Effects of Grapefruit Juice on Intestinal P-glycoprotein

Effects of Grapefruit Juice on Intestinal P-glycoprotein

from Pharmacotherapy

Discussion

Our results indicate that grapefruit juice decreased the rate (ka, Tlag), but not the extent (AUC), of digoxin oral absorption in healthy volunteers. It did not affect systemic elimination of digoxin, as half-life and renal clearance were unchanged in the presence of juice. The decrease in the rate of digoxin absorption and lack of effect on AUC are not consistent with inhibition of intestinal P-gp by grapefruit juice. In fact, inhibition of P-gp-mediated intestinal drug efflux would be expected to increase the rate and extent of digoxin absorption, as reported with known P-gp inhibitors such as quinidine and other drugs.[29-31] Since intestinal P-gp plays an important role in oral digoxin absorption[8] and since the effects of grapefruit juice appear to be confined to the intestine,[15, 32] our results indicate that the juice does not significantly affect P-gp-mediated digoxin intestinal transport.

Similar to our findings, in vitro data show that grapefruit juice, at a concentration of 5% of normal strength, does not affect efflux of the P-gp substrates digoxin or vinblastine.[20] Other in vitro results indicate grapefruit juice constituents may inhibit P-gp.[33] In contrast to these data, it was suggested that grapefruit juice activates P-gp,[22] although that was later attributed to equipment-related artifact.[34] Thus, at the concentrations studied, the juice does not affect in vitro drug transport by P-gp, although applicability of these results to drug interactions in humans is uncertain, since only low juice concentrations can be reliably evaluated in these polarized cell lines. Consequently, in vivo studies are required to characterize any clinical effect of grapefruit juice on P-gp function.

The effect of a single serving of grapefruit juice administered 30 minutes before oral digoxin was evaluated in healthy volunteers in the only other report describing the juice's effect on digoxin disposition.[21] In contrast to our results, grape-fruit juice resulted in slight increases in Cmax, AUC0-4, and AUC0-24; however, it did not change AUC0-48 and renal clearance, in agreement with our findings. The minor differences in the effects of juice early after digoxin administration could be due to differences in the duration and quantity of pretreatment juice (single dose vs 3 times/day for 5 days in our study), variability in active constituents in grapefruit juice products, digoxin tablet formulation (French product vs Lanoxin), or other dietary or environmental factors (dietary salt[35]) that may affect activity and/or expression of intestinal drug transporters. Despite these minor differences in early digoxin absorption, neither study found significant changes in longer-term exposure (>/= AUC0-48) to digoxin when administered with the juice. Collectively, these results indicate that neither short- nor long-term grapefruit juice ingestion has a significant effect on intestinal P-gp activity, and that inhibition of P-gp does not play an important role in drug interactions involving grapefruit juice.

Although the overall results of these two studies indicate that, on average, grapefruit juice has little effect on digoxin oral bioavailability, it led to significant interindividual variability in indexes characterizing digoxin absorption (Cmax and AUC0-4) in our study. Even though the juice's mean effect on digoxin oral availability was small and not likely clinically significant, the large variation in response suggests that in some individuals this interaction could be of clinical significance. Although the variability in the effects of juice could be due to random variation in a small number of subjects, the strong inverse correlation between water-phase digoxin Cmax and AUC0-4 and extent of decrease in each parameter indicates that subjects with the highest net drug uptake during the control phase had the greatest reduction in absorption when given juice. Since intestinal P-gp plays an important role in digoxin absorption,[8] our results suggest that one source of variability in response to grapefruit juice may be related to the level of P-gp activity in the intestine. However, this reduction in digoxin absorption in subjects with high baseline net drug uptake would not be consistent with juice-mediated inhibition of intestinal P-gp, in which availability would be expected to increase. Although our observed individual variability may be due to random variation in a small group of subjects, it is interesting to speculate on other potential sources of this variability in response to grapefruit juice.

