Brachioradial pruritus--an uncommon photodermatosis presenting in a temperate climate.
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Climate↗
Biomedical subjects
D K Armstrong
Publications and source records attributed to D K Armstrong.
Combined therapy trial with interferon alpha-2a and ablative therapy in the treatment of anogenital warts.
OBJECTIVE: To determine whether the combination of systemically administered interferon alpha-2a and ablative surgery for the treatment of genital and/or perianal warts produces a 30% or greater improvement in lasting response rate compared with a control group receiving a combination of placebo and ablative therapy. DESIGN: Randomised, triple-blind, placebo-controlled trial using 1 or 3 MIU of interferon alpha-2a or placebo administered subcutaneously three times weekly for 10 weeks in combination with ablative surgery. SETTING: International, multicentre study in 10 genitourinary medicine clinics. PATIENTS: Two hundred and fifty patients with anogenital warts. MAIN OUTCOME MEASURES: Lasting response at week 38. RESULTS: Standard efficacy analysis at week 38 showed a lasting response in 51% (35/68) of 3 MIU interferon-treated patients, 48% (30/63) of 1 MIU interferon-treated patients and 43% (29/67) of placebo-treated patients. CONCLUSIONS: With the doses and regime described, treatment with interferon alpha-2a in combination with ablative therapy is not significantly superior in the treatment of anogenital warts than placebo and ablative therapy.
Adult↗
Programmed cell death in human breast cancer cells.
The need for improved systemic therapy for breast cancer is great. Cancer growth represents an imbalance between cell proliferation and cell death: thus, effective anti-cancer therapies may act to decrease cell proliferation or increase cell death, or both. This chapter delineates the role of the programmed cell death process in maintaining homeostasis in normal mammary tissues. The preservation of such death pathways in malignant mammary cells and the ability of chemotherapeutic agents to initiate the programmed cell death process in these cells is reviewed. Finally, ongoing research exploring new ways to take advantage of these death pathways in the clinical setting is examined.
Antineoplastic Agents↗
Multiple dermatofibromas in a patient with HIV infection.
We report the case of a 26-year-old man with haemophilia B and human immunodeficiency virus infection (HIV) who presented with a short history of multiple dermatofibromas. He also had troublesome psoriasis for which he was receiving acitretin with UVB therapy and had recently discontinued low-dose daily prednisolone for associated arthropathy. Multiple dermatofibromas are rare and have been reported previously in association with autoimmune disease, especially in individuals receiving immunosuppressive therapy. We believe this to be the first report of multiple dermatofibromas in an individual with advanced HIV infection and propose that it may be related to his viral-mediated immunodeficiency, possibly augmented by UVB and systemic corticosteroid therapy.
Acitretin↗
Phase I and pharmacologic study of the alkylating agent modulator novobiocin in combination with high-dose chemotherapy for the treatment of metastatic breast cancer.
PURPOSE: Resistance to alkylators may potentially be overcome by drugs that inhibits DNA repair, thus improving the efficacy of high-dose chemotherapy. This trial was performed to determine if novobiocin, an agent that inhibits DNA repair, could be given with high-dose alkylators. Study aims were to define the toxicities and maximal-tolerated dose (MTD) of novobiocin and the pharmacokinetics of novobiocin and high-dose cyclophosphamide and thiotepa. PATIENTS AND METHODS: Thirty-eight women with responsive metastatic breast cancer received high-dose cyclophosphamide (3 to 6 g/m2 over 4 days), thiotepa (400 to 800 mg/m2), and novobiocin (0.5 to 5.0 g/d x 7, orally) with autologous marrow support. Toxicity was monitored. The pharmacology of novobiocin, cyclophosphamide, and thiotepa was evaluated. RESULTS: There were no toxic deaths. The MTD of novobiocin was 4 g/d. All seven patients treated at 5 g/d developed grade III/IV mucositis and vomiting. The severity of mucositis correlated with the plasma levels of novobiocin. Other severe toxicities were not observed. Plasma novobiocin levels > or = 100 micrograms/mL, which are associated with reversal of drug resistance in animal models, were consistently seen at dose levels greater than 2 g. The dispositions of cyclophosphamide and thiotepa were not altered by novobiocin. CONCLUSION: Novobiocin may be given with high-dose alkylators in doses that produce plasma levels that augment the activity of these cytotoxics in experimental models. The pharmacology of high-dose cyclophosphamide and thiotepa is unaffected. Novobiocin 4 g/d orally for 7 days is recommended for future study.
