Aspirin reduces cutaneous flushing after administration of an optimized extended-release niacin formulation.

OBJECTIVE: Niacin is an effective treatment for dyslipidemia due to its favorable effects on multiple lipid parameters. Clinical utility of niacin is sometimes limited, however, because of cutaneous flushing. A once-daily, extended-release (ER) niacin formulation has been shown to significantly reduce flushing compared to immediate-release niacin. An optimized (reformulated) version of niacin ER has recently been developed and was shown in a previous study to significantly reduce flushing intensity (severity) compared to the non-optimized (commercial) formulation. The current study was designed to evaluate the effect of aspirin on various indices of flushing when administered with the optimized niacin ER formulation. METHOD: This was a randomized, double-blind, double-dummy, placebo-controlled flush provocation crossover study in healthy males. To increase the probability of flushing, subjects received a single dose of reformulated niacin ER 2,000 mg, which is the upper limit of the approved dosage range. Subjects received 650 mg aspirin orally either 30 minutes before or concomitantly with niacin ER, or placebo with niacin ER, in 3-way crossover fashion. The primary endpoint was the number of subjects who reported at least one flushing event. Secondary endpoints included the perceived intensity and duration of flushing symptoms. RESULTS: In the 148 men who completed all treatments, aspirin significantly reduced flushing incidence (the primary endpoint) following administration of niacin ER compared with placebo. Among subjects receiving placebo, 77% of subjects reported flushing with niacin ER. Among subjects receiving aspirin, 53-61% of subjects reported flushing (pretreatment and concomitant treatment, respectively, both p < 0.001 compared with placebo) with niacin ER. Aspirin also significantly reduced intensity and duration of flushing (by 30-40%) compared with no aspirin. The two aspirin-containing treatments (i.e. pre- or concomitant treatment) were similar in their effects on flushing incidence, intensity and duration. Median intensity on a 100 mm visual analogue scale (VAS) was reduced from 33 mm with placebo to 19-23 mm with aspirin. Median duration was reduced from approximately 1 hour with placebo to 37-48 minutes with aspirin. CONCLUSION: Aspirin significantly reduced the incidence, intensity and duration of flushing associated with reformulated niacin ER. These results support the administration of aspirin prophylactically to decrease niacin-induced cutaneous flushing and to improve patient adherence and acceptability of chronic niacin treatment at therapeutic doses.

Improved control of niacin-induced flushing using an optimized once-daily, extended-release niacin formulation.

INTRODUCTION: Niacin is a recognized treatment for dyslipidemia due to its favorable effects on all lipid parameters. However, the clinical use of niacin has been limited by its adverse effects, particularly cutaneous flushing. A newly reformulated 1,000 mg niacin ER tablet has been designed to reduce flushing relative to the original commercial niacin ER formulation. The aim of this study is to compare the incidence, intensity and duration of flushing between the 1,000 mg reformulated niacin ER and the 1,000 mg commercially available formulation, when administered as a single 2,000 mg dose to healthy male volunteers. METHODS: This was a double-blind, double-dummy, placebo-controlled, 3-way crossover, flush provocation study conducted at a single center. To increase the probability of flushing, subjects were administered niacin ER at the upper limit of the approved dosage range (2,000 mg), and were precluded from using aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) during the study. Subjects received reformulated niacin ER, commercial niacin ER or placebo in a 3-way crossover fashion. The primary flushing variable was the occurrence of a flushing event. Secondary flushing variables included the number of flushing episodes, intensity and duration of flushing for both overall flushing events and for individual symptoms of flushing (redness, warmth, tingling and itching). RESULTS: A total of 156 subjects were enrolled in the study. Of 133 subjects who received at least 1 dose of study medication in at least 2 study periods, 89% of subjects experienced flushing during treatment with reformulated niacin ER, and 98% of subjects experienced flushing during treatment with commercial niacin ER. This difference was statistically significant (p - 0.0027). Reformulated niacin ER resulted in a 42% reduction in median flush intensity (p < 0.0001) and a 43% reduction in median flush duration (p < 0.0001) relative to commercial niacin ER. The duration of first flushing event was more than 1 hour shorter with reformulated niacin ER. During the study, 29% of subjects (45/156) experienced treatment-emergent adverse events, which were mostly mild in intensity and considered to be remotely related or unrelated to the study drug. CONCLUSION: The 1,000 mg reformulated niacin ER tablet substantially decreases the incidence, intensity and duration of flushing relative to the commercially available 1,000 mg niacin ER tablet, and represents an improved niacin therapy option.

