Pharmaceutical Information Network

Genital human papillomavirus (HPV) is a sexually transmitted disease (STD) that affects all races and socioeconomic groups. Most commonly, this infection occurs as anogenital warts – benign epidermal tumors- the incidence of which appears to be reaching epidemic proportions in the US. Genital HPV infection is one of the most common viral STDs in America. According to some surveys, from 5% to 20% of persons aged 15 to 49 years are infected with HPV. There are almost three-quarters of a million new cases each year. In addition, certain types of HPV are associated with 90% of all cervical cancers.

In most cases, anogenital warts have no symptoms and patients are unaware of their presence. These may spontaneously regress or persist for years. Classic warts are flesh- colored, pink, or pigmented with pointed projections on their surfaces. Some warts (sessile warts) are flat with smooth surfaces. In the extreme, the warts may combine into a form that resembles a cauliflower. Some warts may cause itching, burning, pain and bleeding. The psychological distress associated with this infection can also be devastating, with feelings of embarrassment, worry and fear being common. HPV warts are diagnosed by visual inspection, cytologic analysis (PAP smear), colposcopy, biopsy and laboratory tests that detect HPV-DNA.

Genital warts are not considered to be life-threatening and no drug therapy to date has been effective in eradicating the infection. Current treatments include excision or ablation of warts or topical therapies that interrupt cell division; these are often painful and cause tissue destruction. To date, wart therapies have included:

(Some of these therapies are experimental and not FDA approved)

The major problem with these approaches is that no single method eradicates warts and eliminates the virus.

How it Works

Aldara Cream 5% is a new approach to treating HPV warts. The product contains imiquimod, a novel immune-response modifier. Imiquimod has no direct antiviral activity. Cell-mediated immunity appears to be the primary reason for wart regression. Imiquimod cream is believed to stimulate cytokines (IFN-alpha in particular, but also IL-1, IL-6 and IL-8), which are cellular components of the immune system. When imiquimod binds to the surface of monocytes and macrophages, the production of cytokine mRNAs by these cells is directly stimulated. These cytokines affect cell growth and differentiation and may also induce the synthesis of other proteins that may be in part responsible for antiviral activity. Interferon and other cytokines activate natural killer (NK) cells that target tumor and virus-infected cells.

The drug is minimally absorbed through intact skin. A lethal dermal dose of imiquimod in rabbits is more than 1600 mg/m2. Persistent topical overdosing could result in severe local skin reactions.

In clinical trials, imiquimod was found to be significantly superior to placebo in its activity. In one typical study, involving 311 patients, the wart clearance rate was 72% for women and 33% for men treated with imiquimod compared to 20% and 5%, respectively for those treated with placebo. The overall clearance rate after 16 weeks (3 times per week application) was 50% (imiquimod) vs 11% (placebo) (p<0.0001). Women tended to do better than men for several speculated reasons: their lesions were found in moister, non- hair bearing, partially keratinized regions (so the drug could penetrate better) , and they seemed to seek treatment sooner than men.

Itching and burning at the application site are the most common adverse events, being reported 22% and 13% of patients, respectively; the majority of reactions resolved during the first 2 weeks of treatment. Interestingly, skin patch testing comparing imiquimod cream, the cream vehicle, and commercial skin-care lotions found the commercial lotions to be significantly more irritating than the imiquimod preparation or vehicle.

Clinical Tips

The cream is self-administered before sleeping three times a week, before normal sleeping hours, being left in place for 6-10 hours. Treatment should continue until there is a total clearance of genital/perianal warts, or for a maximum of 16 weeks. Although local skin reactions are common, the drug is generally well tolerated, so patients can continue with daily activities while on therapy. Local anesthetics are not required during therapy because associated pain is minimal. However, a rest period (no drug treatment) may be needed if the patient’s discomfort from the drug is too great. Imiquimod is not recommended for use for the treatment of urethral, intravaginal, intra-anal, cervical, or rectal HPV infections.