Adult↗
A survey of the use of prostitutes (commercial sex workers) by new male attenders at a genito urinary medicine clinic.
This study documents the use of prostitutes (commercial sex workers) by new male patients attending a genito urinary medicine clinic. 541 consecutive male patients completed an anonymous self-administered questionnaire. 48 (8.9%) gave a history of previous purchase of sexual services in Northern Ireland and/or elsewhere; 69% of these encounters occurred outside Northern Ireland. The largest group were single men aged 20-29 years. 87% of those who purchased services in Northern Ireland were asked by the prostitute to use a condom compared with 60% elsewhere, but there was no significant difference in actual condom use between both groups (66.7% vs 72.7%) Only 21% of patients who had purchased the services more than once used condoms consistently and 29% were willing to pay more for unprotected sexual intercourse. 40% attributed their attendance at this clinic directly or indirectly to their encounter with a prostitute. Encounters with prostitutes were often related to alcohol consumption, 88% sometimes or always purchasing these services after drinking alcohol. Despite widespread publicity at-risk behaviour involving unprotected sexual intercourse with prostitutes is not uncommon. Health education should be targeted at the young single male who travels outside Northern Ireland.
Adult↗
Interleukin-3 and bryostatin-1 mediate hyperphosphorylation of BCL2 alpha in association with suppression of apoptosis.
Using murine myeloid factor-dependent FDC-P1/ER cells, we demonstrate that the hematopoietic growth factors interleukin-3 and erythropoietin and bryostatin-1, a macrocyclic lactone natural product and potent activator of protein kinase C (PKC), suppress apoptosis and induce the rapid serine phosphorylation of Bc12 alpha. Expression of recombinant wild type Bc12 alpha in NFS/N1.H-7 cells confirms that murine Bc12 alpha is phosphorylated following PKC activation. The PKC inhibitors H-7 and staurosporine, but not the protein kinase A inhibitor HA1004, block not only interleukin-3- and bryostatin-1-induced hyperphosphorylation of Bc12 alpha but also their anti-apoptotic effect on growth factor-dependent cells, suggesting a role for activated PKC in both processes. A potential direct role for a classic isoform of PKC is indicated by the Ca(2+)-dependent nature of phosphorylation of Bc12 alpha mediated by purified PKC in vitro. Comparative phosphopeptide maps confirm that Bc12 alpha phosphorylation occurs on identical serine site(s) whether phosphorylation occurs in cells following agonist treatment or directly by PKC in vitro. These findings strongly support a role for activated PKC in growth factor-induced Bc12 alpha phosphorylation as well as suppression of apoptosis.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Epidermal growth factor-mediated apoptosis of MDA-MB-468 human breast cancer cells.
MDA-MB-468 human breast cancer cells lack estrogen receptors, overexpress epidermal growth factor (EGF) receptors, and are growth inhibited by EGF. We show that treatment of MDA-MB-468 cells with EGF leads to inhibition of cell proliferation, fragmentation of DNA into nucleosomal oligomers, and the development of apoptotic morphology. This treatment is associated with increased expression of c-myc, c-fos, jun family members, and transforming growth factor beta 1 mRNA and with partial proteolytic cleavage of poly(ADP-ribose) polymerase and lamin B. The observation that EGF can mediate apoptosis in EGF receptor-overexpressing cells has important implications for clinical efforts directed at the EGF receptor.
Apoptosis↗
Reasons for patient drop-out from an intracavernous auto-injection programme for erectile dysfunction.