Ethical considerations in the early composite tissue allograft experience: a review of the Louisville Ethics Program.

This paper reviews the formulation and evolution of the ethical component in one of the earliest clinical composite tissue allograft (CTA) programs, the hand transplantation program in Louisville, Kentucky, USA. The purpose was to derive lessons and define principles to give guidance for future programs and introduction of new CTA. We reviewed the initial ethical considerations, including input from respected ethical scholars, guidelines for innovative procedures transparency in public and professional scrutiny, and compliance with human studies regulations (IRB approval). We found the initial focus on ethics, scholarly input, guidelines for innovative procedures, and human studies protection regulations to be valid. Moreover, we noted the effect of autonomy in subjective, quality-of-life benefits on equipoise and effective risk-benefit analysis in effective informed consent. We found that psychiatric screening and support to be exceptionally valuable in protecting autonomy, suitability for participation, assessing personality organization, and determining compliance ability. We conclude that the program ethical principles were validated. For future CTA programs and procedures, we recommend an ethical emphasis with adherence to high standards and transpire to independence to scrutiny and oversight. We recommend protection of autonomy judgments in equipoise judgment and informed consent. We recommend skilled psychiatric screening and support. We endorse scholarship, scientific accuracy, and data sharing.

Candida species and C. albicans biotypes in women attending clinics in genitourinary medicine.

Yeasts were isolated from two or more anatomical sites in 198 women attending genitourinary clinics on at least two occasions. The yeast biotypes isolated concurrently from the vagina and urethra were the same in 138 (99%) of 140 instances, and 94% of 124 concurrent genital and anal isolates were of matching types, whereas only 75% of concurrent genital and oral isolates were of the same type. Mixtures of Candida spp. or C. albicans biotypes were encountered only five times among 545 yeast-positive samples. In instances where Candida spp. were isolated at successive times from the same site in a patient, the same yeast type was encountered on 97 (87%) of 112 occasions when the interval between samples was less than 15 weeks, and on 19 (66%) of 29 occasions when the interval was 15 weeks or more. These data indicate a tendency to carriage of phenotypically consistent types of Candida among most women attending genitourinary clinics.

The artificial heart: how close are we, and do we want to get there?

The artificial heart appears here to stay, and it will become ever more reliable and therapeutic. In the new age of medicine, the attributes of humanity are blended with the mechanical and artificial. While we express our humanness by seeking new and more creative treatments for illness and delaying death, we are inevitably modifying what it means to be human. Ethical issues arise from the interface of the physician-patient relationship and the technologies being developed in today's laboratories. The new Luddites may well be too fearful to tackle the challenges of technology wed to humanity. But they rightly say we seem woefully unprepared to deal with human hubris and will to power.

Ethical considerations in composite tissue allotransplantation.

Ethical issues posed by the hand transplant program conducted by hand and plastic surgeons at Jewish and University Hospitals, Louisville, Kentucky, are examined in this essay. Because a composite tissue allotransplantation (CTA) is an experimental procedure, it raises issues as to the protection of human subjects. The background for the emergence of medical ethics as a discipline is indicated and the processes employed by the CTA team in order to address ethical concerns are discussed. Questions are posed as to the justifications for certain procedures and those pertaining to the goals of medicine, informed consent, and patient quality of life. Other issues include benefits versus risks, patient autonomy and medical paternalism or non-maleficence. The Louisville team seems to have dealt conscientiously with all ethical questions that have been posed and has treated the hand recipient with competence and continuity of care. No reasons based in ethical concerns have surfaced that would in any way discredit the program.

Evaluation of the early morning smear investigation.

A retrospective study on early morning smears confirmed the value of this investigation for diagnosing urethritis in men. In 200 patients 108 new infections were diagnosed.

