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Recent in vitro studies have suggested a possible therapeutic synergism between alpha-IFN 2a and 13cRA in certain neoplasias, while encouraging in vivo findings strongly support the enhanced effectiveness of the two agents when used in combination. The specific aim of our study was to evaluate the efficacy and the toxicity of the association of 13cRA and alpha-IFN 2a in patients with CIN II and CIN III who refused surgical treatment. Twenty-one patients (aged between 25 and 58 years), of which 14 were CIN II and 7 CIN III, entered the study. 13cRA (orally at 0.5-1 mg/Kg/day) and alpha-IFN 2a (intramuscular at 3x10(6) I.U./day for the first 15 days, then 3 times/week for the following four weeks) were administered simultaneously for eight consecutive weeks. 13/21 (62%) histologically verified objective responses (6 complete and 7 partial) were achieved. We also obtained 8 stable diseases. Compliance was generally good and no delays in therapy due to toxicity were recorded (except for two patients presenting WHO degree III cutaneous and mucosal toxicity which regressed one week after suspending treatment). Human Papilloma Virus (HPV) was initially detected in 16/21 (76%) patients, while HPV negativization after treatment was observed in 3/16 (19%). Although preliminary and requiring long-term assessment, the encouraging results of this study confirm the need for further investigation on the role of systemic medical therapy in the treatment of CINs.

The relationship between human papilloma virus (HPV) and cervical cancer is in the process of being defined. This potential opportunity to understand a human oncogenic virus has drawn significant attention to HPV. While cervical cancer is a potentially fatal outcome of HPV infection, genital warts are the most common manifestation of genital HPV infection. In addition to knowledge of etiology, natural history, and therapeutic options, patients and providers need to consider emotional impact to successfully manage the care of patients with this common infection. This article summarizes current knowledge of recent advances of HPV infection of the vulva.

Lipophilic ester prodrugs of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), i.e., bis(pivaloyloxymethyl)-PMEA [bis(POM)-PMEA] and diphenyl-PMEA, have been synthesized in an attempt to increase the oral bioavailability of this broad-spectrum antiviral agent. The antiretroviral efficacy was determined in severe combined immune deficiency (SCID) mice infected with Moloney murine sarcoma virus (MSV). They were treated twice daily for 5 days after infection. Oral treatment with bis(POM)-PMEA at a dose equivalent to 100 or 50 mg of PMEA per kg of body weight per day proved markedly effective in delaying MSV-induced tumor formation and death of the mice. Oral bis(POM)-PMEA afforded anti-MSV efficacy equal to that of subcutaneous PMEA given at equimolar doses. Oral treatment with PMEA or diphenyl-PMEA proved less efficient. Similarly, in mice infected with Friend leukemia virus (FLV), oral treatment with bis(POM)-PMEA at a dose equivalent to 100 or 50 mg of PMEA per kg per day effected a marked inhibition of FLV-induced splenomegaly (87 and 48% inhibition, respectively), the efficacy being equal to that of PMEA given subcutaneously at equivalent doses. Pharmacokinetic experiments with mice showed that the oral bioavailabilities of PMEA following oral gavage of bis(POM)-PMEA, diphenyl-PMEA, or PMEA (at a dose equivalent to 50 mg of PMEA per kg) were 53,3, and 16%, respectively. These data were calculated from the levels of free PMEA in plasma. Also, the recoveries of free PMEA in the urine upon oral administration of bis(POM)-PMEA, diphenyl-PMEA, or PMEA (at a dose equivalent to 25 mg of PMEA per kg) were 48, 4, and 7%, respectively. Oral bis(POM)-PMEA was not recovered from plasma, suggesting that it was readily cleaved to free PMEA. In contrast, diphenyl-PMEA was not efficiently cleaved to free PMEA, resulting in a rather low oral bioavailability of PMEA from this prodrug. Bis(POM)-PMEA appears to be an efficient oral prodrug of PMEA that deserves further clinical evaluation in human immunodeficiency virus-infected individuals.

The authors describe three cases of large vulvar lesions caused by HPV. One patient has condylomata covering entirely the labia majora and minora, the clitoris, the perineum and the perianal area. The lesions made the structures of the vulva hard to distinguish. She was treated with podophyllin, Solcoderm and diathermy without effect. After 2 applications of Laser vaporisation 40 days apart she was completely cured. The other patient had two big squamous papillomata 3.5 by 3.5 cm and 0.5 cm thick situated on both sides of commissura posterior. She was also treated unsuccessfully with Podophyllin, Solcoderm and surgical excision. She was completely cured by a single-stage CO2-laser treatment. The third patient had condylomata acuminata of the labia minora and majora, fossa navicularis, the perineum and the perianal area. No other treatment had been attempted before. After two sessions of laser vaporisation she was cured, too.

