Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts.

Genital human papillomavirus infection is one of the most common sexually transmitted diseases. Imiquimod is a new agent, an immune-response modifier, that has been demonstrated to have potent in vivo antiviral and antitumor effects in animal models. The present prospective, multicenter, double-blind, randomized, vehicle-controlled trial evaluated the efficacy and safety of daily patient-applied imiquimod for up to 16 weeks for the treatment of external genital warts. Wart recurrence was investigated during a 12-week treatment-free follow-up period. In the intent-to-treat analysis, baseline warts cleared from 49 of 94 (52%) patients treated with 5% imiquimod cream, 13 of 90 (14%) patients treated with 1% imiquimod cream, and 3 of 95 (4%) vehicle-treated patients; the differences between the groups treated with vehicle and imiquimod were significant (P < 0.0001). For subjects who completed the follow-up period, recurrence rates after a complete response were 19% (9 of 48 patients) in the 5% imiquimod cream group, 17% (2 of 12) in the 1% imiquimod cream group, and 0% (0 of 3) in the vehicle-treated group. There were no systemic reactions, although local skin reactions (generally of mild or moderate severity) were common, particularly in the 5% imiquimod cream group. Local reactions caused two patients to discontinue treatment. The most frequently reported local skin reactions were erythema, excoriation or flaking, and erosion. Patient-applied 5% imiquimod cream is effective for the treatment of external genital warts and has a favorable safety profile.

Imiqimod in clinical practice.

Imiquimod 5% cream is a new compound which modifies the immune response by stimulating the production of interferon alpha and other cytokines. It has shown remarkable promise in the treatment of external genital and perianal warts when applied overnight, three times a week. It is also associated with a lower recurrence than those found with other current treatments. This paper reviews two of the pivotal multi-centre studies which confirm its efficacy in human papilloma virus (HPV) infections. These studies compared the effectiveness and safety of imiquimod 1% cream, imiquimod 5% cream and vehicle cream in the treatment of external anogenital warts.

Diagnosis of human papillomavirus genital tract infection.

Although visible anogenital lesions are present in some persons infected with human papillomavirus (HPV), the majority of individuals with HPV genital tract infection do not have clinically apparent disease. Conventional viral detection assays, including serologic assays and growth in cell culture, are not available for the diagnosis and tracking of HPV infection. Papanicolaou tests are a valuable screening tool, but they miss a large proportion of HPV-infected persons. Accordingly, HPV DNA detection assays have become a key research tool in the detection of HPV infection, particularly in asymptomatic individuals. Several types of HPV DNA tests are now available, including Southern blots, dot blots, in situ hybridization, polymerase chain reaction, and solution hybridization (Hybrid Capture assay). Of these, the polymerase chain reaction assay is the most sensitive, whereas dot blots and solution hybridization are the least labor intensive. HPV DNA detection assays are not routinely used in screening patients, in part because the clinical relevance of asymptomatic infection is unclear. Nevertheless, these tests may be beneficial in confirming differential diagnoses and in providing prognostic information, particularly with respect to the HPV type involved.

D-dimer test for early detection of HELLP syndrome.

We attempted to predict patients at risk for HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) by using the D-dimer test to screen 81 preeclamptic gravidas and 12 control subjects. Among preeclamptic patients, 43 had positive and 38 had negative results of D-dimer tests. All controls had negative results. Women with positive results had significantly higher mean arterial pressures at admission and postpartum, lower platelet counts, and elevated liver enzyme values. D-dimer-positive women also had infants with significantly lower birth weight and lower Apgar scores. After delivery, those with a positive D-dimer test were at risk for even greater abnormalities of liver enzymes, as well as lower platelet counts. Abnormalities of any of these laboratory parameters were unlikely in the presence of a negative D-dimer test result (negative predictive value = 0.89). Our results suggest that D-dimer-positive preeclamptic women are at high risk of having HELLP syndrome and should receive close follow-up, whereas D-dimer-negative patients are unlikely to have this disorder and tend to have a better maternal-fetal outcome.

Effect of preinduction cervical softening with dinoprostone gel on outcome of oxytocin-induced labor.