Studies characterizing drug uptake transport by organic anion transporting polypeptide (OATP) may provide additional insight into interindividual responses to grapefruit juice. The OATPs are a family of drug uptake transporters expressed in many of the same organs as P-gp, including liver, kidneys, brain, and intestine.[36-39] The two putative pure P-gp substrates, digoxin and fexofenadine, both also appear to be transported by OATP, and considerable overlap is reported in drugs that are inhibitors or substrates for both P-gp and OATP.[36, 37, 40] Grapefruit, orange, and apple juices inhibit OATP-mediated in vitro transport of fexofenadine.[20] Consistent with in vitro findings, these juices also significantly reduced the rate (Cmax) and extent (AUC) of fexofenadine absorption in healthy volunteers, presumably by inhibiting intestinal drug uptake by OATP.[20, 41] It should be noted, however, that specific intestinal uptake transporters for either digoxin or fexofenadine have yet to be identified. Similar to our digoxin data, the juice-mediated decrease in fexofenadine AUC was greatest in subjects with the highest AUC during the water phase of the study.[20] Thus, grapefruit juice reduced absorption of each agent in subjects with the highest net drug uptake during the control phase. These data suggest that, for drugs that are substrates for both P-gp and OATP, relative contributions of intestinal drug efflux (P-gp) and drug uptake (OATP) may be important determinants of net drug absorption, as well as an individual's response to grapefruit juice. If grapefruit juice inhibits OATP but not P-gp,[20] it would be expected to produce its greatest effect on drug absorption when intestinal drug uptake by OATP is high relative to P-gp-mediated efflux. Our results with digoxin, as well as those of others with fexofenadine,[20] of an inverse relationship between drug absorption during the control phase and the effect of grapefruit juice support this concept. Moreover, our findings of a grapefruit juice-mediated delay in digoxin absorption is also consistent with inhibition of uptake rather than efflux transport.

If the effect of grapefruit juice depends on the net balance of drug uptake and efflux transport, recently identified single-nucleotide polymor-phisms (SNPs) in the MDR1 gene that are associated with alterations in intestinal P-gp expression[42, 43] and substrate drug pharmaco-kinetics[42, 44-47] could affect the relative balance of intestinal drug uptake and efflux. Although several MDR1 SNPs have been identified,[44] the exon 26 C3435T polymorphism is the best characterized SNP associated with alterations in P-gp expression and activity. Individuals homozygous for 3435T had high concentrations of intestinal MDR1 mRNA.[43] Consistent with this finding, reduced absorption of digoxin and fexofenadine is also reported in individuals with the TT genotype.[44, 45, 47] In contrast, Caucasian subjects with the TT genotype had lower intestinal P-gp levels and increased digoxin plasma concentrations compared with wild-type homozygotes.[42] Since the C3435T SNP is closely linked to one at exon 21 G2677T, the effect of C3435T and G2677T SNP on digoxin disposition was determined in healthy Japanese volunteers.[46] Similar to the work of others,[42] higher bioavail-ability and decreased renal digoxin clearance were found in individuals homozygous mutant for the MDR1 SNPs compared with wild-type homozygotes. Finally, a study in German Caucasian subjects found no association between C3435T genotype and fexofenadine pharmaco-kinetics.[48]

Our results suggesting an association between digoxin disposition and C3435T genotype are in agreement with those of others suggesting reduced P-gp activity in CC subjects.[44, 45, 47] We observed trends toward higher AUC, Cmax, and ka during the water phase in these subjects compared with those carrying a T allele. After grapefruit juice administration, digoxin AUC0-4, Cmax, and ka, trended down in CC individuals, but not in T allele carriers. Our regression analysis showing that subjects with the highest water-phase digoxin Cmax and AUC0-4 had the largest reductions in these values after juice ingestion suggests an association between degree of intestinal P-gp activity and influence of grapefruit juice on oral digoxin absorption. However, given our small sample, we were unable to establish a clear relationship between MDR1 genotype and the effect of grapefruit juice on digoxin absorption.