The aim of the present study was to test the method of urethral cytologic sampling and to assess its results in the cytologic detection of human papillomavirus infection in the male partners of infected women. Cytologic evidence of abnormal epithelium was found in a total of 50 out of 167 cases (29.94%). It is interesting to note that 9 (5.38%) patients with cytological evidence of flat condylomas of the urethra did not have any other lesion. On the basis of the present study, we conclude that cytobrush urethral cytology should be routinely associated with peoscopy in studying the male partners of women affected by human papillomavirus infection, in an effort to diminish the reservoir of a virus strongly associated with cervical and penile neoplasia.

Human papilloma virus (HPV)-induced condylomata acuminata in both sexes, as well as cervical dysplasias were treated locally with an ointment or a cream containing 25 mg clomiphene citrate per gram for a fortnight. The DNA of HPV 6, 11, HPV 16, 18, and HPV 31, 35, 51 was monitored pre- and post-therapeutically using an in situ hybridization assay. The therapeutic response to the drug was demonstrated by the disappearance of condylomata acuminata (100%), HPV DNA in cervical dysplasia (up to 80%), and penile genital warts (75%). Under this therapeutic regimen 78% of all cases treated became negative for the probed HPV. The pharmacological action of the drug was diminished in HPV 16, 18 positive lesions. Clomiphene is shown to be an effective anti-HPV drug.

Chemosurgical treatment of vaginal/cervical human papillomavirus (HPV) infection with 5-fluorouracil (5-FU) is limited by vulvar pain and dysuria resultant from leakage and vulvar/urethral tissue reaction to the 5-FU. Women with cervical HPV DNA identified by in situ hybridization on colposcopically directed biopsy were treated with topically applied 5% 5-FU cream. A fitted cervical cap was used to restrict exposure to 5-FU. Repeat biopsies and in situ hybridization at least 6 weeks after application failed to detect HPV DNA in 6 of 7 patients. In 1 case, 5-FU treatment was associated with a decreased intensity of detectable HPV DNA. No episodes of vulvar pain or dysuria occurred. 5-FU can be used in the treatment of cervical HPV with minimal side effects when applied utilizing a cervical cap.

We describe an immunocompetent 12-year-old boy with chronic EBV infection and lymphoid interstitial pneumonitis. Lymph node biopsies showed effacement of the architecture with polymorphic cellular infiltrates, consisting predominantly of T cells and natural killer cells. No clonal rearrangement of TCR or immunoglobulin genes was seen. DNA was extracted from hilar lymph nodes; sequencing of the carboxy terminal region of the latent membrane protein 1 (LMP-1) oncogene revealed a 69 base-pair deletion and four point mutations. Immunosuppressive treatment with prednisone and cyclosporine reversed the lymphadenopathy.

58 patients suffering from HPV infection associated with CIN were treated using human fibroblast interferon, via an intramuscolar route, with positive results (87.9% of cases).

Epstein-Barr virus-specific polymerase chain reaction was used to diagnose EBV-meningo-encephalitis in a bone marrow transplant recipient. The patient made complete recovery with ganciclovir treatment. Pitfalls in diagnosis with EBV-PCR and the potential therapeutic efficacy of ganciclovir in EBV infections are discussed.

Interferons exert antiviral, antiproliferative, and immunomodulatory effects on target cells. The effectiveness of interferon treatment can be followed by measuring parameters involved in interferon action. The clinical effectiveness of interferons has been proved in the human papillomavirus (HPV)-associated disease condyloma acuminatum. Because one of the most important goals in the treatment of this condition is the elimination of recurrences, it was asked whether clinically effective interferon therapy was associated with elimination of HPV DNA. The authors used a polymerase chain reaction-based method to detect the HPV from minute amounts of clinical biopsies. Human papillomavirus-transformed cell lines or cloned HPV genomes served as different copy number controls. The intensity ratio of L1 HPV and the human beta-globin (which served as an internal control) fragments was determined and used for estimation of HPV copy number in different biopsies. A direct effect of interferon treatment on HPV viral genome copies was observed in a group of responder patients, but not in the clinically resistant group. With these data, a correlation was found between virologic data and clinical findings. This method also can be used in other lesions to determine the HPV copy number and HPV type and may have value in determining the antiviral activities of other agents used in the treatment of HPV-related lesions.

