judge rules that Roozrokh can abstain from Rosa Navarro’s civil suit, for the time being.

 

Whatever the legal outcome of this unfortunate criminal case, it seems clear that Roozrokh (and Martinez) violated the laws and policies which justifiably dictate that a very large distance should remain between transplant surgeons and a potential, living organ donor. Moreover, Navarro's case reinforces the reasons for adhering strongly to these laws and policies.

 

My own experience indicates a general, hovering aggressiveness among this particular group of occasionally self-righteous physicians, which can be intimidating and requires some degree of backbone in those who should remain advocates for the still living—even if that living is anticipated to be very short. On more than one occasion, when asked to verify brain death in a potential donor, I've been pushed to the point of saying to this particular surgical breed, Back Off.

 

Two very good reasons to get rid of the perennially excruciating category of Best Original Song at the Oscars.

1) "Happy Working Song" (I wish Jon Stewart had sung it.)

2) "That's How You Know" (Wo-hork that dress, Ms. Chenoweth.)

Can we not leave this up to the Golden Globes and be done with it?

As a bone-dry counterpoint to the WSJ's graphic illustration of the heparin-extraction process in China, the Pathophilia blog is providing a chemically overloaded, non-stomach-turning algorithm (see pdf) for the product's manufacture. Much of the following information is obtained from that great bathroom-reading text Polymeric Materials Encyclopedia by Joseph C. Salamone, which is conveniently available through Google Books (so you can take your laptop with you into the toilet).

Notably 40,000 kg of pig intestines creates only 5 kg of heparin. The Pathophilia blog has conjectured that the adverse reactions to Baxter's heparin were likely due to unacceptably high levels of endotoxin, as a result of inadequate depyrogenation (the penultimate step of heparin purification). 

*For you chem geeks and wannabes, quaternary ammonium salts include cetyltrimethylpyridinium chloride, cetyltrimethlammonium bromide, and Hyamine.

†Ion-exchange resins include Dowex, ECTEOLA-cellulose, Amberlite IRA-904, and DEAE-Sephadex.

A longituinal study funded by the National Institute on Aging suggests that cognitive impairment (CI) in the elderly is less likely in persons who have more years of education or greater net worth. The data were published online last month in the journal Alzheimer's & Dementia.

In individuals aged 70 years or older from the University of Michigan Health and Retirement Study, cognitive function was assessed over 2 years and compared between two cohorts from 1993 and 2002. After adjusting for age and sex differences, investigators found that higher education levels and net worth in the 2002 cohort accounted for approximately 40% of the group's decreased prevalence of CI (Table). The authors explain their findings, in part, by suggesting that a higher level of education is associated with the development of greater cognitive reserve in the setting of developing memory disorders, like Alzheimer's disease.

Variable	Cohort		P Value
	1993 (n = 7406)	2002 (n = 7104)
Mean age, years	77.5	77.8	.02
Mean education, years	11.0	11.8	.001
Mean net worth, 1993 $	179,000	284,000	.001
Cognitive function
Normal	87.8	91.3	.001
Mild CI	5.2	3.5	.001
Moderate/severe CI	7.0	5.2	.001

In both cohorts, the 2-year risk of mortality increased significantly with worsening CI (not surprising); however, the mortality risk in individuals with moderate or severe CI was higher in the 2002 cohort than in the 1993 group (adjusted-HR P = .09). In addition, lengthier education was associated with an increased mortality risk in those individuals with CI—a finding that was of greater magnitude in the 2002 cohort.

The authors attempt to explain this curious finding by suggesting that the brains of more educated individuals can sustain a greater load of dementia-causing brain pathology, before reaching a clinically important threshold. However, once this clinical threshold is reached, their cognitive decline is more precipitous, and their mortality risk is consequently greater.

"And when it is time for your period, hold onto your @%*#ing hat."

(Here's the original.)

Recommended this week is the heist knockout The Killing, directed and cowritten by Stanley Kubrick and starring paragon tough guy Sterling Hayden (Dr. Stangelove, The Godfather). The 1956 noir classic features a motley ensemble of stock low-lifes, who get to exchange terrific dialogue like, "All right, sister, that's a pretty head you got on your shoulders," followed by, "You wanna keep it there or carry it around in your hands?" In my next life, I will be the late 21st century's answer to Marie Windsor as Sherry Peatty.