Five hundred fourteen pregnant women at or near term with medically indicated inductions and unfavorable cervical induction features (Bishop score 0-4) were enrolled in an open-label randomized multicenter clinical trial to study the effect of endocervical administration of 0.5 mg of dinoprostone cervical gel as a preinduction cervical ripening agent. Patients in the treatment group (n = 265) received dinoprostone cervical gel 12 hours prior to oxytocin induction; patients in the control group (n = 249) were observed during this period. Thirteen patients in each group were excluded from efficacy evaluations. All patients were included in safety analysis. A mean Bishop score increase of 2.9 points was achieved in the treatment group, as compared with 0.6 point in the control group (P < 0.001). During the observation period, spontaneous labor occurred in a significantly greater percentage of patients in the treatment group (27%) than in the control group (2%). The percentage of patients who achieved labor either during the observation period or during the initial induction attempt was significantly larger in the dinoprostone cervical gel group (71.8%) than in the control group (54.2%). In addition, there was a statistically significant (P < 0.001) difference in median induction-to-vaginal delivery time for the treatment group (10.6 hr) and the control group (13.0 hr). Side effects were reported for 42% and 35% of patients in the treatment and control groups, respectively, with fetal heart rate abnormalities reported for approximately 27% of patients in each group.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of fibrin D-dimer in plasma and urine of pregnant women using Dimertest latex assay.

Eighty-six women admitted for evaluation of preeclampsia had plasma and urine screened for the presence of fibrin D-dimer using the monoclonal antibody DD-3B6 in a latex fixation assay (Dimertest). In 53 of the women screened, results were negative for fibrin D-dimer in both plasma and urine; in 33, results were positive in urine (N = 11), plasma (N = 14), or both (N = 8). D-dimer positive women were at increased risk for earlier delivery (mean 34 versus 36 weeks), lower birth weight babies (mean 2,327 versus 2,669 g), higher mean arterial pressures (mean 104 versus 94mm Hg), liver function test abnormalities (mean lactate dehydrogenase value 256 versus 142 U/L, mean serum glutamic-oxaloacetic transaminase 67 versus 23 U/L), and significantly elevated levels (> 40 micrograms/mL) of fibrin(ogen) degradation products (FDPs). Interestingly, 22 of 33 D-dimer positive women had insignificant levels of FDPs. Generally, D-dimer negative women had no significant abnormalities in results of coagulation tests and liver function tests. This study confirms previous observations on the value of D-dimer detection in screening for preeclampsia coagulopathy and extends this tool to its detection in urine.

Endocervical prostaglandin E2 gel for preinduction cervical ripening. Clinical trial results.

Randomized, clinical trial results of a standardized, stable prostaglandin E2 (PGE2) preparation (0.5-mg PGE2 in a 2.5-mL gel base) applied endocervically as a single dose 12 hours prior to oxytocin induction were studied. The trials, conducted in the United States and Canada, included 538 women; 277 treated with PGE2 gel and 261 controls, with initial Bishop scores of < or = 4. Compared to controls, PGE2 recipients had significant improvement in cervical Bishop scores (P < .01) and a high rate of labor (47.4% vs. 9.6%, P < .001) during the 12-hour ripening period. In reporting centers, delivery during this same interval occurred without use of oxytocin in PGE2 patients (25.4%) vs. controls (4.9%). PGE2 reduced induction to delivery intervals and the duration of oxytocin administration. Although the composite cesarean section rates were lower in PGE2 recipients than in controls (28.5% vs. 32.9%), this difference did not achieve statistical significance. Maternal and fetal outcome and the incidence of complications were similar in the two groups. These studies confirm the safety and efficacy of this standardized PGE2 preparation as a means of cervical ripening in parturients with highly unfavorable cervixes.

Interferon treatment of anogenital human papillomavirus-related diseases.

Because of their antiviral, antiproliferative, and immunoregulatory properties, IFNs are potentially well suited for use in the management of benign HPV-related anogenital diseases. Parenteral and intralesional therapy of condylomata with various natural and recombinant IFN preparations has consistently resulted in beneficial response rates ranging between 40% and 60%, often in patients in whom other therapeutic measures have repeatedly failed. Adverse effects from IFN are dose dependent and generally tolerable at concentrations of IFN found to be effective in the treatment of condylomata, and they are not associated with any known long-term sequelae. When combined with conventional medical and surgical treatment modalities, IFN offers real promise for the control of both extensive primary and recalcitrant HPV-related conditions.