We report a new Japanese family of sialidosis type I. The sialidase activity was deficient in the lymphocytes of 2 patients (6.8% (sister) and 12.5% (brother) of control mean). However, surprisingly, using the transformed lymphocytes by EB virus, this activity was activated to 51.7% (sister) and 49.5% (brother) of control mean, respectively. Although the mechanism for this activation was not known, we discussed the possible mechanisms for this phenomenon.

Forty-six days after renal transplantation for inborn tubulointerstitial nephropathy, an 18-year-old man was rehospitalized for renal failure with creatinine at 200 mumol/l. There was no sign of infection and ciclosporin level was within therapeutic range. Transplant biopsy showed minor interstitial infiltration with mononucleated cells. Methylprednisolone by 10 mg/kg/d bolus did not improve renal function and OKT3 5 mg/d was substituted for ciclosporin but had to be stopped on day 8 because of a severe infectious syndrome. The patient developed fever (39 degrees C), erythemato-pultaceous pharyngitis followed by major multiple lymph node and spleen enlargement. The diagnosis of primary Epstein-Barr infection was confirmed serologically. Histology of a submaxillary lymph node reported monomorphic immunoblastic lymphoproliferation. Immunologic phenotyping showed CD19, CD20 and CD22 surface antigens characteristic of B cells and in situ Epstein-Barr hybridization was positive in 100% of the cells. Southern Blot showed an oligoclonal pattern. Ciclosporin and azathioprin were stopped and the patient was treated with corticosteroids (15 mg/d) and aciclovir given orally (3.2 g/d) for 3 months. Outcome at six months was favorable with normalization of the renal function and complete regression of the infectious syndrome. This case demonstrated the importance of molecular biology techniques for virologic and genotypic assessment of lymphomatous proliferation allowing positive aetiologic diagnosis.

46 patients affected by HPV+CIN were treated with Thymopentin i.m. HPV disappeared in all cases. We also observed complete disappearance or only a partial remission of CIN in 82.6% of cases.

Ribavirin has been reported to enhance the activity of ddI against HIV. We explored this enhancement of antiviral activity in Rauscher murine leukemia virus (RMuLV) models in vitro and in vivo. The significant finding in these studies was that combinations of the drugs exhibited virus titer reductions that were greater than would be expected if the drug interactions were simply additive. These effects were designated synergistic by the method of Prichard and Shipman (Prichard, M.N. and Shipman, C., Jr. (1990). A three-dimensional model to analyze drug-drug interaction, Antiviral Res. 14, 181-206). In addition to the antiviral synergy, we also observed some synergistic toxicity in the animal model.

Twenty-four specific pathogen-free kittens were infected with the Rickard strain of feline leukemia virus (FeLVR). The kittens were divided into four equal groups and were orally administered either a high dose of diethylcarbamazine (DECH, 12 mg kg-1), a low dose of diethylcarbamazine (DECL, 3 mg kg-1), 3'-azido-3'-deoxythymidine (AZT, 15 mg kg-1, b.i.d.), or a placebo (250 mg granular dextrose) daily for 10 weeks. Blood was collected at 2-week intervals for complete blood counts (CBC) and flow cytometric analysis (FACS) of peripheral blood lymphocytes (PBL). Plasma was assayed for antibodies to FeLV gp70 and for FeLV p27 antigen using ELISA assays. For FACS analysis, lymphocytes were incubated with monoclonal antibodies to feline Pan T, CD8+, CD4+, and B cell (Anti-Ig) antigens. In the placebo treated cats, FeLVR infection caused an early (2 weeks p.i.) and persistent decrease in leukocyte numbers attributable primarily to a decrease in neutrophil numbers and a secondary lesser decrease in B and CD4+ lymphocyte numbers. The DEC-treated groups showed a delayed but similar leukopenia by 4 weeks p.i. The lymphopenia in the DEC groups (primarily B cells and CD4+ cells) was reversed by 10 weeks p.i., but the neutropenia persisted. AZT treatment inhibited FeLVR-induced lymphopenia but did not prevent a reduction in neutrophil numbers. A marked p27 antigenemia that peaked at 4 weeks p.i. was noted in the placebo treated cats and in most cats (11/12) treated with either dose of DEC. However, AZT significantly inhibited the p27 antigenemia and all cats were negative for p27 antigen between 6 and 10 weeks of treatment. In general, placebo treated cats as well as DECH and DECL cats had low levels of antibody to gp70 throughout the study, suggesting FeLVR-induced immunosuppression. In contrast, significantly higher titers of anti-gp70 antibodies were seen in AZT-treated cats at 6 weeks p.i., and were maintained throughout treatment. Eighteen month survival rates provide efficacy data for AZT as well as both DEC treatment groups. While all placebo treated cats were euthanized by 52 weeks p.i. due to FeLV associated lymphomas with a mean survival time of 35.5 weeks p.i., median survival time of the AZT treated group was > or = 102 weeks p.i., while that of the DECH and DECL groups was 69.7 and 72 weeks p.i., respectively. Thus, DEC as well as AZT therapy delays the development of lymphomas associated with FeLV infection and significantly improves survival.