OBJECTIVE: To identify factors that contribute to patient drop-out rates from an intracavernous auto-injection programme for erectile dysfunction. PATIENTS AND METHODS: Forty-seven patients who had been successfully treated with intracavernous vasoactive agents but who subsequently failed to attend follow-up appointments were included in the study. Each patient completed a self-administered questionnaire. RESULTS: Thirty (64%) completed questionnaires were returned. The reasons for withdrawal from treatment are outlined. CONCLUSIONS: The majority of patients who discontinued intracavernous therapy did so for reasons unrelated to treatment associated problems.
Adult↗
A randomised, double-blind, parallel group study to compare subcutaneous interferon alpha-2a plus podophyllin with placebo plus podophyllin in the treatment of primary condylomata acuminata.
OBJECTIVES: The primary objective was to determine if six weeks treatment with subcutaneous interferon alpha-2a (IFN) and podophyllin 25% W/V administered twice per week, preceded by IFN alpha-2a three times weekly for one week showed a greater complete response rate in patients with primary condylomata acuminata when assessed at week 10 than treatment with podophyllin and placebo injections in the same schedule. The secondary objective was to compare recurrence rates in complete responders at six months in the two treatment groups. DESIGN: Randomised, double-blind parallel group study. SETTING: Multicentre study in six genitourinary clinics within the U.K. PATIENTS: One hundred and twenty-four patients with primary anogenital warts. MAIN OUTCOME MEASURES: Complete response rate at week 10, and recurrence rate at week 26 in complete responders. RESULTS: At week 10 analysis of the efficacy population showed complete response in 36% (15/42 patients) of IFN-treated group and 26% (11/43 patients) in the placebo group (no significant difference). Analysis of the safety population at week 26 showed persistence of the complete response in 57% (8/14 patients) of the IFN-treated group and 80% (12/15 patients) of the placebo group (no significant difference). Adverse effects were more common in IFN-treated patients, involved particularly application site reaction and malaise but were generally mild. CONCLUSIONS: At the dose and with the regime described treatment with IFN alpha-2a in combination with podophyllin is no more effective in the treatment of primary anogenital warts than podophyllin alone and is associated with more adverse events.
Adolescent↗
Pharmacoeconomic issues of sedation, analgesia, and neuromuscular blockade in critical care.
Neuromuscular blocking agents (NMBAs) are commonly prescribed as adjunct therapy for many critically ill patients. Controversy exists regarding the appropriate long-term use of these agents, particularly since there are severe potential clinical consequences. The expanded use of NMBAs has had a significant effect on the cost of ICU care. One should determine whether or not NMBAs are being used as adjunct therapy, or as a replacement for optimal sedation and/or analgesia. This article reviews some of the indicative economic issues surrounding the use of sedatives, analgesics, and NMBAs in the critical care arena. Understanding the pharmacokinetic and pharmacodynamic differences of these agents can aid in drug selection and route of administration. Appropriate drug selection can influence the pharmacoeconomics of these agents in the ICU.
Analgesia↗
Prostaglandin E1 in the medical management of erectile dysfunction in a genito-urinary medicine clinic.
Fifty consecutive patients with erectile failure who had previously proved refractory to papaverine and phentolamine intracavernosal therapy or were inappropriate candidates for such treatment were treated with intracavernosal prostaglandin E1. Forty patients (80%) achieved an erection sufficient for sexual intercourse and after a mean follow-up period of 5.9 months, 32 patients were continuing to use treatment successfully. The average dose was 14 micrograms (range 2.5 to 30 micrograms). There were no cases of priapism or cavernosal fibrosis and no systemic side effects. A low incidence (8%) of local discomfort was reported. We conclude that prostaglandin is a safe and effective vasoactive agent for the treatment of erectile failure in a genito-urinary outpatient clinic.
Adult↗
Sixteen week dose intense chemotherapy for inoperable, locally advanced breast cancer.