A big nod goes to the In Vivo Blog today for providing more background on APP and its CEO Patrick Soon-Shiong. Seems the company's top boss is not a stranger to less-than-stellar foreign drug suppliers, after all—despite his arguably opportunistic and hyperbolic assurance of the safety of APP's heparin in yesterday's WSJ.*

It all started way back in June 1998, when APP acquired Fujisawa's worldwide injectable pharmaceutical business. At approximately the same time (May 1-June 29), the FDA began receiving reports from a Los Angeles hospital of endotoxin-like adverse reactions (reactions not dissimilar to those recently described with Baxter's recalled heparin) after the administration of Fujisawa-produced IV gentamicin.

According to a 1998 MMWR report, the reactions were likely due to high endotoxin levels in the Fujisawa gentamicin, particularly with once-daily dosing of the drug (an unapproved regimen often used to reduce the risk of antibiotic-related ototoxicity and nephrotoxicity). Endotoxin levels in Fujisawa's product ranged from 25.6 to 32.0 endotoxin units (EU) per mL, while levels in gentamicin samples from another manufacturer were less than 2.0 EU/mL. The allowable limit for endotoxin in antibiotics, per USP standards, is 68 EU/mL. So, although the endotoxin levels in Fujisawa's antibiotic were within USP standards, the larger once-daily administration of the product likely delivered enough endotoxin to cause the pyrogenic reactions. The MMWR indicated that these kinds of reactions had not been observed previously with once-daily gentamicin.

APP voluntarily withdrew the Fujisawa antibiotic in November 1998, while still defending the product's safety and blaming the endotoxin-like reactions on the once-daily dosing, according to a 2002 NYT article. The company reintroduced the gentamicin in June 1999; but after additional adverse reactions were reported, the drug was again withdrawn. The NYT article also indicated that the high endotoxin levels in the gentamicin lots were traced to a Fujisawa plant and further implicated substandard conditions at a Chinese supplier; however, the article did not identify either facility by name or specific location.

Information from a 1998 article in the FDA Consumer and a 2000 article from Health-System Pharmacy News indicate that the suspect gentamicin from APP/Fujisawa had actually been provided by a New Jersey drug broker, Flavine International. According to these reports, Flavine had obtained gentamicin in 1995 from unapproved Chinese sources and had then repackaged the product to resemble antibiotic from Fujisawa's legitmate (and FDA approved) Chinese supplier, Long March Pharmaceutical Plant.** Flavine then sold the counterfeit gentamicin to Fujisawa (as well as to ESI Lederle).

According to HSPN, the FDA became aware of Flavine's counterfeit gentamicin sometime during the mid-90s, while investigating another counterfeit antibiotic (used for veterinary purposes) offered by Flavine. However, the FDA did not follow-up with any of Flavine's gentamicin purchasers (namely, Fujisawa) to ensure that the counterfeit drug was no longer on the market. These events predated the endotoxin-like reactions associated with APP's/Fujisawa's gentamicin in 1998.

*How anybody can ensure the ability to trace a heparin lot to a single pig defies all common sense, especially given the WSJ's images of intestinal slurries and gut-decorated wringing machines in China, even at the ostensibly modernized plant.

**In December 1999, Long March was cited by the FDA for deviating from good manufacturing processes, and the company's gentamicin was recalled at that time.

Tomorrow's issue of the MMWR reports on the multistate outbreak of documented measles cases related to the travel of an infected 12-year-old Japanese baseball player to the 2007 Little League World Series in Williamsport, Pennsylvania. The boy, whose vaccination status was unknown, flew on an international flight from Japan to Detroit and then on a domestic flight from Detroit to Baltimore on August 13, after acquiring the infection from his brother in Japan. Subsequent, documented transmissions of measles from this index case (1) are outlined below.

Case 2: Another 12-year-old Japanese boy was in contact with the index case in Japan on August 12. He arrived in the United States on August 15 and attended the World Series as a spectator; he first became ill August 20.

Case 3: A 53-year-old woman, who sat in front of the index case on the domestic flight from Detroit to Baltimore, became ill with measles on August 25.

Case 4: A 25-year-old federal airport officer, who worked in the customs area of the Detroit airport on August 13, first developed measles symptoms on August 23. He had no documented history of measles vaccination.*

Case 5: A 40-year-old corporate sales rep met the index case on August 14 in Pennsylvania and developed measles symptoms on August 26. He had no documented measles vaccination.

Case 6: An 18-year-old college student attended a sales event in Texas with the 40-year-old rep on August 20. Despite having previously received 2 doses of MMR vaccine, he developed symptoms on September 9.