Use of the fibrin D-dimer in screening for coagulation abnormalities in preeclampsia.

Plasma from pregnant women with preeclampsia was screened for the D-dimer, a degradation product specific for crosslinked fibrin, using a monoclonal antibody (DD-3B6), latex-bead agglutination assay (DIMERTEST). Seventy-nine of 204 (38.7%) of the preeclamptic women and none of 88 healthy non-preeclamptic women were positive for the D-dimer. Presence of the D-dimer correlated consistently with elevated fibrin(ogen) degradation products, detectable fibrin monomer, and platelet count less than or equal to 100 x 10(9)/L, with a 93.0% sensitivity overall for abnormalities of the same. Among D-dimer-positive women, 66.7% had fibrin(ogen) degradation products less than 10 micrograms/mL, 60.3% had no detectable fibrin monomer, and 82.0% had platelets greater than 100 x 10(9)/L. When compared with D-dimer-negative preeclamptic women, D-dimer-positive women had significantly higher blood pressures prompting delivery, greater proteinuria, more abnormal liver function tests, and higher serum creatinine and blood urea nitrogen. In addition, they had a greater risk of cesarean section (49.4 versus 34.4%), premature delivery (58.2 versus 20.0%), low birth weight (54.5 versus 20.3%), low Apgar scores, and an abnormally high ratio of female to male offspring (1.72 versus 0.93). Testing for the fibrin D-dimer may be useful in early screening and follow-up for preeclamptic coagulopathy, and may also help to define the subset of patients with severe disease.

Interferon alpha-n1 (Wellferon) for refractory genital warts: efficacy and tolerance of low dose systemic therapy.

This multi-center trial compared two doses of parenterally administered interferon alpha-n1 (Wellferon) in men and women with recurrent/resistant genital warts. Patients received either 1 or 3 MU/m2 daily for 14 days, then 3 times weekly for 4 weeks; non-responders could receive an additional four weeks of treatment. A total of 107 patients were enrolled, and 102 were evaluable after six weeks of study. The principal dose comparison was in 57 women assigned alternately to the two doses. Median lesion measurements were reduced significantly from baseline at weeks 2, 4 and 6 in both groups. Statistical analysis showed no difference in response to 1 versus 3 MU/m2. The overall complete response (CR) plus partial response (PR) rate at week 6 was 69% for the two doses. Two additional groups of 21 women and 24 men were treated at the higher dose with CR plus PR rates of 75 and 50%, respectively. Week 10 disease evaluations for all groups showed 19 of 77 patients to be completely cleared. Of these 19, only one had recurrent disease at the end of the 6-month study period. Analysis of the incidence of symptomatic side effects showed a significantly higher frequency among women treated with 3 MU/m2 than among women treated with 1 MU/m2. Five dose reductions and two withdrawals for toxicity occurred, all in the high dose group. This study demonstrates that parenterally administered Wellferon produces clearance of resistant genital warts in many patients, and that rates of clearance do not appear to vary between groups receiving moderate or low dose therapy.

Recurrent condyloma acuminatum in women over age 40: association with immunosuppression and malignant disease.

Sixteen women aged greater than or equal to 40 years were studied within a total population of 77 women with recalcitrant condyloma acuminatum. Six of the 16 women (38%) were found to have coincident malignant disease (p less than 0.001). Three of these had lymphoma (non-Hodgkin's), two had squamous cell cancer of the vulva or vagina, and one had breast carcinoma. Two of the three patients with lymphoma had recurrent genital condyloma diagnosed before the coexistent lymphoproliferative disorder was discovered. In all, 11 of 16 patients had dysplasia and neoplasia. Seven of the women had other medical conditions associated with immunosuppression. We conclude that the presence of recurrent condyloma acuminatum in women greater than or equal to 40 years of age should lead to examination for the presence of immunosuppression and its underlying cause. A high index of suspicion for concomitant genital squamous cell neoplasia and lymphoproliferative disorders should be realized. The factors relating age, recurrent condyloma, immunosuppression, and malignant disease are discussed.

A modified biophysical profile for antenatal fetal surveillance.