Although speculative, interindividual differences in intestinal P-gp activity suggest a possible explanation for the variability in response to grapefruit juice. In individuals with MDR1 genotypes consistent with high P-gp activity and thus low net drug uptake, grapefruit juice would not be expected to affect digoxin absorption significantly since it has minimal effect on intestinal P-gp activity.[20] Conversely, in the setting of low intestinal P-gp activity (high net drug uptake), digoxin absorption may be primarily dependent on uptake by OATP. Since grapefruit juice appears to be a potent inhibitor of OATP transport,[20] the net result is a reduction in digoxin absorption. Thus, the effect of grapefruit juice on OATP is unmasked only in the setting in which P-gp activity is low.

It must be noted that it was not the main purpose of this study to determine genotypic differences in digoxin pharmacokinetics. Our findings are limited by the small number of subjects in each genotypic group: four CC, two CT, and one TT subject(s) at MDR1 nucleotide position 3435. Therefore, we grouped together all three subjects harboring a T allele since the presence of a mutant T allele affects P-gp activity.[43-46] However, since heterozygous carriers of the mutant allele appear to have P-gp substrate pharmacokinetic values and P-gp activity that are intermediate between those of the homozygous groups, our ability to detect genotypic differences in digoxin disposition may have been minimized.[44, 45] Studies with larger numbers of subjects in each C3435T genotype, as well as other linked polymorphisms, are required to determine if an association exists between MDR1 genotype and the effects of grapefruit juice.[44, 46] Of interest, such an association between MDR1 genotype and the effect of clarithromycin on oral digoxin disposition was reported.[46] Polymor-phisms in the genes coding for OATP have been recently identified and could also contribute to interindividual variability in drug disposition.[49, 50]Conclusion

The overall results of this study, using digoxin as a probe, do not support inhibition of intestinal P-gp as an important contributor to grapefruit juice-mediated drug interactions, although significant interindividual variability in the effects of juice was observed. Our preliminary findings suggest the net balance of drug uptake and efflux is a source of variability in grapefruit juice's effect on digoxin absorption. Whether this model is applicable to other P-gp substrate drugs or inhibitors or inducers is unknown and likely depends on the relative contribution of efflux and uptake transporters for a given compound, the net effect of potential interacting substances on drug transporters, as well as drug-metabolizing enzymes. Additional studies are required to characterize more fully the role of MDR1 polymorphisms in drug interactions.

Funding Information

Supported by the ACCP-Aventis Cardiovascular Research Award and by a grant (5MO1RR-00211) from the National Institutes of Health, Washington, D.C.Reprint Address

Address reprint requests to Robert B. Parker, Pharm.D., University of Tennessee, Department of Pharmacy, 26 South Dunlap Street, Memphis, TN 38163.

Section 4 of 4
Pharmacotherapy 23(8):979-987, 2003. © 2003 Pharmacotherapy Publications
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Scarring fear over boy’s tattoo

A family holidaying in Cornwall fear their eight-year-old son may have been permanently scarred by what they thought was a harmless henna tattoo.

Nathanial Fuller is having daily hospital treatment for a back burn after getting the tattoo in St Ives.

The artists trading under pedlars' licences in the town say they do warn people about allergic reactions to the chemical dyes they add to the henna.

But the Fuller family, from Hull, have said better regulation is needed.

Father Steve Fuller said most people assume henna is a safe product and has claimed the street artists are acting irresponsibly.

Nathaniel's tattoo cost £7, but within days a burn had developed on his back.

Mr Fuller said: "First of all there was the reddening then it scabbed over and Nathaniel complained it was a bit itchy.

"Then a couple of days later there was some small blistering and within four days it turned into one large blister and the medic related it to a second degree burn."