Vaginal adenosis, with columnar epithelium of endocervical or endometrial type forming glands within the vagina, has been observed as a congenitally acquired process, associated with in utero exposure to diethylstilbestrol; approximately 20% of those women exposed in utero have adenosis. It has been observed that vaginal adenosis may occur in nonexposed women; the origin is thought to be acquired following puberty. This study analyzed eight patients who, following topical vaginal therapy with 5-fluorouracil for vaginal intraepithelial neoplasia, had unresolving, reddened areas in the upper one-third of the vagina. Biopsy of these areas demonstrated columnar epithelium on the vaginal surface, where stratified squamous epithelium would be expected. Superficial vaginal glands (adenosis) lined with epithelium identical to the surface columnar epithelium were also identified. This finding is consistent with a metaplastic process in which stratified squamous epithelium is replaced by columnar representing columnar cell metaplasia, or acquired vaginal adenosis.

The immunomodulatory effects of opiates can modify host defenses against infection. We investigated the mechanisms involved in these effects by studying the influence of morphine on the pathogenesis of murine Friend retrovirus infection. The response to this opiate varied greatly according to the treatment schedule. Daily intra-peritoneal administration of morphine (50 mg/kg) for 16 to 27 days attenuated pathological manifestations in infected animals without modifying the mortality rate. The protective effect increased proportionately with the duration of treatment, and depended on the time of treatment initiation relative to inoculation. Naloxone (10 mg/kg/day i.p.) inhibited the morphine-induced decrease in both splenomegaly and viral titer. Mifepristone--a glucocorticoid receptor inhibitor--had no significant effect on the morphine-induced attenuation of splenomegaly. The influence of the infection on acute morphine toxicity was also analysed, using a non lethal dose in noninfected mice (200 mg/kg). Susceptibility to morphine increased in parallel to the development of the infection, with mortality rates ranging from 20% on D14 to 90% on D21. Simultaneous administration of naloxone (20-100 mg/kg) reduced the mortality rate and postponed death. Administration of mifepristone, terfenadin, phentolamine or propranolol did not modify mortality at the used doses. These findings show that the influence of morphine on the development of Friend virus infection in mice depends on the conditions of administration. The transient protective effect seen in certain conditions of administration seems to be due essentially to the direct effects of morphine on its specific receptors.

The studies summarized have shown that therapy of condylomata acuminata with interferon is effective. The route of administration does not appear to influence the results; the intralesional, intramuscular, and subcutaneous routes were effective. Additional research is required to determine whether the natural interferon or recombinant product is superior. The appropriate administration schedule may also not have been attained.

The anti-Friend leukemia virus (FLV) effects of interferon-alpha-A/D (IFN-alpha) and 2',3'-didehydro-2',3'-dideoxythymidine (stavudine) used alone and in combination were examined in Mus dunni cells using a checkerboard-type experiment design. Strong antiviral synergy and a suggested cytotoxic synergy were seen. In two experiments to evaluate the effect of combining therapy with IFN-alpha and stavudine against FLV disease in the hybrid mouse strain (B10.A x A.By)F1, which is a strong producer of cytotoxic T cells, the drug combination resulted in better inhibition of FLV disease than did either drug used alone. Combination therapy inhibited splenomegaly, splenic virus infectious centers, plasma virus, and the virus-induced increase in hematocrit to a greater degree than did either drug alone. These data indicate that combination therapy with stavudine and IFN-alpha is effective in the treatment of murine retrovirus infections and may be of value in the treatment of human AIDS.

Human papillomaviruses (HPV) are associated with benign lesions and show specificity towards the location or tissues that they infect. HPVs are responsible for warts. Among more than 60 different HPV types known to occur in humans, a strong association has been found between types 16 and 18 and cervical cancer, and such an association is also suspected for types 31, 33, 35, 45, 51, 52, and 56. We describe the effects of (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC), following local intratumoral injection, in a 69-year-old woman with hypopharyngeal and esophageal papillomatous lesions, polymerase chain reaction (PCR) positive for HPV types 16 and 18, that relapsed after surgery and that also failed to respond to Nd-Yag laser photocoagulation and alpha-interferon treatment (6 x 10(6) U five times a week for 4 weeks followed by three times a week for 2 months). HPMPC was given at 1.25 mg/kg, with a sclerosing needle, through the biopsy channel of a video-endoscope, directly into the tumor, from March until July 1993 at seven different occasions. The first four injections were given at an interval of 1 week at the level of the hypopharynx. The next three injections were given at an interval of 3 to 5 weeks. During the fourth to the seventh session, half of the dose was injected into the hypopharyngeal and the other half into the esophageal tumor. Three further injections of HPMPC were administered at the level of the esophageal tumor in September 1993 with 2-week intervals. After HPMPC treatment, the lesions became smaller and flat until they completely disappeared.(ABSTRACT TRUNCATED AT 250 WORDS)

