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Drugs in Context 2018Penile warts are the most common sexually transmitted disease in males. Clinicians should be familiar with the proper evaluation and management of this common condition. (Review)
Review
BACKGROUND
Penile warts are the most common sexually transmitted disease in males. Clinicians should be familiar with the proper evaluation and management of this common condition.
OBJECTIVE
To provide an update on the current understanding, evaluation, and management of penile warts.
METHODS
A PubMed search was completed in Clinical Queries using the key terms 'penile warts' and 'genital warts'. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews.
RESULTS
Penile warts are caused by human papillomavirus (HPV), notably HPV-6 and HPV-11. Penile warts typically present as asymptomatic papules or plaques. Lesions may be filiform, exophytic, papillomatous, verrucous, hyperkeratotic, cerebriform, fungating, or cauliflower-like. Approximately one-third of penile warts regress without treatment and the average duration prior to resolution is approximately 9 months. Active treatment is preferable to watchful observation to speed up clearance of the lesions and to assuage fears of transmission and autoinoculation. Patient-administered therapies include podofilox (0.5%) solution or gel, imiquimod 3.75 or 5% cream, and sinecatechins (polypheron E) 15% ointment. Clinician-administered therapies include podophyllin, cryotherapy, bichloroacetic or trichloroacetic acid, oral cimetidine, surgical excision, electrocautery, and carbon dioxide laser therapy. Patients who do not respond to first-line treatments may respond to other therapies or a combination of treatment modalities. Second-line therapies include topical/intralesional/intravenous cidofovir, topical 5-fluorouracil, and topical ingenol mebutate.
CONCLUSION
No single treatment has been shown to be consistently superior to other treatment modalities. The choice of the treatment method should depend on the physician's comfort level with the various treatment options, the patient's preference and tolerability of treatment, and the number and severity of lesions. The comparative efficacy, ease of administration, adverse effects, cost, and availability of the treatment modality should also be taken into consideration.
PubMed: 30622585
DOI: 10.7573/dic.212563 -
Molecules (Basel, Switzerland) Nov 2018Herein, we present an expeditous synthesis of bioactive aryldihydronaphthalene lignans (+)-β- and γ-apopicropodophyllins, and arylnaphthalene lignan...
Herein, we present an expeditous synthesis of bioactive aryldihydronaphthalene lignans (+)-β- and γ-apopicropodophyllins, and arylnaphthalene lignan dehydrodesoxypodophyllotoxin. The key reaction is regiocontrolled oxidations of stereodivergent aryltetralin lactones, which were easily accessed from a nickel-catalyzed reductive cascade approach developed in our group.
Topics: Catalysis; Cyclization; Lactones; Lignans; Models, Molecular; Molecular Structure; Podophyllin; Podophyllotoxin
PubMed: 30469319
DOI: 10.3390/molecules23113037 -
Toxicology and Applied Pharmacology Oct 2018We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more...
We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more sensitive to radiation and chemotherapeutic agents. In an attempt to enhance PA activity, we synthesized 34 derivatives based on podophyllotoxin (PPT). Screening of the derivative compounds for anti-cancer activity against NSCLC led to the identification of β-apopicropodophyllin (APP) as a strong anti-cancer agent. In addition to its role as an immunosuppressive regulator of the T-cell mediated immune response, the compound additionally showed anti-cancer activity against A549, NCI-H1299 and NCI-460 cell lines with IC values of 16.9, 13.1 and 17.1 nM, respectively. The intracellular mechanisms underlying the effects of APP were additionally examined. APP treatment caused disruption of microtubule polymerization and DNA damage, which led to cell cycle arrest, as evident from accumulation of phospho-CHK2, p21, and phospho-Cdc2. Moreover, APP stimulated the pro-apoptotic ER stress signaling pathway, indicated by elevated levels of BiP, phospho-PERK, phospho-eIF2α, CHOP and ATF4. We further observed activation of caspase-3, -8 and -9, providing evidence that both intrinsic and extrinsic apoptotic pathways were triggered. In vivo, APP inhibited tumor growth of NSCLC xenografts in nude mice by promoting apoptosis. Our results collectively support a novel role of APP as an anticancer agent that evokes apoptosis by inducing microtubule disruption, DNA damage, cell cycle arrest and ER stress.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Death; Cell Line, Tumor; DNA Damage; Endoplasmic Reticulum Stress; Humans; Molecular Structure; Podophyllin
PubMed: 30170025
DOI: 10.1016/j.taap.2018.08.022 -
EBioMedicine Feb 2018The circadian system controls the behavior and multiple physiological functions. In mammals, the suprachiasmatic nucleus (SCN) acts as the master pacemaker and regulates...