"The full area where the henna's been applied is oozing pus from the blister which runs down Nathaniel's back.

Nathaniel's brother Jacob also had a henna tattoo at the same time, but he has suffered no allergic reaction.

The trader who applied the tattoo to Nathanial's skin admitted that hair dye is added to the natural henna to make it black and also to make it last longer, but said there is a warning on price boards.

The woman, who did not want to be named said: "Henna comes in red and brown and to get it any other colour you need to mix it.

"Natural henna comes from a plant, so people are not getting allergies from henna, but from the dye."

The trader said parents of children who want a tattoo are offered an allergy test, but only about 40% have the test done.

Penwith District Council says a pedlar's licence can be issued by any police force and allows people to trade anywhere in the country.

Simon Mansell said the council's powers were not strong enough.

"We cannot regulate people such as henna tattooists and we do have concerns on health grounds and safety grounds."

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Hospital pet cash plan under fire

A hospital in Suffolk has been criticised for a fundraising plan to offer radiotherapy to family pets.

Ipswich Hospital proposes using equipment unused at weekends to treat pets with cancer in Saturday clinics.

The hospital aims to raise £50,000 a year from the idea to help pay off debts of more than £24m.

The Patients Association condemned it as "horrifying" but the hospital said no patients would be disadvantaged and there would be no infection risk.

Hospital spokeswoman Jan Rowsell said the idea was among 700 put forward by staff to raise funds.

She said the hospital was considering teaming up with a veterinary school. If the idea became a reality the hospital would use stringent infection control procedures.

"Everything will be covered in anti-allergy drapes and hygiene will be of the utmost importance," she said.

"The radiotherapy room would be thoroughly deep cleaned after each session and the costs we would charge would include very strong, robust cleaning and infection control measures."

She pledged to thoroughly discuss this idea with patient-user groups if it were adopted.

'Desperate measures'

But Patients Association spokeswoman Katherine Murphy said she was horrified by the idea.

"Do we really have to resign ourselves to such desperate measures as to begin treating animals where people are treated?" she said.

"Is this really the way forward?

"I hope this idea never gets off the ground. I think it is a disaster waiting to happen. Surely there are other ways of identifying areas where costs could be reduced?"

Shadow Health Secretary Andrew Lansley said: "These are the lengths the NHS is being driven to by the Ggovernment's financial mismanagement and the way deficits are impacting on hospitals.

"One would normally expect NHS equipment to be fully occupied providing services to NHS patients."
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Diagnosing Pulmonary Artery Hypertension in a Woman With Systemic Sclerosis

Summary and the Case

Summary

Background: A 42-year-old woman with limited cutaneous systemic sclerosis presented with rapid-onset dyspnea on exertion, which had developed over the previous 8 weeks. She had not experienced any dyspnea before this period. Transthoracic Doppler echocardiography performed 6 months before presentation demonstrated an estimated right ventricular systolic pressure of 32 mmHg. Lung function tests also performed at that time revealed a decreased diffusion capacity for carbon monoxide of 54% and normal lung volumes, and high-resolution CT scan of the lungs was normal.
Investigations: Physical investigation, CBC, analysis of C-reactive protein and pro-brain natriuretic peptide, transthoracic Doppler echocardiography, six-minute walk test, lung function tests including diffusion capacity for carbon monoxide, right heart catheter, high-resolution CT scan, and ventilation/perfusion scan.
Diagnosis: Pulmonary arterial hypertension associated with limited cutaneous systemic sclerosis.
Management: Treatment with oral anticoagulation therapy and the endothelin-receptor antagonist bosentan. Monitoring of adverse effects of bosentan therapy was performed using liver function tests.The Case