We report on the case of a 51-year-old female patient who had been suffering from multiple itching nodules for 3 years. Some of these lesions were classified clinically and histologically as keratoacanthomas (KA), whereas the multiple smaller nodules were found on histological examination to be either early stage KA or lesions of prurigo simplex subacuta. In two KA, HPV subtype 2 was identified by in situ hybridization. Treatment with etretinate resulted in remission of the fully developed KA and reduced the occurrence of new ones. The outbreak of multiple KA in our patient resembled a rare subtype described by Witten and Zak. Postclinical follow-up for 28 months to date has revealed that the KA arise from the subacute prurigo lesions. This mode of prurigo-dependent KA development has not previously been reported.

Objective: To evaluate the potent photosensitizer m-tetra (hydroxyphenyl) chlorin (m-THPC) by using rabbits with cottontail rabbit papillomavirus-induced tumors and the canine larynx as model systems., Design: Nonrandomized control trial., Setting: Division of ear, nose, and throat research at a tertiary care teaching hospital., Materials: Rabbits were used for relative retention ratio studies and tissue tolerance tests. Studies on the swelling of normal tissues in the larynx after photoactivation were done with canines., Intervention: Animals were injected with 0.3 mg/kg of m-THPC. At varying intervals, tissues were exposed to 652 nm of light., Outcome Measures: Outcome measures consisted of four elements: (1) decay of plasma concentration over time, (2) interval to and duration of maximal ratio between drug concentration in normal tissue and tumor, (3) maximal permissible light exposure to normal tissue (skin and laryngeal mucosa) at an optimal interval, and (4) efficacy--number of tumors with partial and complete response., Results: The largest papilloma to skin ratio (10:1) occurred 4 to 8 days after drug injection. The rabbit skin damage threshold was 40 to 60 J/cm2 at 6 days. The canine laryngeal edema and erythema thresholds were 50 to 70 J. A 75% cure rate of papillomas was achieved with tumors that were less than 100 mm2 in area at light doses that ranged from 25 to 75 J/cm2., Conclusions: m-THPC shows efficacy in treating papilloma virus-induced tumors. We present a protocol for rapid optimization of the factors required for tumor destruction with minimal normal tissue damage, thus permitting determination of an optimal therapeutic protocol for any photosensitizer.

This article will review the 1993 STD Treatment Guidelines of particular importance to dermatologic clinical practice. Topics include STD/HIV prevention, management of sexual partners, STD in persons with HIV co-infection, genital ulcer disease (GUD) including syphilis, herpes simplex virus (HSV) infection, lymphogranuloma venereum (LGV) and chancroid, therapy of nongonococcal (NGU) and chlamydial urethritis and cervicitis, gonococcal (GC) infections, HPV infection, hepatitis B virus (HBV) infection, pediculosis pubis, and scabies.

The microbiological study of vaginal secretions of 39 female patients of reproductive age (20-30 years) with papilloma virus infection associated with cervical intraepithelial neoplasia (CIN) was carried out. Of these patients, 28 with papilloma virus infection associated with CINI-II made up group I and II having this infection associated with CINII made up group 2. Dysbiotic disturbances in vaginal bacterial flora, found in these patients, were manifested by a decrease in the isolation rate and number of the lacto- and bifidobacteria simultaneously with the excessive growth of opportunistic bacteria. The results of the oral administration of Solco-Trichovac are indicative of the effectiveness of this preparation, which was confirmed by the data of clinical and bacteriological studies. Together with an increase in the isolation rate of lacto- and bifidobacteria, the level of the contamination of the cervicovaginal niche with opportunistic and pathogenic bacterial strains decreased. The results thus obtained make it possible to recommend Solco-Trichovac for the complex treatment of with papilloma virus infection associated with CIN.