Three hundred thirty-seven high-risk pregnancies were screened using a modified biophysical profile consisting of nonstress testing (NST) and ultrasound evaluation of amniotic fluid volume. Ultrasound assessment of fetal breathing and body movements was performed only to evaluate the nonreactive NST. Decreased amniotic fluid volume and spontaneous fetal heart rate (FHR) decelerations were considered abnormal findings during antenatal testing, and served as indications for delivery regardless of FHR reactivity. Despite intervention, decreased amniotic fluid volume and spontaneous decelerations were associated with an increased incidence of meconium staining, decelerations during labor, cesarean section for fetal distress, and small for gestational age infants. Perinatal morbidity also occurred in patients with spontaneous decelerations and normal amniotic fluid volume. The search for spontaneous FHR decelerations by electronic fetal monitoring should continue during antepartum testing because FHR decelerations cannot be identified by conventional ultrasound assessment. The modified profile seems practical for routine assessment of fetal well-being in high-risk pregnancy, and affords insights unavailable with ultrasound surveillance alone.

Twin pregnancy. Management of delivery.

Management of the twin delivery remains controversial, particularly when the second twin in nonvertex and has an estimated fetal weight of 600 to 1500 gm. Management of schemes based on fetal presentation and estimated weights, as well as specific techniques and options for intrapartum care, are discussed.

Interferon.

Interferons are proving useful in the management of recalcitrant condylomata acuminata. Dosage schedules have been established that balance efficacy and systemic toxicity. Alone, however, interferons are not entirely effective in every patient. In combination with conventional medical and surgical modalities, they offer hope for the control of an often frustrating and potentially serious virus infection.

Pregnancy-induced changes in the fibrinolytic balance: evidence for defective release of tissue plasminogen activator and increased levels of the fast-acting tissue plasminogen activator inhibitor.

Pregnancy is accompanied by an increased risk of thromboembolic disease. One contributing factor to such disease in the nonpregnant patient is disordered fibrinolysis. It has been suggested that defective fibrinolysis may occur in pregnancy, but this defect has been poorly characterized. In the present study of 52 women with normal pregnancies and 56 nonpregnant control women, we found a marked change in levels of releasable tissue plasminogen activator in pregnant women beginning in the first trimester. Whereas nonpregnant women demonstrated releasable levels of tissue plasminogen activator of 0.74 +/- 0.15 IU/ml of plasma, in the pregnant women the amount released was only 0.06 +/- 0.02 IU/ml of plasma (p less than 0.01). These levels were observed beginning in the first trimester. Levels of the recently described fast-acting tissue plasminogen activator inhibitor increased significantly throughout pregnancy. Values ranged from 8.40 +/- 0.27 IU/ml of plasma in the first trimester to 9.92 +/- 0.09 IU/ml of plasma in the third trimester (p less than 0.05) compared with the level of 8.46 +/- 0.19 IU/ml of plasma in nonpregnant subjects. These data suggest that alterations both in releasable tissue plasminogen activator and in the fast-acting tissue plasminogen activator inhibitor contribute to the physiologic hypercoagulable state of pregnancy.

Human lymphoblastoid interferon (Wellferon) in primary therapy of two children with condylomata acuminata.

Human lymphoblastoid interferon (Wellferon) was administered parenterally to two prepubertal girls as primary therapy for genital condylomata acuminata. One child probably had contracted the disease as the result of sexual molestation. Both patients experienced minimal side effects during therapy and underwent complete remission within six weeks. These cases support use of interferon as primary therapy in young patients with extensive condylomata and in those who may have contracted the disease as the result of sexual abuse.

Preinduction cervical ripening with prostaglandin E2 (Prepidil) gel.

The effect of preinduction cervical ripening with Prepidil, a commercially prepared prostaglandin E2 gel (0.5 mg), on the outcome of induction of labor with intravenous oxytocin was investigated. Fifty-nine pregnant women were randomized either to receive intracervical application of the gel or to undergo sham application. Compared to control subjects, patients in the group given Prepidil had significant increases in cervical Bishop scores, shorter induction-to-delivery intervals, lower maximum doses of oxytocin, and fewer days of induction. Systemic side effects were minimal, but 37% (11 of 30) of the gel-treated patients experienced labor prior to receiving oxytocin and 20% (six of 30) were actually delivered during the 12-hour ripening period. No differences in route of delivery or fetal outcome were found between the two groups.