A 42-year-old woman was diagnosed with limited cutaneous systemic sclerosis (SSc) three years ago. At the time of diagnosis, she had suffered from Raynaud's phenomenon for six years and recurrent finger-tip ulcers during the last two winter seasons. The patient reported having no other problems, including no dyspnea on exertion. Physical examination demonstrated two small inactive ulcers at the tips of the third and fourth fingers of the left hand, acrosclerosis with a total modified Rodnan skin score of nine, and telangiectasias on the face. Physical examination did not reveal any other pathological findings. Nailfold capillaroscopy demonstrated a reduced capillary density with dilated and giant capillaries, two microhemorrhages and a few avascular areas highly suggestive of SSc. Lung function tests revealed normal lung volumes and a predicted diffusing capacity for carbon monoxide (DLCO) of 54%. High-resolution CT (HRCT) scanning of the lungs did not demonstrate pathologic findings. The right ventricular systolic pressure (RVSP), as estimated by transthoracic Doppler echocardiography (TTE) was 32 mmHg. Laboratory tests showed an antinuclear antibody titer of 1:10000 and presence of anticentromere antibodies, but not anti-topoisomerase I antibodies or other extractable nuclear antigens. Serum level of N-terminal pro-B-type natriuretic peptide (pro-BNP), which was measured at baseline for comparison at later follow-ups, was within normal limits. The patient was prescribed nifedipine and paraffin baths, and advised to avoid exposure to cold.

The patient responded well to this symptomatic treatment. The intensity and frequency of her Raynaud's attacks decreased considerably and she did not develop digital ulcers during the following years. At the first two annual follow-ups no evidence of progression of SSc was observed. The patient's modified Rodnan skin score remained unchanged, lung function tests demonstrated normal lung volumes, and her DLCO was stable. The TTE-estimated RVSPs were 28–33 mmHg, and chest X-rays were normal.

At the third, and most recent, annual follow-up the patient reported experiencing shortness of breath when climbing stairs. She first noted these symptoms eight weeks before the follow-up appointment and dyspnea had progressed since then. She was otherwise well and had noticed no other physical changes. On physical examination, a slightly accentuated pulmonary component of the second heart sound was noticed, but no murmurs were audible. Lung sounds were normal. No peripheral edema, ascites, hepatomegaly, or jugular vein distension were detectable. The patient's body temperature and CBC were within normal ranges, and her C-reactive protein level was not elevated. TTE was performed and revealed an estimated RVSP of 41 mmHg without evidence of left heart disease. Lung function tests demonstrated a further decrease of the DLCO from 54% to 43%, whereas lung volumes remained normal. In addition, pro-BNP level was found to be elevated to threefold higher than normal values. Right heart catheterization was used to confirm the suspected diagnosis of pulmonary arterial hypertension (PAH). The resting mean pulmonary arterial pressure in this patient was 36 mmHg, with a normal pulmonary wedge pressure of 8 mmHg, an increased pulmonary vascular resistance of 509 dynes/sec/cm5, and a cardiac index of 2.2 l/min/m2. After confirming the diagnosis of PAH by using right heart catheterization, interstitial lung disease and thromboembolic disease were excluded by HRCT and ventilation/perfusion scans. The patient was, therefore, classified as having PAH associated with limited cutaneous SSc. A six-minute walk test was performed with a result of 460 meters and a Borg dyspnea index of 3.

The patient's dyspnea progressed rapidly, with symptoms occurring after slight to moderate exercise, and her PAH was classified as New York Heart Association (NYHA) functional class III. Therapy with oral anticoagulation (phenprocoumon, prothrombin time target international normalized ratio 2.0–3.0) and the oral endothelin A and B receptor antagonist bosentan (62.5 mg twice daily for four weeks, followed by a maintenance dose of 125 mg twice daily) was initiated for the treatment of PAH. The patient responded well to the treatment, with an improvement to NYHA class II after four weeks and an increase in the six-minute walking distance from 460 to 520 meters. In addition, pro-BNP levels dropped to within 1.5 fold of the upper normal range. Bosentan therapy was well tolerated and liver function tests remained normal.  Printer- Friendly Email This