Up to 15% of women with breast cancer have locally advanced disease at diagnosis. The poor response of these patients to local therapy alone and the frequent development of disseminated disease suggest that early intensive systemic therapy may benefit these women. Twenty-four patients with non-metastatic, locally advanced, primarily inflammatory, inoperable breast cancer were treated with a 16-week dose-intense chemotherapy regimen as induction therapy. Treatment consisted of 8 repetitive 2-week cycles consisting of 100 mg/m2 cyclophosphamide orally D1-7, 40 mg/m2 doxorubicin intravenously (IV) D1, 1 mg vincristine IV D1, 100 mg/m2 methotrexate IV D1, 10 mg/m2 leucovorin every 6 hours for six oral doses D2-3, and 600 mg/m2 5-FU IV over 2 hours D2. A continuous infusion of 300 mg/m2 5-FU per day was given IV D8-9 of each 2-week cycle. After induction all patients had at least a partial clinical response and were operable; 9/24 (37%) achieved a clinical complete response. All patients underwent at least a simple mastectomy. Pathologic examination revealed no evidence of gross macroscopic tumor in 11/24 patients (46%) and no evidence of microscopic disease in 4/24 patients (17%). Seven of 24 patients (29%) had no microscopic disease in the breast. At a median follow-up of 45 months, there have been 10 relapses in the 24 patients treated with this induction regimen. The actuarial relapse-free survival at 5 years is 58%. Actuarial overall survival at 5 years is 75%. We conclude that this regimen is safe and well-tolerated and that the results of this therapy are sufficiently promising to warrant further study of this regimen in patients with locally advanced breast cancer.
Antineoplastic Combined Chemotherapy Protocols↗
Vancomycin and tobramycin clearance in an infant during continuous hemofiltration.
OBJECTIVE: To report a case of vancomycin and tobramycin clearance by continuous veno-venous hemofiltration in an infant. Hemofiltration clearance (ClHF) was calculated by two methods and compared for ease and reliability. METHODOLOGY: Case report of a hospitalized four-month-old infant. With method A, ClHF calculation for vancomycin and tobramycin was determined by accurate collection of ultrafiltrate in five 24-hour periods and a midpoint serum sample. With method B, ClHF calculation was determined by obtaining prefilter sample, postfilter sample, and blood flow through filter (Fick principle) over three study periods, correlating to three of five study periods in method A. RESULTS: The infant received continuous veno-venous hemofiltration. With method A, vancomycin ClHF ranged from 0.27 to 0.80 mL/min; tobramycin ClHF ranged from 0.32 to 0.91 mL/min. With method B, ClHF for vancomycin ranged from 0 to 2.08 mL/min. Tobramycin ClHF ranged from 0 to 1.6 mL/min when calculated with method B. CONCLUSIONS: Continuous veno-venous hemofiltration increased the clearance of vancomycin and tobramycin requiring dosage modifications. It appears that method A, which uses the ultrafiltration concentration compared with the serum concentration is more accurate than method B, as it averages fluctuations in ultrafiltrate flow rates. Method B compares a single pre- to postfilter drug concentration and relies on an accurate measurement of ultrafiltration flow rate. Determining ClHF based upon one point in time may overestimate ClHF when the ultrafiltration flow rate varies, as it does in the critically ill. Daily serum concentrations for vancomycin and tobramycin are recommended during continuous veno-venous hemofiltration.
Female↗
Programmed cell death in an estrogen-independent human breast cancer cell line, MDA-MB-468.