Podophyllin 10% and 25% in the treatment of ano-genital warts. A comparative double-blind study.

One hundred and forty male patients with ano-genital warts were randomly allocated to a double-blind study of 10% and 25% podophyllin in tincture of benzoin compound. One hundred and nine patients attended for a three-month period of surveillance. Only 24 (22%) patients were free of warts after having podophyllin treatment alone, 12 each after treatment with 10% and 25% podophyllin. There was no significant difference in the number of applications needed with each treatment. Neither hypersensitivity nor chemical ulceration occurred.

Follow up of patients with hepatitis B surface antigen.

One hundred and five patients attending clinics for sexually transmitted diseases were found to carry hepatitis B surface antigen (HBsAg). Of these, 87 patients had liver function tests performed of which 44 gave abnormal results. Fifteen patients underwent liver biopsy, which showed chronic hepatitis in eight cases.

A method for recognising non-bacterial prostatitis: preliminary observations.

Chronic non-bacterial prostatitis is a difficult condition to diagnose accurately either by symptoms and signs or by investigations. Four groups of patients were assessed for the number of leucocytes and the presence of pathogens in expressed prostatic secretions before and after treatment with co-trimoxazole two tablets twice daily for three months. The pretreatment findings suggest that the upper limit of normal for the number of leucocytes in expressed prostatic secretions is about five per microscope field (X 40 magnification) and that for the cell count about 0.5 X 10(9)/l using the method described. Increased microscopical cell estimations and cell counts in the expressed prostatic secretions of patients with symptoms of prostatitis and those with recurrent non-specific urethritis seem to indicate the presence of prostatitis.

Minocycline in chronic abacterial prostatitis: a double-blind prospective trial.

In patients with chronic abacterial prostatitis, a double-blind trial of 3 months of treatment with minocycline 100 mg twice daily compared with diazepam 5 mg twice daily was undertaken. The percentage fall in polymorphonuclear leucocyte counts in the expressed prostatic secretions was much more marked after treatment with minocycline than with diazepam. Over a follow-up period of at least 12 months, further treatment was necessary in more patients originally treated with diazepam than with minocycline.

Review of results of four regimens for treatment of chronic non-bacterial prostatitis.

Review of the treatment of chronic non-bacterial prostatitis, defined by the presence of more than 500 leucocytes per mm3 in the expressed prostatic secretion (EPS), showed symptomatic response after 3 months of minocycline, trimethoprim, co-trimoxazole or diazepam. Reduction in the EPS cell count was most marked with minocycline, trimethoprim was less effective and poor results were obtained with co-trimoxazole and diazepam. In the absence of established treatment for chronic non-bacterial prostatitis it is suggested that antimicrobial therapy is worth consideration.

Chronic bacterial and non-bacterial prostatitis.

Chronic prostatitis is ill-understood, difficult to diagnose and often unresponsive to treatment. To clarify some of the diagnostic difficulties 135 patients and 28 control subjects were prospectively studied. Patients with chronic bacterial prostatitis, chronic non-bacterial prostatitis and recurrent non-specific urethritis (NSU) without prostatitis resembled each other in demographic characteristics. Patients with prostatodynia were more often married and born abroad. Symptoms were more common in prostatodynia but diagnosis of prostatitis and prostatodynia depended on examination of the expressed prostatic secretion (EPS) for leucocytes and microorganisms. An inflammatory response in the EPS was found in both forms of prostatitis but not in the other conditions. Leucocyte counts of the EPS appeared to be more sensitive than simple microscopic estimation. The EPS leucocyte figures support a previous finding that the upper limit of normal for the EPS count is around 500 cells per mm3 by the method used. The pathogenic micro-organisms cultured from the EPS of the patients with chronic bacterial prostatitis were the usual urinary pathogens reported by others. For reasons which are not clear, saprophytic organisms were more common in chronic non-bacterial prostatitis than in the other groups. While the demographic differences and increased symptoms in patients with prostatodynia will not help in diagnosis, there may be a relationship with emotional stress and this should be considered in the management of these patients.