The circadian system controls the behavior and multiple physiological functions. In mammals, the suprachiasmatic nucleus (SCN) acts as the master pacemaker and regulates the circadian clocks of peripheral tissues. The SCN receives information regarding the light-dark cycle and is thus synchronized to the external 24-hour environment. In contrast, peripheral clocks, such as the liver clock, receive information from the SCN and other factors; in particular, food intake which leads to insulin secretion induces strong entrainment of the liver clock. On the other hand, the liver clock of insulin-depleted mice treated with streptozotocin (STZ) has been shown to be entrained by scheduled feeding, suggesting that insulin is not necessary for entrainment of the liver clock by feeding. In this study, we aimed to elucidate additional mechanism on entraining liver clock by feeding a protein-only diet and/or amino-acid administration which does not increase insulin levels. We demonstrated that protein-only diet and cysteine administration elicit entrainment of the liver clock via glucagon secretion and/or insulin-like growth factors (IGF-1) production. Our findings suggest that glucagon and/or IGF-1 production are additional key factors in food-induced entrainment.
Topics: Animals; Circadian Clocks; Cysteine; Diet; Dietary Proteins; Glucagon; Insulin-Like Growth Factor I; Liver; Mice, Inbred ICR; Podophyllin; Signal Transduction; Streptozocin
PubMed: 29396301
DOI: 10.1016/j.ebiom.2018.01.012 -
Journal of the American Academy of... Feb 2018
Topics: Administration, Cutaneous; Administration, Oral; Condylomata Acuminata; Dermatologic Agents; Drug Therapy, Combination; Humans; Isotretinoin; Keratolytic Agents; Male; Penile Diseases; Podophyllin; Recurrence
PubMed: 29332721
DOI: 10.1016/j.jaad.2017.08.057 -
Biochimica Et Biophysica Acta. General... Mar 2018Polyphyllin I (PPI), one of the steroidal saponins in paris polyphylla, has been reported to exhibit antitumor effects. However, the detailed molecular mechanism...
BACKGROUND
Polyphyllin I (PPI), one of the steroidal saponins in paris polyphylla, has been reported to exhibit antitumor effects. However, the detailed molecular mechanism underlying this has not been elucidated.
METHODS
Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and Flow cytometry assays, respectively. Cell invasion and migration were examined by Transwell invasion and wound healing assays. Western blot analysis was performed to examine the protein expressions of zeste homolog 2 (EZH2), DNA methyltransferase 1 (DNMT1). QRT-PCR was used to examine the levels of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR). Small interfering RNAs (siRNAs) method was used to knockdown HOTAIR. Exogenously expressions of HOTAIR, DNMT1 and EZH2 were carried out by Transient transfection assays. EZH2 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. A nude mice xenograft model was used to confirm the findings in vitro.
RESULTS
We showed that PPI significantly inhibited growth, induced cell cycle arrest of castration-resistant prostate cancer (CRPC) cells. In addition, PPI also reduced the migration and invasion in CRPC cells. In mechanism, we found that PPI decreased the protein expressions of EZH2, DNMT1 and levels of HOTAIR. Interestingly, silenced HOTAIR reduced EZH2 and DNMT1 protein expressions. On the contrary, exogenously expressed HOTAIR resisted PPI-inhibited EZH2 and DNMT1 protein expressions, EZH2 promoter activity and cell growth. Moreover, excessive EZH2 antagonized PPI-suppressed DNMT1 protein expression or vice versa. Consistent with this, PPI inhibited tumor growth, HOTAIR, the protein expressions of DNMT1 and EZH2 in vivo.
CONCLUSION
Our results show that PPI inhibits growth of CRPC cells through inhibition of HOTAIR expression, subsequently; this results in the repression of DNMT1 and EZH2 expressions. The interactions among HOTAIR, DNMT1 and EZH2, and reciprocal regulation of DNMT1 and EZH2 contribute to the overall responses of PPI. This study reveals a novel mechanism for HOTAIR-mediated regulating DNMT1 and EZH2 in response to PPI in inhibition of the growth of CRPC cells.
Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Cell Cycle; Cell Line, Tumor; Cell Movement; DNA (Cytosine-5-)-Methyltransferase 1; Enhancer of Zeste Homolog 2 Protein; Epigenetic Repression; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Nude; Neoplasm Invasiveness; Neoplasm Proteins; Podophyllin; Prostatic Neoplasms; RNA, Long Noncoding; RNA, Neoplasm; Random Allocation; Transcription, Genetic; Transfection; Xenograft Model Antitumor Assays
PubMed: 29221985
DOI: 10.1016/j.bbagen.2017.12.001 -
International Journal For Parasitology.... Dec 2017Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages....
Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids. The colchicine binding domain has inspired the discovery and development of several drugs currently in clinical use against parasites. However, this domain is less conserved in kinetoplastids and may be selectively targeted by new compounds. This report shows the antileishmanial effect of several series of compounds (53), derived from podophyllotoxin (a natural cyclolignan isolated from rhizomes of Podophyllum spp.) and podophyllic aldehyde, on a transgenic, fluorescence-emitting strain of Leishmania infantum. These compounds were tested on both promastigotes and amastigote-infected mouse splenocytes, and in mammalian - mouse non-infected splenocytes and liver HepG2 cells - in order to determine selective indexes of the drugs. Results obtained with podophyllotoxin derivatives showed that the hydroxyl group at position C-7α was a structural requisite to kill the parasites. On regards podophyllic aldehyde, derivatives with C9-aldehyde group integrated into a bicyclic heterostructure displayed more potent antileishmanial effects and were relatively safe for host cells. Docking studies of podophyllotoxin and podophyllic aldehyde derivatives showed that these compounds share a similar pattern of interaction at the colchicine site of Leishmania tubulin, thus pointing to a common mechanism of action. However, the results obtained suggested that despite tubulin is a remarkable target against leishmaniasis, there is a poor correlation between inhibition of tubulin polymerization and antileishmanial effect of many of the compounds tested, fact that points to alternative pathways to kill the parasites.
Topics: Animals; Hep G2 Cells; Humans; Leishmania infantum; Liver; Mice; Microtubules; Podophyllin; Podophyllotoxin; Spleen; Structure-Activity Relationship; Tubulin; Tubulin Modulators
PubMed: 28719882
DOI: 10.1016/j.ijpddr.2017.06.003 -
Journal of the American Academy of... Sep 2017Cryotherapy is one of the most commonly used therapeutic modalities to treat anogenital warts (AGWs), but this treatment was not clearly established in the recent... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
Cryotherapy is one of the most commonly used therapeutic modalities to treat anogenital warts (AGWs), but this treatment was not clearly established in the recent international recommendations.
OBJECTIVE
To compare the efficacy and safety of cryotherapy versus other AGW treatments.
METHODS
Through a systematic search of 12 electronic databases, we identified 11 randomized controlled trials, screened from database inception through October 2016, that met the inclusion criteria (including immunocompetent adults with AGWs receiving cryotherapy in 1 of the comparison groups). Primary endpoint was complete clearance of AGW. Risk-for-bias assessment was based on Cochrane Handbook recommendations. Meta-analyses used Review Manager v5.3 software.
RESULTS
Cryotherapy efficacy did not appear to differ from that of trichloroacetic acid, podophyllin, or imiquimod. Electrosurgery was weakly associated with better AGW clearance than cryotherapy (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.65-0.99). Cryotherapy was associated with more immediate low-level adverse events (erythema, stinging, or irritation; RR 3.02, 95% CI 1.38-6.61) and immediate pain requiring oral analgesics (RR 2.11, 95% CI 1.07-4.17) but fewer erosions (RR 0.57, 95% CI 0.36-0.90).
LIMITATIONS
All but 1 randomized-controlled trial had a high risk for bias.
CONCLUSION
With low-level quality of the evidence, cryotherapy is an acceptable first-line therapy to treat AGWs.
Topics: Anus Diseases; Condylomata Acuminata; Cryotherapy; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Randomized Controlled Trials as Topic
PubMed: 28651824
DOI: 10.1016/j.jaad.2017.04.012 -
Sexually Transmitted Infections Dec 2017Anogenital warts (AGW, condylomata acuminata) and intraepithelial neoplasia (IEN) do not only impact health and social well-being, they are also associated with... (Meta-Analysis)
Meta-Analysis Review
Anogenital warts and other HPV-associated anogenital lesions in the HIV-positive patient: a systematic review and meta-analysis of the efficacy and safety of interventions assessed in controlled clinical trials.