Previous studies have demonstrated that estrogen-responsive human breast cancer cells can be induced to undergo an energy-dependent, genetically programmed series of biochemical changes that result in the active suicide of the cells following estrogen ablation. In contrast, estrogen-independent human breast cancer cells do not activate this programmed cell death pathway following estrogen ablation. This could be due either to the absence of the cellular machinery required for programmed cell death or simply to the inability of estrogen ablation to activate this machinery. To discriminate between these two possibilities, the MDA-MB-468 estrogen-independent human mammary adenocarcinoma cell line was used as a model system to study the mechanism of cell death following cytotoxic drug treatment. Exposure of these cells to the fluorinated pyrimidines, 5-fluoro-2'-deoxyuridine or trifluorothymidine, resulted in growth inhibition and loss of proliferative capacity within 24 h. These changes occurred while cell membrane integrity was intact as measured by either cellular morphology or trypan blue exclusion. After 48 h of drug treatment, loss of cell membrane integrity was followed by cell lysis and a rapid decline in cell number. The addition of 16 microM thymidine prior to drug treatment prevented cell death, but thymidine did not rescue these cells once drug treatment was initiated. Analysis of DNA revealed the characteristic fragmentation into nucleosomal oligomers that is a hallmark of programmed cell death. Associated with this death pathway was a 15-fold induction of transforming growth factor beta 1 gene expression that has been previously observed in a variety of cellular systems undergoing programmed cell death. These results indicate that MDA-MB-468 estrogen-independent human mammary carcinoma cells retain the ability to undergo programmed cell death after treatment with cytotoxic drugs that induce a "thymineless" state.
Breast Neoplasms↗
Hepsulfam sensitivity in human breast cancer cell lines: the role of glutathione and glutathione S-transferase in resistance.
Hepsulfam (NSC 329680, 1,7-heptanediol disulfamate) is an alkylating agent that showed excellent activity against mouse and human mammary carcinoma in preclinical studies. We therefore studied the cytotoxicity of this drug in six human breast cancer cell lines (AdrRMCF7, WTMCF7, Hs578T, MDA-MB-231, T47D, and MDA-MB-468). Clonogenic assays of these cell lines showed a range of sensitivity with the 90% inhibitory concentration ranging from 3.1 microM hepsulfam (MDA-MB-468) to 32.3 microM hepsulfam (AdrRMCF7) after 24-h exposure to the drug. To evaluate possible mechanisms responsible for this observed variation in sensitivity to hepsulfam, we have studied glutathione S-transferase (GST) activity and glutathione (GSH) in these cell lines. Total cytoplasmic GST activity correlated with sensitivity; the most sensitive cell lines had the lowest GST activity, while the two most resistant cell lines, AdrRMCF7 and Hs578T, had the highest GST levels of the six cell lines. Western blot analysis showed that the only detectable isoenzyme was GST-pi. The amount of GST-pi isoform correlated with hepsulfam sensitivity in the three most resistant cell lines and was undetectable in the three most sensitive cell lines. Cellular concentrations of GSH did not correlate with hepsulfam sensitivity. However, GSH depletion with buthionine sulfoximine increased sensitivity to hepsulfam in a dose-dependent fashion in all six cell lines. Evaluation by mass spectrometry revealed that glutathione can form conjugates with hepsulfam. We conclude that the GST/GSH detoxication system plays a role in the sensitivity of these breast cancer cell lines to hepsulfam.
Antimetabolites, Antineoplastic↗
Sodium hyaluronate as a carrier for intravitreal gentamicin. An experimental study.
Fifty mcg of gentamicin was combined with saline or with 0.8% sodium hyaluronate and injected into the vitreous cavity of rabbit eyes with moderate to severe Staphylococcus aureus endophthalmitis. Endophthalmitis was controlled in 9 of 10 eyes. There was no evidence of toxicity with either treatment regimen. Although the clearance study demonstrated statistical differences at all time points studied, the half-lives of both treatment regimens were similar (3.3 h for aqueous gentamicin and 3.6 h for sodium hyaluronate/gentamicin). These results suggest that the vitreous played a role in keeping the aqueous gentamicin in the eye for a longer time, as similar half-lives were shown with both types of treatment. Thus, if a vitrectomy has to be done for the treatment of endophthalmitis, as much as possible of the vitreous should be left in situ to maintain the drug for longer periods in the eye. Also, if it is necessary to remove all vitreous during vitrectomy, it may be more effective to administer the drug with sodium hyaluronate so as to prolong its action inside the eye.
Animals↗