What Patients Should Know: Patients should be told that the effect of imiquimod on the transmission of genital perianal warts is unknown. The cream may weaken condoms and vaginal diaphragms and the concurrent use of these with the drug is not recommended. Contact with the eye should be avoided and hands should be washed before and after applying the cream. A thin layer of cream should be applied and rubbed until no longer visible. The treated area should NOT be bandaged or wrapped occlusively. Sexual contact (genital, anal, oral) should be avoided while the cream is on the skin. About 6-10 hours following application of the cream, the treated area should be washed with mild soap and water. It is common for patients to experience skin reactions such as redness, flaking, or edema at the treatment site, and these reactions are usually mild or moderate in intensity. This treatment may worsen preexisting inflammatory skin conditions. Any severe skin reactions should be reported at once to the physician. An uncircumcised man treating warts under the foreskin should retract the foreskin and clean the area daily. Because imiquimod is not a cure, new warts may develop during therapy.

Indication: non-insulin-dependent diabetes mellitus (NIDDM)

- Drug Tradename: Precose
-Manufacturer: Bayer

The FDA’s Endocrinologic and Metabolic Advisory Committee has recommended that acarbose (Precose/Bayer) be approved for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). The drug would be the first of a new class of antidiabetic drugs, the oral alpha-glucosidase inhibitors. These drugs act by impeding the digestion and absorption of carbohydrates and their subsequent conversion into glucose. The result should be improved control of blood glucose, the focus of diabetes therapy. Effective control of blood glucose may retard the development of complications such as blindness, renal failure, and neuropathy that are common in diabetes.

Acarbose has 100,000 times the binding affinity of glucose for alpha-glucosidase. It binds to the enzyme competitively in the brush border within the small intestine. By slowing the conversion and absorption of glucose, the drug reduces blood concentrations of glycosylated hemoglobin (HbA1c) by 0.5% to 1.0%. (Although glycosylated hemoglobin concentrations of 10% to 11% are associated with rapid progression of retinopathy, reducing the concentrations to 7% to 9% slows this progression significantly.) Acarbose improves postprandial hyperglycemia and maintains or lowers secretion of insulin (which is stimulated by hyperglycemia). As monotherapy, acarbose causes no hypoglycemia.

The mechanism of action of acarbose differs from that of other oral drugs such as sulfonylureas and metformin, which appear to control hyperglycemia by stimulating surviving beta cells in the pancreas to produce more insulin. These drugs can cause hypoglycemia. Acarbose, which shows little or no systemic absorption, has not been linked to serious adverse events. The main complaints are gastrointestinal symptoms (eg, flatulence, diarrhea) resulting from carbohydrate malabsorption. These can be minimized by using a low starting dose. In early studies, increases in serum hepatic transaminases were a concern, but these increases have been dramatically reduced with the lower dosages currently recommended by the sponsor (150 to 300 mg a day).

The advisory committee’s recommendation was based, at least in part, on a National Institutes of Health Diabetes Control and Complications Trial that demonstrated improved control of blood glucose with acarbose. Although that trial involved patients with type I (insulin-dependent) diabetes, panel members believe the findings will also apply to patients with NIDDM. In support of this hypothesis, a recently reported study indeed demonstrated the safety and efficacy of acarbose in a NIDDM patient population. In a multicenter, double-blind, randomized trial conducted by Coniff et al., 290 NIDDM patients were randomly assigned to receive 200 mg acarbose, 250 to 1000 mg tolbutamide, acarbose plus tolbutamide, or placebo three times a day for 24 weeks. All active treatments were superior to placebo in controlling postprandial hyperglycemia and HbA1c. The two-drug combination was most effective, followed by tolbutamide and acarbose.

Tolbutamide increased body weight and postprandial insulin levels, but these effects were ameliorated when acarbose was given with tolbutamide. Elevated hepatic enzymes were observed in three patients receiving acarbose alone and two receiving acarbose plus tolbutamide; transaminase levels returned to normal when treatment was discontinued. The researchers concluded that acarbose was effective and well-tolerated and produced significantly better results than dietary restriction.