OBJECTIVES
Anogenital warts (AGW, condylomata acuminata) and intraepithelial neoplasia (IEN) do not only impact health and social well-being, they are also associated with considerable costs for the healthcare systems. Immunocompromised and HIV-positive patients carry the highest epidemiological burden of human papillomavirus (HPV) infection and comprise a population specifically susceptible to treatment failures and recurrences. This systematic review aimed at identifying and appraising the available evidence from controlled studies of interventions for the treatment of AGW and IEN in immunocompromised patients.
METHODS
We conducted a comprehensive literature search. The Cochrane Collaboration's tool was used to assess risk of bias in included studies. Our confidence in the (pooled) effect-estimates was evaluated according to the Grading of Recommendations Assessment, Development and Evaluation approach. All evaluations were based on data independently extracted by two review authors.
RESULTS
Nine randomised controlled trials and two controlled studies were eligible, investigating external AGW, intra-anal and/or vaginal warts, and intra-anal and/or perianal IEN. The identified studies assessed imiquimod, cidofovir, fluorouracil, electrocautery, systemic interferon-α and interferon-β, and the combination of intralesional interferon-α and podophyllin. Four studies combined an ablational intervention with either imiquimod, cidofovir, intralesional or systemic interferon-α. One study investigated an experimental therapeutic vaccination (HPV 16 E7) at different concentrations.
CONCLUSIONS
The quality of the evidence ranged from 'very low' to 'moderate' and was limited by the often small samples. Evidence was available for the efficacy of electrocautery for intra-anal IEN, and imiquimod cream for external AGW. Some further interventions should be subjected to investigations in larger samples. No data on some interventions established for the treatment of AGW in immunocompetent patients such as podophyllotoxin, sinecatechins, laser ablation or trichloroacetate were available. Future trials should address these gaps and include relevant patient-reported outcomes such as health-related quality of life.
Topics: Aminoquinolines; Antiviral Agents; Anus Diseases; Coinfection; Female; Genital Diseases, Female; Genital Diseases, Male; HIV Seropositivity; Humans; Imiquimod; Immunocompetence; Male; Neoplasm Recurrence, Local; Papillomavirus Infections; Randomized Controlled Trials as Topic; Warts
PubMed: 28637906
DOI: 10.1136/sextrans-2016-053035 -
Journal of Clinical and Diagnostic... Mar 2017Condyloma Acuminata (CA) is a common viral sexually transmitted disease. Although various treatment modalities are available for treating CA, but none of them can...
INTRODUCTION
Condyloma Acuminata (CA) is a common viral sexually transmitted disease. Although various treatment modalities are available for treating CA, but none of them can achieve 100% response rate. In a search for better response rate and less recurrence rate, the combination of cytotoxic agent Podophyllin with ablative liquid nitrogen cryotherapy was evaluated over cryotherapy alone.
AIM
To evaluate the synergistic effect of Podophyllin as a chemotherapeutic adjunct to an ablative therapy of liquid nitrogen cryotherapy versus liquid nitrogen cryotherapy alone in the treatment of CA.
MATERIALS AND METHODS
Sixty patients with multiple CA were randomly assigned to two groups in the study. Thirty patients in group A received double freeze thaw cycle of 25 seconds of liquid nitrogen cryotherapy. Thirty patients in Group B were subjected to liquid nitrogen cryotherapy in a similar manner followed by application of not more than 0.5 ml of 25% Podophyllin solution. All patients were followed up at 1, 4, 8, 12 and 24 weeks after the treatment to monitor the response to therapy and evaluation for any recurrence. When the number of unresponsive lesions were more than 30% of original lesions at 4 weeks follow-up, then the whole procedure was repeated again.
RESULTS
The complete response rate and the recurrence rate in the Group B in our study were comparable to Group A as the difference was statistically insignificant. But the differentiating point was that the similar results were obtained in Group B with an average1.2 sessions per patient in comparison to an average of 1.67 sessions per patient in Group A.
CONCLUSION
Cryotherapy represents a simple, safe and effective regimen for the treatment of multiple CA which in combination with Podophyllin is even more effective as a single session procedure; thereby shortening the treatment regimen.
PubMed: 28511487
DOI: 10.7860/JCDR/2017/23797.9339