Management of women with HIV infection or AIDS should follow the established guidelines for antiretroviral therapy and prevention and treatment of opportunistic complications of HIV infection. Gynecological manifestations of HIV are primarily cervical dysplasia and cancer associated with human papillomavirus (HPV) infection and vaginal and mucocutaneous candidiasis. Human papillomavirus-associated cervical dysplasia/neoplasia is more common in women with advanced rather than early HIV disease, and monitoring with Pap smears should probably increase to every 6 months in patients with CD4+ cell counts < 500 cells/microliter (and certainly when this value falls below 200), with positive Pap smears confirmed by colposcopy and biopsy. For patients with CD4+ cell counts > 350 cells/microliter, cryotherapy is probably adequate, but therapy should be increasingly aggressive at lower CD4+ cell counts. Results of ongoing studies should be available soon to guide therapy. Optimal treatment of candidiasis in HIV-infected women includes prevention of recurrence with a combination of topical and systemic antifungal agents. Women with child-bearing potential should be treated as medically indicated for other HIV-infected patients, including during pregnancy. In fact, preliminary results of ACTG 076 indicated that zidovudine therapy during pregnancy reduces vertical transmission of HIV about threefold.

D-aspartic acid beta-hydroxamate (DAH), an aspartic acid analogue, exerts anti-tumoral activity against murine leukemia L5178Y both in vitro and in vivo. We show here that DAH displays activity against Friend leukemia cells (FLC) in vitro: a concentration of 2 mM results in a total inhibition of cell growth. DAH is also active in vivo against Friend virus (FV-P)-induced erythroleukemia. Treatment with DAH, given for 95 days as a single daily i.p. injection to DBA/2 mice 3 days following FV-P inoculation, induced a marked increase of 212% in the mean survival time (MST) of treated animals. Since FV-P-induced erythroleukemia is characterized by the proliferation of mature erythroid precursors, we examined the effect of DAH treatment on erythroid colony-forming cells (CFU-E) and observed that the number of CFU-E per spleen was 30 times lower in DAH-treated mice than in the controls. To gain further insight into the early effects of DAH treatment on the early phase of Friend disease, we examined the effects of short DAH treatment on spleen size, hematocrit and viremia in FV-P-infected mice. DAH treatment initiated 3 days post infection (p.i.) inhibited splenomegaly, prevented virus-induced polycythemia, and reduced serum viremia. Late DAH treatment (18 days p.i.) induced regression of FVP-induced disease as evidenced by reduction of spleen weight.

Preclinical evaluation of the effectiveness of interferon (IFN) therapy on human papillomaviruses (HPV) has been hampered by the inability to propagate these viruses in cell culture. Nonetheless, interferon is used extensively in the treatment of HPV infections. Alpha interferons in particular have found a place in the treatment of anogenital disease, plantar warts, and laryngeal papillomas. While their is significant clinical evidence to suggest that interferon is useful in therapy of disease, the cellular mechanism(s) (i.e., antiviral, antiproliferative, immunomodulatory) by which IFN is able to control HPV-induced pathology is not well understood. This review focuses on experimental animal and cell culture models which are currently being used to help identify the antiviral, antiproliferative and immunomodulatory effects of IFN on HPV infection.

Human papillomavirus (HPV) infections usually present as benign warts (e.g., condyloma acuminatum, CA) but can also be responsible for dysplasia and carcinoma. Therapeutic options include chemotherapeutic agents, cryotherapy and surgery, but all these treatments are anti-tumor, not anti-viral. Interferons (IFNs) are the only anti-viral drugs approved for the therapy of benign HPV-related lesions. While IFN-alpha, IFN-beta and IFN-gamma have all been tested against CA, most information is available on IFN-alpha which appears efficacious via a number of routes of administration, schedules and dosages with an acceptable safety profile. The highest rate of success with IFN-alpha therapy, in terms of reduced recurrence rates of CA was reported from studies in which all visible lesions were surgically removed with subsequent administration of subcutaneous local IFN-alpha. Less data is available on the efficacy of IFNs in the treatment of HPV-related dysplasia and carcinoma, but combination therapy (e.g., IFN-alpha plus retinoids for cervical carcinoma) appears promising. Future advances in control of HPV-related lesions are expected to continue to involve IFN combined with non-antiviral therapies as well as the use of exogenous inducers of IFNs and other cytokines.

Herpes simplex virus and human papillomavirus are epitheliotrophic viruses common to the oral cavity. They produce acute and chronic disorders of oral mucosa of interest to the dermatologist. Most of these lesions are benign in nature. However, both viruses are harbored latently, and their malignant potential remains to be defined.

CTC-96, a cobalt containing complex, was tested as a putative topical therapeutic agent for the treatment of papillomavirus-induced tumors in our cottontail rabbit papillomavirus (CRPV)-rabbit model system. Following experimental infection of domestic rabbits with CRPV, CTC-96 was applied to infection sites twice daily, 5 days a week for a total of 8 weeks. Two levels of concentrations of aqueous CTC-96 were compared to placebo control-treated animals. With increasing dose of CTC-96 we observed tumors earlier, larger, and more often across eight infected sites on each animal.