Case 7: A 19-year-old college student, the roommate of case 6, attended the same sales event of the 40-year-old rep on August 20. He also had a history of receiving 2 MMR vaccine doses but developed symptoms on September 10.

According to the MMWR, the viral genotype from the index case was identical to the genotypes obtained from cases 2, 3, 5, 6, and 7. (Amplification attempts to genotype case 4 were unsuccessful.) The report provides a useful graphic, which illustrates the chain of measles transmission, and reinforces the importance of vaccination regardless of travel history. While 2 doses of measles vaccine are reportedly 99% effective, the disease remains possible in those persons who have been vaccinated (namely, cases 6 and 7). The report also emphasizes that those individuals who were born before 1957—before the institution of routine MMR vaccination during childhood—may be susceptible to infection (eg, case 3). 

Although all of the affected individuals recovered, measles is not necessarily a benign illness. The 40-year-old rep required hospitalization for high fever and pneumonia and experienced an epileptic fit, according to the report. Widely reported is the statistic that approximately 1 measles case in 1000 is associated with the development of encephalitis.

*A coworker of the officer developed measles approximately 1 month later; however, it is unclear if this case is related to case 4, either directly or indirectly. (The typical incubation period for measles is 7-18 days.)

After "blowing brains" at the "head table," today's WSJ describes in words and pictures possibly the second worst job in the world and answers my question, Where Does Heparin Come From? Specifically the article features an unsettling slide show in which Chinese workers wring and slurry pig intestines for heparin extraction (thanks, Mr. Fairclough).

The article also highlights contrary views on the importance of being able to trace heparin's source for safety purposes, possibly to an individual pig. The FDA contends that heparin's chemical-purification process ensures the product's safety, regardless of the source animal, while the chairman of APP (Baxter's heparin rival) asserts that a heparin-pig provenance record is essential.

According to the WSJ, APP's Chinese heparin supplier claims that it can trace its product to a single animal. However, given the seemingly routine maze of middlemen and facilities—some very crude—that exist between slaughterhouse and final supplier in China, this claim would be best viewed skeptically.

Still unknown is whether any of this information has anything to do with the severe allergic reactions associated with Baxter's recalled heparin. Buried deep (graf 6) in a WSJ article from February 19 is the claim that "Baxter disclosed that the variations [of its recalled heparin] from standard product occurred in the Chinese-made batches," but the company has otherwise kept mum.

A recent review of the world status of leprosy at the Pathophilia blog produced a curious footnote: a substantial percentage of armadillos (Dasypus novemcinctus, aka 9-banded or long-nosed armadillos) in Louisiana and Texas harbor the infectious agent that causes human leprosy. This notation begs the question: How did US armadillos—which are the only known natural hosts for the leprosy pathogen Mycobacterium leprae, other than humans—acquire the infection?

 

The answer is provided at least partly in a 2005 review article by Richard W. Truman, PhD, of Louisiana State University and the National Hansen's Disease (Leprosy) Program, who reports that a leprosy-like illness was first discovered in wild US armadillos as early as 1975 and later confirmed to be prevalent among these animals in the lowlands of Louisiana and Texas. The armadillo appears to be particularly susceptible to M. leprae as a consequence of its naturally low core body temperature, which runs from 32°C to 35°C (89.6°F-95°F).

 

Truman notes that captive armadillos were first used to propagate M. leprae experimentally in 1968, after it was recognized that the animal's cool temperature would be favorable to the organism's growth. However, it was observed 7 years later that some wild armadillos near New Iberia, Louisiana, already harbored M. leprae, raising the issue of how these animals became infected.

 

Original speculation raised the possibility that leprosy in wild US armadillos was the result of the escape or improper disposal of experimentally infected, captive animals. However, this contentious hypothesis was disproved in 1985, Truman writes, when armadillo sera from 1960-1964, collected and stored at LSU before experimental animal inoculation, demonstrated antibodies to M. leprae.

 

Through animal surveys, it is now known that approximately 15% of armadillos living along the coastal areas of Louisiana and Texas are infected with M. leprae; although one third or more of all adult armadillos may be infected in concentrated areas. Yet it has still not been definitively established when or where US armadillos acquired leprosy. According to Truman, single-nucleotide polymorphism (SNP) analysis indicates that leprosy was brought to North America by European and African immigrants, and that armadillos—which are indigenous to North America and likely migrated to the United States from Mexico—harbor the same M. leprae strain that originated in Europe and Africa. Truman concludes that the animals must have acquired the organism from immigrant humans some time during the last 400 years, but that the animals "could be commonly exchanging the organism with humans today."