Cryotherapy versus electrocautery in the treatment of genital warts.

Forty-two male patients with ano-genital warts were randomly allocated to a single-blind study of cryotherapy versus electrocautery. There was no significant difference in the success rates of these two forms of treatment in patients followed for three months. Cryotherapy was qualitatively much more acceptable to the patients than electrocautery. It seems particularly suited to patients with widely scattered warts who are unable to attend for regular treatment.

Identification of immunodominant antigens of Candida albicans in patients with superficial candidosis.

The aims of this study were to identify the immunodominant protein antigens of Candida albicans in patients with superficial infections of the oral and vaginal mucosa. Cytoplasmic protein extract from C. albicans was analyzed by the immunoblot technique using sera from 20 patients with chronic atrophic oral candidosis, from 8 patients with vulvovaginal candidosis, and from 20 control subjects. A significantly greater proportion of patient sera reacted with the 65- and 32-kDa antigens when compared with sera from controls (P less than 0.001). Sera from patients also reacted more often with 38- and 29-kDa antigens (P less than 0.05), while sera from both patients and controls reacted with the 47-kDa antigen. The identified 65-, 38-, 32-, and 29-kDa antigens may be of importance for the development and also for the recurrence of superficial candidosis of the oral and/or vaginal mucosa.

Candida concentrations in the vagina and their association with signs and symptoms of vaginal candidosis.

Among 106 women harbouring yeasts in the vagina and with other causes of genital pathology excluded, there was a statistically significant association between numbers of yeasts recovered semi-quantitatively from vaginal swabs and symptoms of pruritus and signs of abnormal vaginal discharge but no association between yeast numbers and other individual symptoms or signs of vaginal candidosis, including patients' own subjective assessment of abnormal vaginal discharge. The presence of yeasts detectable by direct microscopic examination was statistically associated with pruritus, discharge and vaginitis. There was no relationship between numbers of vaginal yeasts and histories of antibiotic or oral contraceptive usage or the stage of the menstrual cycle. Distributions of Candida species and Candida albicans biotypes were not statistically related to any symptoms, signs or other factors. The results of this study suggest that vaginal pathology caused by Candida species may be related to the quantity of the fungus in the vagina and that only pruritus and objectively assessed vaginal discharge are firm clinical indicators of Candida infection.

Vaginal oxytetracycline concentrations.

Although tetracycline preparations are widely used in departments of genitourinary medicine, or sexually transmitted diseases clinics, little is known of the concentrations of these preparations in genital secretions. For this reason a microbiological method was used for estimating oxytetracycline concentrations in vaginal secretions. These concentrations varied from 0.6 to 6.5 microgram/ml in 19 women who had had sexual contact with a man with non-specific urethritis and who were taking oxytetracycline dihydrate 250 mg four times daily. They were well in excess of the minimum inhibitory concentration of oxytetracycline (0.2 microgram/ml) for the strains of Chlamydia trachomatis isolated from the patients with positive culture results. Thus, oxytetracycline 250 mg four times daily appears to be a satisfactory regimen for the treatment of chlamydial genital infection in women.

Rapid diagnosis of chlamydial infection of the cervix.

A rapid serodiagnostic test for the presumptive diagnosis of chlamydial infection of the cervix has been developed. The method used in based on the modified micro-immunofluorescence test using pooled chlamydial antigens and the detection of different immunoglobulin classes of chlamydial antibody in sera and cervical secretions. The presence of IgG chlamydial antibody at a level of 1/64, or IgM antibody at a level of 1/8 or greater, or both in sera and IgG or IgA antibody at a level of 1/8 or more or both in cervical secretions was closely associated with the isolation of Chlamydia trachomatis and non-specific genital infection. In general, serodiagnosis was three to nine times more sensitive than cultural methods, and the detection of IgG chlamydial antibody in cervical secretions alone provided the most sensitive of the serological tests. This sensitive, low-cost, rapid, and simple serodiagnostic test for the presumptive diagnosis of chlamydial infection of the cervix, coupled with transportation of specimens by post, offers advantages over conventional isolation techniques for the routine diagnosis and management of chlamydial genital infections.