The antiretroviral activity of two new lipophilic derivatives of azidothymidine (AZT), N4-hexadecyl-2'-deoxyribocytidylyl-(3',5')-3'-azido-2',3'-deoxythy midine (N4-hexadecyldC-AZT) and N4-palmitoyl-2'-deoxyribocytidylyl-(3',5')-3'-azido-2',3'-deoxythy midine (N4-palmitoyldC-AZT) was evaluated in comparison to AZT. In vitro the drugs were tested in human immunodeficiency virus 1 (HIV-1) infected CD4+ HeLa and H9 cells. The in vivo antiviral effect of these derivatives was analysed in Rauscher leukemia virus (RLV) infected mice. The derivatives were incorporated into small liposomes. In vitro both derivatives inhibited virus proliferation in both HIV-1 infected cell lines in a similar dose-responsive manner as AZT. In a plaque reduction assay, using HeLa cells, the IC50 values were 0.035 microM for AZT, 0.5 microM for N4-hexadecyldC-AZT and 4.5 microM for N4-palmitoyldC-AZT, whereas p24 antigen analysis on H9 cells gave IC50 values of 0.005 microM, 0.05 microM and 0.05 microM, respectively. RLV infected mice were treated with intermittent schedules i.p. or i.v. on days 1, 6, 11, and days 16 or 0, 3, 7, and 11 after infection. Regimens with further delayed drug application were on days 3, 7, and 11 and 7 and 11 only. While i.p. treatment with total doses of 380-1140 mg/kg free AZT resulted in 10-30% inhibition of RLV induced splenomegaly, the derivatives gave inhibitions of 37-94%. Late onset of treatment with the derivatives was significantly more effective as compared to free AZT. Intravenous treatment with N4-hexadecyldC-AZT was effective, but with AZT was inactive. The discrepancy in antiviral activity of the AZT derivatives found between the in vitro and in vivo test systems emphasizes the importance of investigating the activity of drug derivatives in vivo.

The features and clinical course of chronic balanitis in 5 patients are presented. In each case, histological examination of a cutaneous biopsy sample showed pronounced features of human papillomavirus (HPV) infection. In addition, HPV DNA was demonstrated in each biopsy specimen by a polymerase chain reaction and was found to be type 6 by Southern blot hybridization in 4 of the cases. Although the association of histological features of HPV infection with balanitis does not prove that HPV is causal, the failure to find other causes, the prolonged and distressing symptoms, and the ineffectiveness of topical steroids in improving symptoms, all suggest the importance of HPV infection. While effective treatment needs to be sought and developed, the response of one patient to oral isotretinoin suggests that this agent may be appropriate for a larger trial.

Local treatment was administrated to 130 women, in whom colposcopy, cytology and (if the latter was abnormal) histology pointed to HPV infection in uterine cervix. The best results were obtained with 13-cis-retinoic acid (provitamin A) in conjunction with interferon beta (94.2% cured patients), followed by interferon beta in combination with TFX (90% cured patients) and interferon beta administered alone (88% cured patients).

In the past 4 years, interest in drug-resistant herpesviruses has evolved from the realm of academic laboratory studies to that of great clinical importance. Recurrent and persistent infections due to the herpes simplex viruses, varicella-zoster virus, and human cytomegalovirus have been an unwelcome consequence of immunosuppression in graft recipients, cancer patients, and those suffering from AIDS. Treatment of these infections with the available antiviral drugs, such as acyclovir, ganciclovir, and foscarnet, has resulted in both clinical benefit and the emergence of drug-resistant variants. In addition, the role of Epstein-Barr virus is being clarified for an array of disease syndromes, and therapeutic approaches are beginning to emerge. In the present review, the emergence and clinical importance of drug resistance among the herpesviruses have been explored. Furthermore, particular attention has been focused on our understanding of the mechanisms of drug resistance and how that understanding will guide us in the development of more effective antiviral drugs and drug usage.

The virus-associated T cell leukaemias/lymphomas are characterized by a poor prognosis primarily because of the rapid emergence of drug resistance which may lead to failure of subsequent chemotherapy. We report here a case of Epstein-Barr virus-associated T cell lymphoma which relapsed soon after chemotherapy and radiotherapy. The neoplastic cells of the relapsed tumour expressed high levels of multi-drug resistance gene (mdr1)-related P-glycoprotein and glutathione-S-transferase-pi, both of which were absent in the pre-chemotherapy tumour tissues. Empirical treatment with oral 13-cis-retinoic acid (RA) was then given with subsequent complete disappearance of the tumour. The therapeutic effect of RA appears to act through an apoptotic process. In accordance with our previous report of a successful salvage of a refractory Ki-1 large cell lymphoma. RA appears to be a potentially useful drug for some specific type T-cell lymphomas.