 

Surveys of leprosy rates in armadillos outside of the United States, and specifically those in Mexico, are slim to nonexistent, according to Truman; although, diagnosed cases of leprosy among Mexican immigrants in Houston and Los Angeles suggest that armadillo exposure is a significant risk factor for the illness. A study published just last year assessed the leprosy rate in 37 field-tested armadillos in the State of Espírito Santo, Brazil, where leprosy is particularly prevalent and exposure to armadillos common.* Investigators found an armadillo infection rate of approximately 30%.

 

In an e-mail communication, Truman indicates that several groups are beginning to survey for leprosy in Venezuelan and Colombian armadillos, as well as those in Brazil. But a substantial amount of information must be collected before any conclusions can be drawn about the relationship between US and South American infection data. To better understand the role of armadillos in the perpetuation or spread of leprosy, Truman and his colleagues are engaged in large genotyping studies of M. leprae strains that are circulating throughout the United States. He reports, "We have found that infection among armadillos appears to be more widespread than previously known."

 

* The potential relationship between armadillo exposure and human leprosy in Brazil is important, because infected Brazilians make up approximately one half of all registered leprosy cases in the Americas. The study authors note that, in the State of Espírito Santo, armadillos are often killed and consumed.

In its gosh-darn eagerness to respond to a potential heparin shortage (due to the recall of Baxter's heparin products), rival APP announced yesterday that it would ramp up its production of the "critical therapeutic heparin multi-dose vials." In its press release, APP reminded the world that it acquires the active ingredient in its heparin products from several manufacturers, including a Chinese plant, which have all been inspected by the FDA (unlike the Chinese facility of Baxter's heparin supplier).

Also in the press release, APP President Tom Silberg states that, "prior to this crisis," his company supplied approximately 50% of the therapeutic heparin prescribed in the United States. Baxter reportedly provided the other 50%, before the recall—which consequently leaves a nice big share of the therapeutic heparin market for APP to gobble up, unless Baxter can recover the trust of prescribers with lightening speed.

Life's current purpose is to promote the comedy of Mitchell and Webb.

"It's a medical drama, but with the emphasis on drama rather than medsun."

On February 15, The Netherlands Health Care Inspectorate reported its identification of large doses of tadalafil (Cialis; Eli Lilly), vardenafil (Levitra; Bayer, GSK, Schering) and acetildenafil, an analog of sildenafil (Viagra; Pfizer), in imported Chinese "herbal" impotence pills. According to an AP report, thousands of the pills were intercepted approximately 2 weeks ago at Amsterdam's Schiphol Airport and sent for analysis by the Dutch authorities.

 

The confiscated pills were to be sold under the names Herb Vigour, Natural Vigour, and China Vigour* and were found to contain as much as 2.5 times the maximum dose of one of the selective phosphodiesterase inhibitors, which are FDA approved for the treatment of erectile dysfunction (ED) and available only by prescription. Common, reported serious adverse events associated with these medications in the postmarketing setting—such as cardiovascular events and vision or hearing changes—are more likely to occur with the use of higher-than-approved doses.

 

A web search reveals that identically named products are currently sold through a number of dubious web sites, several of which identify Kunming Dali Industry & Trade Co, Ltd, in the Yunnan Province as the producer and/or distributor. However, the company's web site—which features a prominent head shot of Jessica Alba and offers a number of questionable "herbal" remedies—does not list male-enhancement products in its online catalog. Nevertheless, a "Man Sex Product Message Board" at the web site indicates the availability of "Herbal Viogra" from the company to resellers as of November 2007.

 

The Dutch authorities report that they have not yet identified the manufacturer of the intercepted pills. According to a statement made to the AP, the company name printed on the pills' packaging (which was not revealed in the AP report) has not been verified. The Inspectorate did inform relevant authorities worldwide, including the FDA, of the intercepted pills.

 

Since 2003, the FDA has recalled a number of nonprescription sex-enhancement pills—"Viga for Women," "Nasutra," "Liviro3," "H S Joy of Love," "True Man's Sexual Energy Nutriment Men's Formula," and "Long Weekend" (big eyeroll there)—because they contained undeclared tadalafil, vardenafil, or sildenafil or chemical analogs.