Nat Clin Pract Rheumatol.  2008;4(3):160-164.  ©2008 Nature Publishing Group
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HIV and HCV Intervention

Applications to HCV-Seropositive IDUs

HCV incidence among IDUs is consistently higher relative to that of HIV, due at least in part to its greater transmissibility; it is ten times more infectious than HIV when spread through the parenteral route (Gerberding, 1995). Worldwide, HCV prevalence among IDUs can be as high as 90 percent (Hagan and Des Jarlais, 2000), whereas HCV incidence ranges between 13 and 22 per 100 person-years (Crofts et al., 1997; Garfein et al., 1998; van Beek et al., 1998) and is highest among the susceptible pool of young IDUs. Furthermore, 20-30% of IDUs in the United States are co-infected with HIV and HCV, which can complicate the treatment of both infections. HIV infection can hasten the progression of HCV disease although it remains controversial whether or not the reverse is true (Thomas et al., 2000).

HCV infection can result in serious liver disease including cirrhosis and hepatocellular carcinoma. Approximately 80-85% of HCV infections result in a chronic carrier state where patients are infectious and capable of transmitting the virus to others (Alter et al., 1999). In some settings, morbidity and mortality attributable to HCV infections among IDUs could exceed that for HIV, since both infections are highly prevalent among drug users (Hagan and Des Jarlais, 2000). Since HCV is often acquired before HIV among IDU populations, interventions that effectively reduce high risk transmission behaviors among HCV-infected IDUs could also have a significant impact on HIV prevention (Garfein et al., 1996).

In comparison to HIV, there is limited awareness of HCV among drug users, as evidenced by the coverage of voluntary testing and counseling for both infections. In a recent study of ten publicly funded methadone maintenance treatment programs in Baltimore, MD, approximately 20% of IDUs tested HIV-seropositive, 80% of whom were aware of their infection and had sought care. On the other hand, 91% of these IDUs tested HCV-positive but three quarters had not previously been tested and were thus unaware of their infection and had not sought treatment (Loughlin et al., 2004). Clearly, IDUs will require improved HCV counseling and testing strategies as well as accessible and affordable HCV medical care.

The benefits of integrating treatment for substance abuse and HIV infection discussed above can be extended to the treatment of HCV infection. In San Francisco, Sylvestre found that HCV therapy (i.e., alpha interferon) offered in conjunction with methadone maintenance therapy was feasible, and had promising short-term outcomes (Sylvestre, 2002; Sylvestre et al., 2004). There is growing realization that patients with co-occurring HCV infection, substance use, and psychiatric illness can complete interferon treatment with careful monitoring and aggressive intervention although few programs are designed to manage these co-occurring conditions.

Although few empirical studies have evaluated interventions focused on HCV-seropositive IDUs, one such multicenter study is underway. Referred to as the Study to Reduce Intravenous Exposures (STRIVE), this study uses a peer-mentor approach to reduce injection related risk behaviors (e.g., distributive needle sharing) and facilitate access to HCV care. Even in the absence of proven behavioral interventions to reduce transmission behaviors among HCV-seropositive IDUs, important prevention messages should be shared with these patients. Regardless of the route of their infection, HCV-seropositive IDUs should be counseled to abstain or at least reduce their alcohol use, since alcohol can accelerate progression to HCV-related liver disease (Thomas et al., 2000). Additionally, these patients should be offered vaccines for both Hepatitis A and B, since these infections can further compromise the liver.  Printer- Friendly Email This

AIDS Behav.  2006;10(2):115-130.  ©2006 Springer
Springer Science+Business Media
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From The $800 Million Pill - Me Too

In This ArticleChapter 8: Me Too!Section 1Section 2Section 3Section 4Section 5Section 6Section 7Section 8Section 9Section 10Section 11ReferencesRelated Links

Section 8

The Prilosec-to-Nexium transition exemplified a common industry practice. Throughout the 1990s, the drug industry poured billions of research dollars into developing alternatives to drugs that were approaching the end of their patent terms. In most cases, the alternatives were little changed from the originals. The better the original sold, the more likely it was that the company would devote considerable research resources to generating a copycat version with renewed patent life.