We tested the hypothesis that infiltrating leukocytes might contribute to papilloma destruction following podofilox treatment. New Zealand White (NZW) rabbits were inoculated with cottontail rabbit papillomavirus (CRPV) onto abraded areas of the dorsal skin. At 21 d after viral inoculation, 5.0% podofilox solution was applied to some papillomas, whereas others were used as controls. Three rabbits were sacrificed at each of three different periods after treatment initiation (1, 4, and 7 d). Four monoclonal antibodies (MoAbs), RG-16 (for B cells), L11/135 (specific for T cells), 2C4 (specific for class II antigen), and Ki67 (specific for proliferating cells), were used in an immunohistochemical study. All positive cells and total cells in the field were counted with an ocular grid. After 1 d of treatment, proliferation of papilloma cells was strongly suppressed in treated papillomas, but leukocytic infiltration was not altered. At 4 d and 7 d of treatment, there were substantial increases (about two to three times) in the numbers of B and T cells and class II-expressing leukocytes. The upper layers of the papillomas were highly necrotic and cell proliferation was absent in all layers. These data support the view that podofilox has a direct toxic effect on papilloma tissue. Leukocyte infiltration is not strongly associated with papilloma tissue and may not contribute to papilloma destruction.

The antiviral drug ribavirin was used as an adjunct to laser surgery for the treatment of patients with laryngeal papillomatosis (LP). An uncontrolled clinical trial for four patients with ribavirin treatment at a daily dose of 23 mg/kg was performed. Three adults received drug prior to laser surgery and continuing orally for 6 months. One infant was treated for 3 months. Two adults achieved complete remissions for at least 2 consecutive months, and both patients developed only minimal recurrent disease in 4 months of follow-up. The other adult and the child sustained a partial response and an increased interval between the required surgeries. Ribavirin caused only a mild, reversible reduction in hemoglobin and reticulocytosis. This preliminary trial shows that ribavirin may be an effective therapy in combination with surgery for LP in a larger controlled clinical trial.

Objective: To assess whether oral acyclovir can eliminate persistent Epstein-Barr virus (EBV) infection and thereby prevent EBV-associated lymphoma development in HIV-seropositive homosexual men., Method: Persistent EBV infection was examined in a group of 21 HIV-seropositive homosexual men before, during and after treatment with oral acyclovir at a dose of 800 mg every 6 h (10 individuals) or with a placebo (11 individuals)., Results: In 13 individuals, EBV was isolated from the oropharynx before and after treatment (seven cases from the acyclovir-treated group and six from the placebo-treated group). A significant reduction in virus isolation occurred during treatment in the acyclovir-treated group, but not in the placebo-treated group. In seven cases in whom EBV shedding was detected before and after treatment, the EBV strain isolated was identical throughout the study, even when acyclovir had abolished detectable shedding for the duration of the treatment. In two other cases more than one strain was detected. On examination of the EBV type present, 89% of a group of 18 patients consistently shed type A virus, 5.5% type B virus and 5.5% showed evidence of co-infection with both virus types. This compares with figures of 100, 0 and 0%, respectively, in a control group of HIV-seronegative individuals., Conclusions: High-dose acyclovir therapy does not eliminate persistent EBV infection from the oropharynx of healthy HIV-seropositive individuals and therefore would not necessarily prevent lymphoma development. Our results suggest that infection by type B EBV, and co-infections of both A and B type, are more common in HIV-seropositives than HIV-seronegatives.

Most of the human herpesviruses have a unique relationship with the central nervous system. In this review we summarize recent developments in the establishment of viral latency, and discuss the nervous system illnesses instigated by direct viral cytopathic effect, by immune activation, and by neoplastic events. Special consideration is given to herpesvirus infections in the context of acquired immunodeficiency syndrome, and in association with neonatal infections. New diagnostic techniques and treatments are also summarized.

Human papillomavirus (HPV) type 6e DNA was detected in a laryngeal papilloma, in a papilloma recurring after an interval of six years and in the counterpart clinically-normal false cord of the same patient. No detectable subgroup change of HPV DNA occurred during the clinical course, which included therapy by CO2 laser followed by intramuscular alpha-interferon injection. The data demonstrated a single subtype of HPV to have persisted, and the prevention of a recurrence of laryngeal papilloma during our patient's long clinical course to have failed, in spite of the interferon treatment.