 

*Herb Vigour (orange capsules) contains 2.5 times the maximum dose of tadalafil; Natural Vigour (red capsules) contains 1.5 times the maximum dose of vardenafil; and China Vigour (orange-and-gray capsules) contains 1.5 times the maximum dose of acetildenafil, an analog of sildenafil.

Buried deep in today's WSJ update of the investigation into allergic reactions associated with Baxter Healthcare's heparin ("Baxter Rival APP Steps in Quickly to Supply Heparin") is an indication that irregular heparin batches came from a supplier's Chinese plant (Scientific Protein's Changzhou SPL).

[Y]esterday Baxter disclosed that the variations from standard product occurred in the Chinese-made batches.

There is otherwise little information regarding the nature or source of variations in Baxter's affected heparin lots that may have caused the adverse reactions, and the WSJ story implies that Baxter is tight lipped about further details. The Pathophilia blog has speculated that inadequate heat treatment during heparin manufacture may have resulted in higher-than-trace amounts of bacterial endotoxin in the product.

Numerous news stories reveal that Scientific Protein's Changzhou plant had not been inspected by the FDA, because the name of the plant was confused with that of another Chinese facility, which the FDA had reportedly already inspected. Baxter claims that it inspected the Changzhou facility approximately 6 months ago, according to the WSJ, and an FDA team plans to conduct an on-site inspection this week. The WSJ also reports that the FDA is inspecting a Baxter facility in Cherry Hill, NJ, and Scientific Protein's plant in Wisconsin.

Meanwhile, rival heparin maker APP of Schaumburg, IL, has moved to fill the void created by Baxter's heparin-lot withdrawals and is likely to capitalize on the desire of hospital and dialysis-center administrators to avoid Baxter's heparin altogether. Some of the active ingredient in APP's heparin is manufactured at a Chinese facility, which has been inspected by the FDA, according to the WSJ.

In memoriam Baba Amte: a review of the worldwide status of leprosy.

 

First described in the 6th century BCE, leprosy is a chronic, nonfatal disease due to infection with the acid-fast bacillus Mycobacterium leprae. Following inoculation with the organism and a lengthy incubation period of years or even decades, clinical illness typically manifests in the cooler parts of the body—the skin, peripheral nerves, anterior eye, upper respiratory tract, and testes. Untreated, the disease is notorious for causing permanent disfigurement and deformity—often the result of neuropathy-associated injury—which consequently leads to social stigma and isolation.

 

Despite the historical segregation of lepers in colonies, the disease is not highly contagious. In untreated individuals, M. leprae is most likely transmitted to close and frequent contacts by means of respiratory droplets; however, transmission through colonized soil has also been postulated. Infected individuals are no longer contagious, however, after the first dose of multidrug therapy (dapsone, rifampicin, and clofazimine), and within 12 months of treatment, the disease is cured with (according to WHO) virtually no risk of relapse. Leprosy-related disability is averted with early treatment.

 

In 1991, the World Health Assembly resolved to eliminate leprosy (that is, to reduce the prevalence rate to <1 case per 10,000 persons) by the year 2000, and WHO claims that this goal overall was achieved. From 1985 to 2007, the number of world citizens affected by leprosy dropped by 96%, from 5.2 million to less than 225,000. As of 2007, leprosy was virtually eradicated in all but 4 of 122 countries where the disease was believed to be a public health problem in 1985 (Wkly Epidemiol Rec. 2007;82:225-32; Wkly Epidemiol Rec. 2007;82:388). Leprosy cases in these 4 countries—Brazil, the Democratic Republic of the Congo, Mozambique, and Nepal—accounted for nearly one quarter of all new cases globally in 2006 and one third of all registered cases at the beginning of 2007, according to WHO.

 

The number of leprosy cases in Brazil (60,567) makes up approximately half of all registered cases in the Americas. The National Hansen’s Disease (Leprosy) Program indicates that 166 new cases of leprosy were reported in the United States in 2005 (the most recent year for which data are available), and 60% of these cases occurred in 5 states: California, Texas, Louisiana, Massachusetts, and New York.* Although leprosy in the United States has been reported to affect immigrants preferentially, approximately half of the individuals infected in 2005 described themselves as white.

 

WHO advises that those with leprosy can receive free multidrug therapy from the organization, through a donation from Novartis and the Novartis Foundation for Sustainable Development. WHO acknowledges that the stigma of leprosy continues to hinder self-reporting and treatment and urges that “[a] new environment, in which patients will not hesitate to come forward for diagnosis and treatment at any health facility, must be created.”