Another example that garnered considerable public attention was Schering-Plough's Claritin, one of the antiallergy medicines developed in the early 1980s as a nonsedating alternative to an earlier generation of antihistamines. By the late 1990s, the drug was generating over $2 billion a year in sales for Schering-Plough, a figure that was growing rapidly because of the 1997 legalization of direct-to-consumer advertising. To reach the estimated thirty-five million allergy sufferers in the United States, Schering-Plough poured hundreds of millions of dollars a year into ads for the drug. Consumers were encouraged to ask their doctors for a pricey prescription–it cost eighty dollars for a month's supply–that, according to the original studies submitted to the FDA, worked only marginally better than a placebo.

Though you would never know it from the television advertisements featuring handsome women frolicking through flowering fields oblivious to the pollen-laden air, the FDA's reviewer was openly skeptical about the drug's efficacy at the low dose offered by Schering-Plough. The company, which tested the drug on thousands of patients, needed a low dose to ensure that it would be nonsedating, which was the only way the new drug would be able to gain a toehold in the already crowded antihistamine market. But at the low, nonsedating dose, clinical trials showed that only 43 to 46 percent of Claritin users gained relief of allergy symptoms compared to a third of patients on a sugar pill. A separate study that asked doctors to assess the patients on the placebo found that 37 to 47 percent of them had a "good to excellent response to treatment," which as a practical matter was no different than those who took the real pill.[19] In addition to questioning its marginal medical significance, other reviewers at that late 1980s FDA hearing worried that Claritin, whose generic name is loratadine, might be a carcinogen. It took the company several more years of studies before it could dispel those fears. Finally, in 1993, the drug was approved. The delays actually proved to be an auspicious event for Schering-Plough. In the early 1990s, patients on Seldane and Hismanal, the first nonsedating antihistamines to hit the market, began turning up in hospital emergency rooms because of the drugs' violent interactions with other drugs and the development of life-threatening heart irregularities. By the time Claritin hit pharmacists' shelves, there was pent-up demand for a safe alternative, and the new drug immediately jumped to number one in sales in its class.

Yet in the late 1990s, as Claritin neared the end of its patent term, Schering-Plough launched a massive lobbying campaign in Washington to get an extension on its patent. The company claimed the long delays at the FDA had robbed it of years of market exclusivity. Aware of the history, Congress rebuffed Schering-Plough's frequent requests.

Forced to fall back on research and development, Schering-Plough scientists took apart loratadine to see what made it tick. They discovered the active part of the drug was actually a metabolite of the whole molecule, which became active in the stomach after patients began digesting the pill. They patented this metabolite, called it desloratadine, and filed a new drug application with the FDA. It was approved in late 2001, just months before the expiration of loratadine's patent. The company launched a massive advertising campaign that convinced millions of their customers to switch to the new, equally expensive but no more effective drug. Then, to frustrate the generic companies getting ready to sell loratadine, Schering-Plough announced it would begin selling Claritin as an over-the-counter allergy remedy.[20] Public-sector science has sometimes pushed industry researchers down the road to better medicine, only to discover as they neared the end of their labors that they developed yet another me-too drug. During the late 1990s, few drug classes received more media attention than a new pain reliever known within the medical community as Cox-2 inhibitors. The original members of this new drug class were Celebrex, made by G.D. Searle (later bought by Pharmacia), and Vioxx, made by Merck. In 2001, Pharmacia came out with a follow-up drug to Celebrex called Bextra.Previous PageSection 9 of 12Next Page: Section 9
Medscape General Medicine.  2004;6(2):57.  ©2004 Medscape


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